D
The Interaction of Social, Behavioral, and Genetic Factors in Sickle Cell Disease

Robert J. Thompson, Jr., Ph.D.*

Professor of Psychology

INTRODUCTION

The genomics revolution has added powerful new potentialities and renewed impetus for understanding how biological, social, and behavioral processes act together in health and illness. More specifically, the genomics revolution is driving a paradigm shift from reductionistic approaches that focus on elements in isolation to systems approaches that focus on the interconnectedness of networks of elements acting as a whole. The challenge is “to connect the dots” and delineate patterns of transactions with regard to mechanisms of effect across scale. In particular, the genomics revolution has increased awareness of the role of promoters and enhancers in switching on and off specific genes as one mechanism of effect for health outcomes that can be triggered by social and behavioral factors as well as biological factors. In this way, genes are viewed as more than units of heredity but as mechanisms for extracting information from environmental experiences (Ridley, 2003).

The current paradigm shift, propelled by the genomics revolution, can be viewed as the most recent progression in conceptualization of health and illness. By the mid-1970s there was growing recognition of the limits of the biomedical model that explained illness in terms of single-factor biological malfunction with little attention to behavioral and social processes. George Engel (1977) traced the historical origins of the reductionistic biomedical model to assumptions of mind-body dualism and advo-

*

Department of Psychology, Social and Health Sciences, Duke University.



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D The Interaction of Social, Behavioral, and Genetic Factors in Sickle Cell Disease Robert J. Thompson, Jr., Ph.D.* Professor of Psychology INTRODUCTION The genomics revolution has added powerful new potentialities and renewed impetus for understanding how biological, social, and behavioral processes act together in health and illness. More specifically, the genomics revolution is driving a paradigm shift from reductionistic approaches that focus on elements in isolation to systems approaches that focus on the interconnectedness of networks of elements acting as a whole. The chal- lenge is “to connect the dots” and delineate patterns of transactions with regard to mechanisms of effect across scale. In particular, the genomics revolution has increased awareness of the role of promoters and enhancers in switching on and off specific genes as one mechanism of effect for health outcomes that can be triggered by social and behavioral factors as well as biological factors. In this way, genes are viewed as more than units of heredity but as mechanisms for extracting information from environmental experiences (Ridley, 2003). The current paradigm shift, propelled by the genomics revolution, can be viewed as the most recent progression in conceptualization of health and illness. By the mid-1970s there was growing recognition of the limits of the biomedical model that explained illness in terms of single-factor biological malfunction with little attention to behavioral and social pro- cesses. George Engel (1977) traced the historical origins of the reduction- istic biomedical model to assumptions of mind-body dualism and advo- *Department of Psychology, Social and Health Sciences, Duke University. 281

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282 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT cated a biopsychosocial model as a way to “broaden the approach to disease to include the psychosocial without sacrificing the enormous ad- vantages of the biomedical approach” (p. 131). The biopsychosocial model maintains that health and illness are a function of multiple processes— biological, psychological, and social—and these processes must be consid- ered simultaneously. In particular, the emergence of multifactorial approaches to the pathogenesis of disease enabled linkage between the behavioral and biomedical sciences (Weiss, 1987). Also important were systems theory perspectives and models of how biological and psychoso- cial processes act together in human development across the life span (Bronfenbrenner, 1977, 1979). A systems theory perspective focuses on the accommodations that occur through the life span between the developing organism and the changing environment. The biopsychosocial model focuses on multiple factors in the etiology and progression of disease. Three primary mechanisms of effect have emerged: health behaviors, psychosocial processes, and genetics. Health behaviors include exercise, nutrition, smoking, and adherence to medical regimes. Psychosocial processes include a range of interpersonal and social processes that affect interpretation of environmental experiences and re- sponses to stress. Risk-resiliency models are also prevalent and seek to identify factors and processes that enhance or decrease vulnerability to disease processes. A particular area of focus has been neuroendocrine and immune responses to stress. One mechanism of effect is through the impact of how individuals interpret and respond to the environment which influ- ences the degree of stress experienced which in turn influences health be- haviors and neuroendocrine and immune responses that in turn affect the etiology and progression of disease. Genetic mechanisms of effect involve the identification of internal and external factors that trigger the switching on or off of genes that modulate physiological processes. The primary interest prompting this paper is enhanced understanding of the interaction of social, behavioral, and genetic factors on health. Sickle cell disease was selected as a good model for this investigation because it is a monogenetic event but the phenotype is multigenetic resulting in consid- erable individual differences in severity of the disease. More specifically, this paper addresses the following questions: • What do we know about the influence of social and behavioral factors and the effects of other genes? • What data do we have? • What data do we need? • What important questions remain to be answered about the influ- ences of social and behavioral factors, including mechanisms, on sickle cell disease?

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283 APPENDIX D • Given the same genes, what is the evidence that social environment affects genes? • What additional research on sickle cell would enlighten the broader relationship between single gene disorders and the social environment? This review focused on the factors and processes associated with indi- vidual differences in clinical manifestations of sickle cell disease. Three lines of research are apparent that correspond to the three mechanisms of effect that have emerged from the biopsychosocial model. There are data about the effects of health behaviors on sickle cell disease, such as avoiding cold and maintaining hydration. Similarly, there are data regarding the role of psychosocial processes in the psychological adjustment of children, adoles- cents, and adults with sickle cell disease and with regard to the specific symptom of pain, and health services utilization. There are also data about the role of polymorphic genetic factors in the variability in the phenotypic expression of sickle cell disease as reflected in various indicators of patho- physiology. However, data do not yet exist regarding the interaction of psychosocial, behavioral, and genetic factors in the variability in the clinical manifestations and course of sickle cell disease. It is rare for markers of behavioral and psychosocial processes and genetic markers to be included in the same study. In contrast, the interaction of behavioral, psychosocial, and genetic factors in the variability in the physiological response to stress has been investigated. This suggests that the way to advance our under- standing of this interaction of factors in sickle cell disease, as a model of a single gene disorder, is to focus on the interaction of behavioral, psychoso- cial, and genetic factors in the neuroendocrine and immune physiological response to stress and the subsequent impact on the pathophysiological processes of vasoocclusion, infection, and neurocognitive dysfunction that are central to sickle cell disease. This paper is intended for a broad audience with varying degrees of background in the genetic, pathophysiological, and psychosocial aspects of sickle cell disease. The general, nontechnical level of this paper is a necessity given that the author’s background is that of a pediatric psychologist and not a molecular biologist or physician. References are provided to facilitate fuller consideration and specific processes. This report is organized in four parts. The first section reviews the etiology, pathophysiology, and clinical manifestations of sickle cell disease and considers what is known about the role of polymorphic genetic factors in the phenotypic expression of the disease. The second section reviews what is known about the impact of social and behavioral factors on the clinical manifestations of sickle cell disease, particularly on psychological adjustment, pain, and neurocognitive functioning. The third section consid- ers stress as a common mechanism of effect through which behavioral,

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284 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT social, and genetic processes affect health outcomes. The paper concludes with a consideration of future research needs and directions. SICKLE CELL DISEASE: ETIOLOGY, PATHOPHYSIOLOGY, AND CLINICAL MANIFESTATIONS The adult hemoglobin molecule (Hb A) is compromised of a duplicated pair of alpha (α) and a pair of beta (β) chains. The α-globin gene cluster is located on chromosome 6 and the β-globin gene cluster is located on chro- mosome 11. The structure of hemoglobin changes during development. Embryonic hemoglobin is replaced by fetal hemoglobin (Hb F) shortly before birth which in turn is replaced by adult hemoglobin (Hb A) over the first year of life (Weatherall, 2001). Sickle cell disease refers to a group of related autosomal recessive blood disorders caused by a variant of the β-globin gene called sickle hemo- globin (Hb S). A single nucleotide substitution (GTG → GAG) in the sixth codon of the β-globin gene results in the substitution of valine for glutomic acid which in turn allows Hb S to polymerase when deoxygenated. “A polymerization of deoxygenated Hb S is a primary indispensable event in the molecular pathogenesis of sickle cell disease” (Stuart and Nagel, 2004, p. 1343). Inherited autosomal recessively, either two copies of Hb S (Hb SS), referred to as sickle cell anemia, or one copy of Hb S plus another β- globin variant are required for sickle cell disease. In addition to sickle cell anemia, homozygotic Hb SS disease, there are several other compound heterozygote sickle genotypes of Hb S plus one copy of another β-globin gene variant, Hb C or Hb β-thalassemia. The carrier state, sickle cell trait, has one copy of the normal β-globin gene and one copy of the sickle variant (Hb AS) (Ashley-Koch et al., 2000). Four major β-globin gene haplotypes have been identified. Three are named for regions in Africa in which the mutations first appeared: BEN (Benin), SEN (Senegal), and CAR (Central African Republic). The fourth haplotype, Arabic-India, occurs in India and the Arabic peninsula (Quinn and Miller, 2004). Disease severity is associated with several genetic factors. “Genotype is the most important risk factor for disease severity” (Ashley-Koch et al., 2000, p. 842). The highest degree of severity is associated with Hb SS followed by Hb s/β0-thalassemia and Hb SC and Hb S/β+-thalassemia are associated with a more benign course of the disease (Ashley-Koch et al., 2000). Disease severity is also related to β-globin haplotypes, probably due to variations in hemoglobin level and fetal hemoglobin concentrations. The Senegal haplo- type is most benign, followed by the Benin, and the Central African Republic

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285 APPENDIX D haplotype is the most severe form (Ashley-Koch et al., 2000). Another genetic factor associated with disease severity is α-globin gene compliment. Thus, although sickle cell disease is a monogenetic disorder, its pheno- typical expression is multigenetic. Epistatic or modifier genes include the co-presence of α-thalassemia, the .158 C → T mutation that enhances Hb F expression, particularly in the Senegal and the Arab-Indian globin cluster haplotypes, and the female population (Stuart and Nagel, 2004). Steinberg (2005) maintains that: “Understanding the vascular and inflammatory com- ponents of the disease pathophysiology provides many loci where the dis- ease phenotype can be impacted by modifying genes” (p. 465). Pathophysiology There are two cardinal pathophysiologic features of sickle cell disease: chronic hemolytic anemia and vasoocclusion. The polymerization of the hemoglobin S molecule (Hb S) within the red blood cells upon deoxygen- ation causes the red blood cells to change from the usual biconcave disc to an irregular sickled or crescent shape. Upon reoxygenation, the red cell initially resumes a normal configuration but after repeated cycles, the erythrocyte is damaged permanently, resulting in red cell dehydration and erythrocyte destruction. Sickled red blood cells also have a propensity to adhere to the walls of blood vessels and are susceptible to hemolysis, causing chronic anemia (Ashley-Koch et al., 2000). The deformed red blood cells cause microcirculatory obstruction and prevent normal blood flow and decreased delivery of oxygen to organs and tissues resulting in the vasoocclusive crisis. However, information summarized by Stuart and Nagel (2004) indicates that the actual mechanism is more complicated. One of the factors complicating the pathophysiology is cell heterogene- ity. Sickle cells vary in their density and deformity because cation homeo- stasis is impaired in some cells. The amount of hemolysis is related to the number of irreversibly sickled cells and dense cells (Steinberg and Rodgers, 2001). Another factor that varies is fetal hemoglobin (Hb F) concentra- tions. Vasoocclusive events depend on the interaction of features intrinsic to the sickled erythrocyte, including degree of polymer formation and cellu- lar damage, interacting with other factors in the cells environment such as endothelial cells and leukocytes (Steinberg and Rodgers, 2001). Other po- tentially contributing factors include neutrophil transmigration that “adds to the increased inflammation in the microvascularture” and “disregulation of vasomotor tone by perturbations in vasodilator mediators such as ni- trous oxide (NO)” (Stuart and Nagel, 2004, p. 1345). The abnormal cation homeostasis contributes to dehydrated dense sickle cells which in turn con- tributes to anemia and hemolysis.

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286 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT The recognition that the adherence of sickled erythrocytes to the endo- thelium correlated with disease severity focused attention on the mecha- nisms involved (Stuart and Nagel, 2004). As a barrier between blood and tissue, endothelial cells have a number of functions that may contribute to the vascular pathology of sickle cell disease and “genetic differences are likely to cause different responses among patients” (Steinberg and Rodgers, 2001, p. 300). One of the functions of endothelial cells is to control vascu- lar tone by elaborating vasoconstrictors and vasodilators. Endothelial cells also express genes adhesion molecules for blood cells and proteins (Steinberg and Rodgers, 2001). Endothelial cell activators are generated by a number of factors such as hypoxia, thrombin, and infection (Steinberg and Rodgers, 2001). Other extra-erythrocyte related pathophysiological factors include leukocyte size, rigidity, and adhesive characteristics and coagulation activa- tion, with thrombin hypothesized as potentially providing a crucial link between coagulation activation and adhesion (Stuart and Nagel, 2004). Of particular interest is the finding that laminin bonds strongly to sickle eryth- rocytes via the protein that carries Lutheran blood-group antigens (B-CAM/ Lu) and epinephrine increases this adhesion. “Since stress is a potential initiation factor for vasoocclusion, epinephrine modulation of adhesion provides a powerful biological link between intraerythrocytic signaling path- ways and the external milieu” (Stuart and Nagel, 2004, p. 1346). Clinical Manifestations Two primary consequences of hypoxia secondary to vasoocclusive cri- sis are pain and damage of organ systems. The organs at greatest risk are those where blood flow is slow, such as the spleen and bone marrow, or those with a limited terminal arterial blood supply, including the eye and the head of the femur and humerus, and lung as the recipient of deoxygen- ated sickle cells that escape the spleen or bone marrow. Major clinical manifestations of sickle cell disease include painful events, acute chest syn- drome, splenic dysfunction, and cerebrovascular accidents. Painful events occur as a result of ischemic tissue injury and can be precipitated by hypoxia, dehydration, and extreme cold. The frequency and severity of painful events are varied. Musculoskeletal pain is the most com- mon, followed by abdominal pain, and low back pain. Painful events typi- cally last 4-6 days. Transduction is the process whereby noxious inflamma- tory mediators that are generated by tissue damage in turn activate nocioceptors to chemical or mechanical forms of energy to an electrochemi- cal impulse, which is transmitted along the spirothalamic tract to the thala- mus which in turn transmits the signal to the brain where it is perceived as pain (Ballas, 2001a). Descending fibers in the midbrain can inhibit the transmission of painful stimuli via endogenous endorphins and communi-

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287 APPENDIX D cations through the limbic system can modulate the emotional response to pain and thereby enhance or inhibit the intensity of the perception of pain (Ballas, 2001a). Acute chest syndrome involves chest pain, fever, increased leukocyto- sis, hypoxemia, and pneumonia-like symptoms. Typical causes include in- fection and pulmonary infarction (Ballas, 2001b). This acute illness can be self-limiting or can rapidly progress and may be fatal. “Risk factors include HB SS genotype, low HB F concentrations and high steady state leukocyte and HB concentrations” (Stuart and Nagel, 2004, p. 1350). Splenic dysfunction develops during infancy and predisposes the infant to overwhelming infection from encapsulated bacteria, particularly strepto- coccus pneumonia and haemophilus influenza. Between the ages of 5 months and 2 years, children with sickle cell anemia are at risk for sudden intrasplenic pooling of vast amounts of blood, known as splenic sequestra- tion. The hemoglobin level can drop precipitously, causing hypovolemic shock and death. High concentrations of Hb F serve as a protection factor (Stuart and Nagel, 2004). Stroke affects 6-12% of patients with sickle cell disease. In children, the most common cause of stroke is cerebral infarction; intracerebral hem- orrhages become increasingly common with age. Recurrent stroke causes progressive impairment of cognitive functioning. “Risk factors include the HB SS phenotype, previous transient ischemic attacks, low steady state HB concentrations, high leukocyte counts, raised systolic blood pressure, and previous acute chest syndrome” (Stuart and Nagel, 2004, p. 1351). Silent brain lesions have been evidenced on magnetic resonance imaging (MRI) accompanied by neurocognitive deficits (Armstrong et al., 1996). The efforts to enhance clinical care are focusing on increasing under- standing of the pathophysiology of sickle cell disease to enable a precise prognosis and individualized treatment. What is required is knowledge about which genes are associated with the hemolytic and vascular compli- cations of SCD and “how variants of these genes interact among themselves and with their environment” (Steinberg, 2005, p. 465). Genetic Modulation of Disease Severity Individual differences occur in part through differences in the order and pattern of gene expression (i.e., variations in the regulatory sequence of the genome, referred to as promoters). A promoter is a special sequence of bases usually found immediately upstream of the gene itself. A gene is expressed or transcribed into messenger RNA by the binding of a protein called a transcription factor to a promoter. The binding of a transcription factor and the expression of a gene can be altered by experience (Ridley, 2004). An example is the elevation of cortisol that occurs upon appraisal of

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288 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT a situation as stressful, which in turn alters gene expression in the immune system by reducing the expression of interleukin II and turning down the activity, number, and life span of lymphocytes (Ridley, 2004). Two broad molecular genetic strategies have been employed to identify the role of genes (de Gues, 2002). One strategy involves whole genome scans through linkage analysis. The advantage of this approach is that all relevant genes are examined but the disadvantage is that it requires large samples of genetically related subjects. A second approach is an allelic association or candidate gene studies. Associations with known functional candidate genes are investigated, for example “genes suspected to influence neurotransmission in the brain because they code for protein constituents of receptors, transporters, or enzymes involved in neurotransmitter synthe- sis and degradation (Plomin and Crabbe, 2000)” (de Gues, 2002, p. 4). The advantage of this approach is the ability to use smaller samples of unrelated subjects but the disadvantage is that some genetic influences are missed because they are not among the candidate genes studied. It is easier to identify the effect of the gene on a more elementary trait than on a complex one. The strategy is to identify an endophenotype that is upstream of the more complex effect, determine the amount of variance that the gene explains in the endophenotype, and then determine the vari- ance explained in the disease outcome by the endophenotype. Identifying allelic candidate genes is a matter of looking for genes that are part of a system known to influence the disease. The genes influence the disease by influencing the concentration of a protein or its functionality or efficiency or responsiveness to the environment. Ridley (2004) maintains that “Diversity in the human population is starting to be explained at least as much by variations in the number of repeats of a genetic phrase in the regulatory region of the gene as by single- nucleotide polymorphisms” (p. 97). “Varying the number of repeats of a phase has a much subtler effect on gene function then does changing a single nucleotide in a codon, which tends to shut a gene down” (p. 97). Steinberg (2005) views the use of Bayesian networks as a promising approach for the discovery of the genetic basis of complex traits in large association studies and describes a Bayesian network that was developed to analyze 235 single nucleotide polymorphisms (SNPs) in 80 candidate genes in 1398 unrelated patients with sickle cell anemia. The findings indicated that “SNP’s on 11 genes and four clinical variables, including α-thalassemia and Hb F, interacted in a complex network of dependency to modulate the risk of stroke. This network of intersections included three genes, BMP6, TGFBR2, and TGFBR3 with a functional role in the TGF-β [transforming growth factor-β pathway and one gene (SELP) associated with stroke in the general population” (Steinberg, 2005, p. 472). Subsequently, this model was validated by predicting the occurrence of stroke in a different popula-

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289 APPENDIX D tion with a true positive rate of 100%; a true negative rate of 98.14%; and an overall predictive accuracy of 98.2% (Sabastiani et al., 2005). In his comprehensive review of predictors of SCD complications, Steinberg (2005) considers both established predictors, including fetal hemoglobin and α- thalassemia, and potential predictors. Fetal Hemoglobin Fetal hemoglobin (Hb F) inhibits Hb S polymerization and higher levels are associated with a reduction of most vasoocclusive complications of sickle cell anemia (Steinberg, 2005). However, Hb F concentrations vary among patients with sickle cell anemia, ranging from 0.1% to 30%, and there is considerable variability in severity of complications among patients with similar concentration levels. Typical levels of Hb F vary across the four major β-globin haplotypes. The highest Hb F level and mildest clinical course is found in carriers of the Hb S gene on the Senegal or Arab-India haplotype, intermediate levels and severity on the Benin haplotype, and the lowest levels and most severity on the Bantu (Central African Republic) haplotype (Steinberg, 2005). Fetal hemoglobin expression is a quantitative trait and investigations are addressing complex interactions among transcription factors, genes modulating erythropoiesis, and elements linked to the β-globin cluster. In addition, similar genetic analyses are being undertaken in an effort to pre- dict responsiveness to hydroxyurea, which is used to treat the complica- tions of SCD and is thought to work by increasing Hb F levels (Steinberg, 2005). α-Thalassemia Alpha thalassemia is the result of the deletion of one of two α-globin genes from a chromosome (Nagel and Steinberg, 2001). Coincidental α- thalassemia occurs in approximately 30% of patients with sickle cell ane- mia and affects the phenotype of sickle cell anemia by reducing the concen- tration of Hb S polymerization (Steinberg, 2005). The presence of α-thalassemia with sickle cell anemia is also associated with less hemolysis, higher concentration of hemoglobin (Nagel and Steinberg, 2001) and higher packed cell volume (PCV), and lower mean corpuscular volume and reticulocyte counts (Steinberg, 2005). However, the clinical effects of co- existing α-thalassemia are mixed. Benificial effects are generally found with vasoocclusive events that are dependent on PCV, such as stroke and leg ulcer, whereas deleterious effects are associated with complications that are dependent on blood viscosity, such as painful episodes and acute chest syndrome (Steinberg, 2005).

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290 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT Since the diversity of sickle cell anemia cannot be explained entirely by Hb F and α-globin gene-linked modulation, attention is being directed to epistatic or modifying genes that act independently of Hb S polymerization. The genes that potentially could modulate the phenotype of sickle cell anemia include: “mediators of inflammation, oxidant injury, NO biology, vasoregulation, cell-cell interaction, blood coagulation, haemostasis, growth factors, cytokine and receptors and transcriptional regulators” (Steinberg, 2005, p. 470). However, studies of candidate genes, seeking associations of SNP with phenotypes, are in the beginning stages and present many inter- pretative challenges (Steinberg, 2005). ROLE OF BEHAVIORAL AND PSYCHOSOCIAL FACTORS IN SICKLE CELL DISEASE Consistent with the biopsychosocial model, investigations of the role of behavioral and psychosocial factors in sickle cell disease have been bidirec- tional. One line of research has focused on the impact of sickle cell disease on psychological adjustment in children and adolescence with sickle cell disease and their parents, and adults with sickle cell disease. Another line of research has focused on the impact of behavioral and psychosocial pro- cesses on selected dimensions of disease outcome, particularly with regard to pain and neurocognitive functioning. Psychological Adjustment The findings with regard to the psychological adjustment of children with sickle cell disease are consistent with those for children with chronic illnesses in general (Thompson and Gustafson, 1996). The risk of psycho- logical adjustment problems in children with chronic illness is 1.5 to 3 times as high as with their healthy peers (Thompson and Gustafson, 1996). In addition to determining the type and frequencies of adjustment problems, effort has been directed to identifying the mediating and moderating role of illness parameters, typically disease severity, and psychological and social processes to adjustment to the stress of chronic illness. The transactional stress and coping model (Thompson and Gustafson, 1996; Thompson et al., 1992) has proven to be a useful conceptual framework for these inves- tigations and psychological adjustment was the target of a number of stud- ies done through the Duke University of North Carolina Sickle Cell Center. Psychological adjustment was assessed in a study of 50 children, age 7 to 17 years of age with sickle cell disease, (Hb SS 60%; Hb SC 12%; sickle β-thalassemia syndromes 16%). In terms of mother reported behavioral problems, 64% of the children were classified with poor adjustment, pri- marily of the internal behavior problem type. In terms of child self-report,

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291 APPENDIX D as assessed through a semi-structured diagnostic interview, 50% reported symptoms that met the criteria for one or more DSM-III diagnosis. Internal- izing problems reflected in anxiety, phobic, and obsessive-compulsive diag- noses were most frequent. In contrast, externalizing problems reflected in conduct disorder and oppositional disorder were relatively infrequent. Hi- erarchal multiple regression analysis was utilized to assess the increment in psychological adjustment accounted for by maternal psychological adjust- ment and children’s cognitive processes and pain coping strategies over and above that accounted for by demographic parameters and illness severity parameters, including type of sickle cell disease, pain frequency, pain sever- ity, and number of complications. In terms of the variance in mother- reported internalizing behavioral problems, the demographic variables of gender, socioeconomic status, and age accounted for 8% and the illness parameters of pain frequency and type of sickle cell disease accounted for another 9% and 8%, respectively. Maternal anxiety accounted for 16% of the variance in mother-reported internalizing behavioral problems and 33% in mother-reported externalizing behavioral problems. In terms of child- reported total symptom score, sickle cell type did not account for any of the variance, the number of illness complications accounted for 2%, and pain frequency accounted for 1%. The demographic variables of socioeconomic status and gender only accounted for 6% of the variance. However, children’s pain coping strategies characterized by negative thinking ac- counted for a 21% increment in child reported total symptom score. Psychological adjustment over time was assessed at 3 points across 2 years with a sample of 50 children with sickle cell disease (Hb SS, 54%; Hb SC, 34%; sickle β-thalassemia, 12%; males, 64%; females, 36%). In terms of child-reported symptoms, 12% met diagnostic criteria for a DSM-III diagnosis across all three time points whereas 17% consistently demon- strated good adjustment. The variability in report of symptoms meeting diagnostic criteria over time is also reflected by the percentage of children who had 1 (49%) or 2 (27%) changes in adjustment classification over the three-time periods. In terms of specific diagnoses, internalizing disorders were most frequent at each time but there was very little consistency in specific diagnoses across time. In terms of mother-reported behavioral prob- lems, 47% met the criteria for poor adjustment and 19% for good adjust- ment across all three assessment points. One change in classification oc- curred for 25% and two-changes occurred for 4% (Thompson et al., 1999a). Maternal psychological adjustment was assessed in a study of 78 moth- ers of children and adolescence, 7 to 17 years of age, with sickle cell disease (Hb SS, 62%; Hb SC 23%; and sickle β-thalassemia syndromes; 15%) (Thompson et al., 1993b). In terms of self-reported symptoms of psycho- logical distress, 36% of mothers’ met criteria for poor psychological adjust-

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299 APPENDIX D immune system suppression, for example decreased lymphocyte prolifera- tion and cytokine production, damage to the hippocampus, and hyperten- sion (Dickerson and Kemeny, 2004). The vasoconstrictive and immuno- logical impact of the activation of the HPA axis is of relevance for sickle cell disease. The effect of cortisol on tissues is mediated by the glucocorticoid recep- tor (GR) through direct binding to hormone-responsive elements in the RNA or by interactions with, and modulation of, other transcription fac- tors (Wüst et al., 2004b). The response of a cell to cortisol is a function of the level of the steroid and its GC sensitivity. Variants of the GR gene (located on chromosome 5, locus 5q31) affect sensitivity (Wüst et al., 2004b). Support has been provided for the hypothesis that common poly- morphisms in the GR gene may have modulating effects on the HPA re- sponse to psychological stress. In a recent study, the impact of three GR gene polymorphisms (BclI RFLP, N363S, and ER22/23EK) on cortisol and ACTH responses to psychological stress and pharmacological stimulation was assessed (Wüst et al., 2004b). In comparison to subjects with two wild- type alleles, 363S carriers showed a significant increased salivary cortisol response to stress whereas the cortisol response of the BclI homozygotes was diminished. This study provides evidence that common polymorphisms of a single gene impact HPA regulation and contribute to the individual variability in response to psychological stress. The impact of genetic factors on HPA axis activity was reported from findings of twin studies and asso- ciation studies with polymorphisms in the GR gene (Wüst et al., 2004a). In addition, a number of polymorphisms were identified as good candidate genes for future studies (Wüst et al., 2004a). Evidence suggests that the GCs act through genetic mechanisms, to modify transcription of key regulatory proteins, and by non-genetic mecha- nisms on cell signaling processes that have a more rapid impact on homeo- static regulation (Herman et al., 2003). The HPA mediated response to stressful stimuli differ depending upon whether the threat to homeostasis is “real” or “predicted.” By real stressor is meant stimuli that are recognized by somatic, visceral, or circumventricular sensory pathways as a challenge to homeostasis. These stimuli include hormonal signals, such as renin- angiotensin, visceral or somatic pain, or humoral inflammatory signals such as blood-borne cytokines signaling infection (Herman et al., 2003). In addition to these “reactive” responses, GC responses can occur in “antici- pation” of homeostatic disruption under situations in which threat may be predicted or associated with learned experience. The anticipatory responses are under the control of limbic regions such as the hippocampus, amygdale, and prefrontal cortex (Herman et al., 2003). These two systems act to- gether in an integrated, hierarchal manner. The reactive pathway evokes direct PVN activation whereas the anticipatory pathway involves forebrain

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300 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT processing of polysensorial and associational input that also mediate reac- tive responses. “The resultant hierarchal organization of stress-responsive neurocircuitries is capable of comparing information from multiple limbic sources with internally generated and peripherally sensed information, thereby tuning the relative activity of the adrenal cortex” (Herman et al., 2003, p. 151). Both genetics and early life experiences can modulate re- sponse characteristics of the HPA axis (Herman et al., 2003). Changes in limbic system integration patterns as a function of experience are hypoth- esized to play a role in HPA axis dysfunction (Herman et al., 2003). The importance of psychological stress processing for the understand- ing of the psychobiological stress response is becoming increasingly clear (Gaab et al., 2005). Conceptualizations of stress have moved from that of a stimulus or response to “A relationship between the person and the envi- ronment that is appraised by the person as taxing or exceeding his or her resources and endangering his or her well being” (Lazarus and Folkman, 1984, p. 19). A recent study provided support for the role of anticipatory cognitive appraisal, but not general personality factors or retrospective stress appraisal, in the salivary cortisol response to psychological stress (Gaab et al., 2005). Whereas there is evidence that psychological stressors are capable of activating the HPA axis, the effects are highly variable. For example, sev- eral aspects of perceived chronic stress, more specifically worries, social stress, and lack of social recognition, were found to be significantly associ- ated with increased cortisol awakening response (Wüst et al., 2000). To evaluate the characteristics of psychological stressors that evoke a cortisol response, a meta-analysis of 208 empirical studies was undertaken (Dickerson and Kemeny, 2004). The findings indicated that psychosocial stressors that involved social evaluative threat and uncontrollability were significantly associated with increased cortisol response. The findings were also similar for ACTH response. However, psychological distress in and of itself was not associated with increased cortisol response. The findings indicate that only those threats to central goals, such as physical self- preservation or preservation of the social self, and not having control over these situations, triggers cortisol activation. Sickle cell disease provides just such a situation of threat to self-preservation and social evaluative threat and the negative self-appraisals generated under these conditions rather than emotional stress in general could constitute psychological stressors that impact the HPA axis. Stress and the Immune System In understanding the relationship of psychosocial stressors to the im- mune system, Segerstrom and Miller (2004) maintain that it is useful to

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301 APPENDIX D distinguish between natural and specific immunity. Natural immunity in- volves cells that do not provide a defense against a particular pathogen but operate broadly in a short time frame. These cells include the granulocytes, both neutrophil and macrophage, which releases cytokines such as inter- leukin, and natural killer (NK) cells. Specific immunity involves cellular response to intracellular pathogens and humoral responses to extracellular pathogens. Lymphocytes have receptor sites that respond to a specific anti- gen and when activated divide to create a population of cells in a process referred to as colonal proliferation (Segerstrom and Miller, 2004). The immune system is of importance in sickle cell disease and one way of examining the impact of genetic, behavioral, and psychosocial processes on the immune system is through the impact of stress and stress processing. There are several ways that stress can affect the immune response (Segerstrom and Miller, 2004). The immune system is regulated both by neural inputs from the sensory, sympathetic, and parasympathetic system as well as by circulating catecholamines and GCs (McEwen, 2000). The substances released through the action of the nervous system bind to spe- cific receptors on white blood cells and have a regulatory effect on their distribution and function (Segerstrom and Miller, 2004). More specifically, sympathetic fibers release substances that bind to receptors on lympho- cytes, and “the hypothalamic-pituitary-adrenal axis, the sympathetic- adrenal-medullary axis, and the hypothalamic-pituitary-ovarian axis se- crete the adrenal hormones, epinephrine, norepinephrine, and cortisol; the pituitary hormones prolactin and growth hormone; and the brain peptides melatonin, β-endorphin, and enkephalin” (Segerstrom and Miller, 2004, p. 604). Under acute stress, elevations of stress hormones (catecholamines and GCs) facilitate the movement of immune cells, lymphocytes, monocytes, and NK cells which are reduced in other tissues where other mediators of immune function activation become involved. For example, interferon gamma “is known to induce expression of antigen-presenting and cell- adhesion molecules on endothelia cells and macrophages and cell adhesion molecules on leukocytes” (McEwen, 2000, p. 175). Stress also affects the immune system through behaviors, such as changes of sleep patterns, that could modify immune system processes (Segerstrom and Miller, 2004). Another association of the immune system with stress arises through the immunological activation of “sickness behav- ior” which refers to a constellation of behavioral changes that accompany infection that include a “reduction in activity, social interaction, and sexual activity, as well as increased responsiveness to pain, anorexia, and de- pressed mood” (Segerstrom and Miller, 2004, p. 604). Support for the relationship of psychological stress and immune sys- tem response was provided through a meta-analysis of more than 300 empirical studies (Segerstrom and Miller, 2004). The findings across these

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302 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT studies indicated that acute stressors were associated with upregulation of natural immunity parameters and downregulation of specific immunity functions (Segerstrom and Miller, 2004). Acute stressors were associated with an increase in the number of NK cells, neutrophils, and large granular lymphocytes in peripheral blood, increased production of proinflamma- tory cytokines and cytokines, and decrease in colonal proliferation re- sponse (Segerstrom and Miller, 2004). Chronic stressors were associated with suppression of both cellular and humoral responses (Segerstrom and Miller, 2004). Furthermore, stress appraisal was found to be associ- ated with a reduction in NK cell cytotoxicity (Segerstrom and Miller, 2004). Chronic stress leading to sustained levels of stress hormones can also affect the immune system (Cruess et al., 2004). A proinflammatory cytokine, interleukin-6 (IL-6) is elevated under stress and stimulates SNS and HPA activation (Cruess et al., 2004). Furthermore, inflammation is critical in the development and progression of atherosclerosis which is associated with the rupture of plaque that can block blood flow (Cruess et al., 2004). Low-density lipoprotein cholesterol retained in the cell wall undergoes oxidative modification and the “resultant modified lipids can induce the expression of adhesion molecules and proinflammatory cytokines as mediators of inflammation in macrophages and vascular cell walls” (Cruess et al., 2004, p. 40). Psychological factors such as depres- sion and stress have been associated with decrements in lymphocyte pro- liferative response and lower NK cell cytotoxicity (Cruess et al., 2004). Thus, alterations in neuroendocrine functioning affect the immune sys- tem and neurohormonal changes have been linked to a number of psy- chosocial factors including cognitive appraisals, coping responses, per- ceived loss of control, attributions of helplessness, and feelings of hopelessness, low self-efficacy, passive coping strategies, and lack of so- cial support (Cruess et al., 2004). Stress and Erythrocyte Adhesion The vasoocclusive process in sickle cell disease is complex and increas- ing attention is focused on the role of the adhesion of sickle erythrocytes (SS RBCs) to endothelial cells (ECs). A direct relationship between the rating of vasoocclusive pain and biological markers of erythrocytes/EC adhesion has been reported (Dampier et al., 2004). In addition, there is evidence that the stress hormone epinephrine enhances adhesion of sickle erythrocytes (SS RBCs), but not normal RBCs, to ECs (Zennadi et al., 2004). Febrile epi- sodes are frequently associated with vasoocclusive pain episodes in sickle cell anemia and are hypothesized to be viral in origin. Support was pro- vided for the hypothesis that viruses, through double-stranded RNA, can

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303 APPENDIX D induce sickle erythrocytes adherence to ECs through alpha4beta1-VCAM- 1-mediated adhesion (Smolinski et al., 1995). A recent review summarizes the increasing knowledge about how membrane structures contribute to cell adhesion (Telen, 2005). Stress and Neurocognitive Functioning Chronic high levels of stress hormones and GCs contribute to impair- ment of cognitive function through effects on the hippocampus (McEwen, 2000). The hippocampus has two types of adrenal steroid receptors, type 1 (mineralocoiticoid), and type 2 (glucocorticoid), that mediate hormone ef- fects on gene expression (McEwen, 2000). It is the combined action of circulating GCs and catecholamines interacting with local tissue mediators, such as cytokines, that affect the immune system and the excitatory amino acids, such as glutamate, and neurotransmitters, particularly serotonin, that affect the brain and cognitive functioning (McEwen, 2000). Brain atrophy has been shown to occur, particularly of the hippocampus, as a result of elevated GCs and severe stress and declines in hippocampally related cognitive functions such as episodic memory are correlated with increases in HPA activity (McEwen, 2000). Adrenocortical stress responses to ordinary daily stress is sufficient to produce atrophy of hippocampal structures (McEwen, 2000). However, individual differences in stress responsiveness also play a role (McEwen, 2000). “Individuals with a more reactive stress hormone profile will expose themselves to more cortisol and experience more stress-related neural activ- ity, than other people who can more easily habituate to psychosocial chal- lenges” (McEwen, 2000, p. 183). In assessing the impact of stress, it is useful to have multiple physiologi- cal measures within the same study. In a study of monozygotic and dizy- gotic female twin pairs, genetic and environmental effects on autonomic reactivity to a psychologically stressful situation was examined for both single physiological variables and functional combinations of seven of these variables (Lensvelt-Mulders and Hettema, 2001). The findings supported the hypothesis that autonomic response profiles would yield larger genetic effects than single autonomic measures and that the idiosyncratic relation- ship of a person and his/her environment is a heritable trait. Up to 80% of the variance in the functional profiles were accounted for by differences in individual genotypes. The authors comment, “there are at least two ways people physiologically respond to a situation: Directly, by making people more genetically liable to express a certain trait, and indirectly by influenc- ing idiosyncratic interactions between a person and his environment” (Lensvelt-Mulders and Hettema, 2001, p. 38).

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304 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT Stress and Cardiovascular and Renal Response It has been hypothesized that exaggerated cardiovascular response to stress is a mechanism in the pathogenesis of essential hypertension and CHD. Snieder et al. (2002) have developed a biobehavioral model of stress- induced hypertension to explain how repeated exposure to stress, in combi- nation with genetic susceptibility, could lead to the development of hyper- tension. This model is useful to consider, not only because of the cardiovas- cular problems in sickle cell disease, but because the biobehavioral model enables a systems perspective. The biobehavioral model focuses on the complex interrelationship of three underlying physiological systems that mediate the stress response of the heart, vasculature, and kidney: the SNS; the renin-angiotensin-aldosterone system (RAAS), and the endothelial sys- tem (ES). In support of this model, evidence is reviewed for a genetic influence on the two major intermediate phenotypes of the model: cardio- vascular reactivity to psychological stress and the renal stress response in terms of stress-induced sodium retention. The data reviewed were from twin and family studies and a limited number of candidate gene association studies. The authors acknowledge that other biological systems, such as the HPA axis, parasympathetic autonomic reactivity, and serotonin function- ing in the central nervous system may mediate the influence of stress on the development of the essential hypertension, and the importance of genetic variation of these systems has been demonstrated as well. The biobehavioral model of stress-induced essential hypertension proposes that in response to stress there is an increased central nervous system activity that in turn results in the release of catecholamines, norepinephine and epinephrine, which in turn increases heart rate. In addition, norepinephrine causes vaso- constriction and epinephrine causes vasoconstriction in some vessels and vasodilation in others (Snieder et al., 2002). The ES influences the control of vascular smooth muscle function through the production of nitric oxide (NO), a vasodilator, and endothelin- 1 (ET-1), a vasoconstrictor. SNS arousal potentiates the release of these vasoactive substances. Under stress there is evidence of increased release of ET-1 and decreased production of NO resulting in increased vasoconstictive tone (Snieder et al., 2002). The RAAS is activated by both the activity of the ES and SNS arousal. This results in further vasoconstriction and an increase in sodium retention enhances the vasoconstrictive effects of norepinephrine on peripheral vasculture (Snieder et al., 2002). A complex interaction of these three systems contributes to increase total peripheral resistance in response to stress and repeated exposure leads to disregulation in appropriately activating, and/or turning off, cardiovas- cular function (Sneider et al., 2002). The responses to stress result in in- creases in cardiac and vascular wall tension and intravascular shear stress

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305 APPENDIX D that leads to secondary renal damage and cardiovascular remodeling, in- cluding diminished endothelium-dependent arterial dilation to reactive hy- peremia (Snieder et al., 2002). Another manifestation of vascular remodel- ing is increased arterial stiffness which in turn is associated with stroke, renal failure, and coronary artery disease and left ventricular hypertrophy, which is a strong predictor of cardiovascular morbidity and mortality (Snieder et al., 2002). Snieder et al. (2002) also examined the evidence for the role of specific candidate genes on cardiovascular response to stress. Since the β2-adrener- gic receptor mediates peripheral vasodilation, polymorphic variation in this gene may influence response to stress. Evidence has been provided for an association between Arg16Gly polymorphism β2-adrenergic receptor gene (ADRB2) and the Arg389Gly and Arg16Gly polymorphisms in the β1-adrenergic receptor gene (ADRB1) were associated with blood pressure at rest and reactivity to stress. The Gln27Glu polymorphism of the β2- adrenergic receptor gene also showed significantly higher levels of blood pressure at rest and stress but interestingly, no associations were found between these polymorphisms and cardiovascular reactivity for African Americans (Snieder et al., 2002). It should also be noted that an increase in cardiovascular response to stress has also been associated with a promoter polymorphism of the serotonin transporter gene (5HTTLPR) through higher levels of serotonin (Williams et al., 2001). Snieder et al. (2002) suggested that future studies investigating genetic influences on cardiovascular and renal stress should employ measures of polymorphic variation in candidate genes that underlie the SNS, the ES, and the RAAS. They argue that rather than studying the effects of candidate genes in isolation that the biobehavioral model provides a framework for describ- ing the interrelated physiological network underlying blood pressure regula- tion in response to stress. More specifically, Snieder et al. (2002) suggest the following candidate genes for the respective systems. SNS: “the α1- and α2- adrenergic receptor gene (ADRA1, ADRA2) and the β1- and β2-adrenergic receptor genes (ADRB1, ADRB2)”; RAAS: “the genes for angiotensin con- verting enzyme, and the angiotensin II type-1 receptor (AGTR1), aldosterone synthase (CYP11B2) and angiotensinogen”; ES: “the ET-1 gene (EDN1), the gene for ET-1 receptor A (EDNRA) and the genes for the three types of nitric oxide synthase (NOS1, NOS2, NOS3)” (Snieder et al., 2002, p. 87). SUMMARY AND RECOMMENDATIONS This review provides some information with regard to the specific ques- tions of interest but may have its most significant contribution in terms of guidance of future research. In terms of what knowledge/data we have, the following findings are most salient:

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306 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT • Among social and behavioral factors, stress—primary related to daily hassles, and stress processing—primarily in relation to cognitive appraisals and attributions, coping methods, and family support, are associated with variability in the manifestation of sickle cell disease—primarily psychologi- cal adjustment, pain, and neurocognitive functioning. • Stress and stress processing are related to an array of neuroendo- crine-mediated physiological responses, that in turn are associated with variability in vascular and inflammatory processes of importance in sickle cell disease. • Pain management is related to variability in health care utilization and activity level. • A number of candidate genes have been identified as mediators/ modulators of the physiological response to stress and of the vascular and inflammatory manifestations of sickle cell disease. The data that we do not yet have and the questions remaining to be answered are at the systems level of analysis, to which the biopsychosocial model aspires but has not yet reached. The current stage of research can most appropriately be described as multiple dimensions—biological, psychologi- cal, and social—considered concurrently but not transactionally. That is, current studies examine the contribution of biological and psychosocial fac- tors in terms of their independent and combined contributions to variability in some aspect of sickle cell disease manifestations. This is one level of consideration of how multiple processes “act together.” The next level is considering “acting together” in terms of mutual influence through continu- ous transactions over time. In addition, the studies of the contribution of behavioral and social factors have been limited in terms of outcome measures to primarily psychological adjustment, pain and health care utilization, and neurocognitive impairment but not other physiological manifestations of sickle cell disease. Finally, there are very few studies that include an examina- tion of behavioral and psychosocial factors and candidate genes in the same study. This review suggests that the next research step is to develop requests for proposals for studies that are longitudinal, evaluate the role of stress appraisal, stress processing, and candidate genes on physiological stress re- sponses as the endophenotype and on vascular and immunological physi- ological measures and cell adhesion as the endpoints. ACKNOWLEDGMENT I want to thank Meghan Von Isenburg, Information and Education Services Librarian, Duke University Medical Center Library, for her assis- tance with the literature search.

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307 APPENDIX D REFERENCES Armstrong, D.F., Thompson, R.J., Jr., Wang, W., Zimmerman, R., Pegelow, C., Miller, S., Moser, F., Bello, J., Hurtig, A., and Vass, K. (1996). Cognitive functioning and brain magnetic resonance in children with SCD. Pediatrics, 97, 864-870. Ashley-Koch, A., Yang, Q., and Olney, R.S. (2000). Sickle hemoglobin (Hb S) allele and sickle cell disease: A HuGE review. American Journal of Epidemiology, 151(9), 839-845. Ballas, S.K. (2001a). Effect of α-globin genotype on the pathophysiology of sickle cell disease. Pediatric Pathology and Molecular Medicine, 20, 107-121. Ballas, S.K. (2001b). Sickle cell disease: Current clinical management. Seminars in Hematology, 38(4), 307-314. Bronfenbrenner, U. (1977). Toward an experimental ecology of human development. American Psychologist, 32, 513-531. Bronfenbrenner, U. (1979). The ecology of human development. Cambridge, MA: Harvard University Press. Cruess, O.G., Schneiderman, N., Antoni, M.H., and Penedo, F. (2004). Biobehavioral bases of disease processes (pp. 31-79). In T.J. Boll (Series Ed.) and R.G. Frank, A. Baum, and J.L. Wallander (Vol Eds). Handbook of Clinical Health Psychology. Volume 3: Models and Perspectives in Health Psychology. Washington, DC: American Psychological Association. Dampier, C., Setty, B.N., Eggleston, B., Brodecki, D., O’Neal, P., and Stuart, M., (2004). Vaso- occlusion in children with sickle cell disease: Clinical characteristics and biologic corre- lates. Journal of Pediatric Hematology/Oncology, 26(12), 785-90. de Gues, E.J.C. (2002). Introducing genetic psychophysiology. Biological Psychology 61, 1-10. Dickerson, S.S., and Kemeny, M.E. (2004). Acute stressors and cortisol responses: A theoretical integration and synthesis of laboratory research. Psychological Bulletin, 130(3), 355-391. Engel, G.L. (1977). The need for a new medical model: A challenge for biomedicine. Science, 196, 129-136. Farber, M.D., Koshy, M., and Kinney, T.R. (1985). Cooperative study of sickle cell disease: Demographic and socioeconomic characteristics of patients and families with sickle cell disease. Journal of Chronic Diseases, 38, 495-505. Gaab, J., Rohleder, N., Nater, U.M., and Ehlert, U. (2005). Psychological determinants of the cortisol stress response: The role of anticipatory cognitive appraisal. Psychoneuroendocri- nology, 30, 599-610. Gaston, H.H., and Rosse, W. (1982). The cooperative study of sickle cell disease: Review of study design and objectives. American Journal of Pediatric Hematology and Oncology, 4, 197-200. Gil, K.M., Abrams, M.R., Phillips, G., and Keefe, F.J. (1989). Sickle cell disease pain: Relation of coping strategies to adjustment. Journal of Consulting and Clinical Psychology, 57, 725-731. Gil, K.M., Thompson, R.J., Jr., Keith, B.R., Tota-Faucette, M., Noll, S., and Kinney, T.R. (1993). Sickle cell disease pain in children and adolescents: Change in pain frequency and coping strategies over time. Journal of Pediatric Psychology, 18, 621-637. Gil, K.M., Williams, D.A., Thompson, R.J., Jr., and Kinney, T.R. (1991). Sickle cell disease in children and adolescents: The relation of child and parent pain coping strategies to adjust- ment. Journal of Pediatric Psychology, 16, 643-663. Herman, J.P., Figueredo, H., Mueller, N.K., Ulrich-Lai, Y., Ostrander, M.M., Choi, D.C., and Cullinan, W.E. (2003). Central mechanisms of stress intergration: Hierarchical cir- cuitry controlling hypothalamo-pituitary-adrenocortical responsiveness. Frontiers in Neu- roendocrinology, 24, 151-180.

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308 GENES, BEHAVIOR, AND THE SOCIAL ENVIRONMENT Kanner, A.D., Coyne, J.C., Schaefer, C., and Lazarus, R.S. (1981). Comparison of two modes of stress measurements: Daily hassles and uplifts versus major life events. Journal of Behavioral Medicine, 4, 1-39. Lazarus, R.S., and Folkman, S. (1984). Stress, appraisal, and coping. New York: Springer Publishing Company. Lensvelt-Mulder, G., and Hettema, J. (2001). Genetic analysis of autonomic reactivity to psychologically stressful situations. Biological Psychology, 58, 25-40. McEwen, B.S. (2000). The neurobiology of stress: From serendipity to clinical relevance. Brain Research Bulletin, 886, 172-189. Nagel, R.L., and Steinberg, M.H. (2001). Role of epistatic (modifier) genes in the modulation of the phenotypic diversity of sickle cell anemia. Pediatric Pathology and Molecular Medicine, 20, 123-136. Plomin, R., and Crabbe, J. (2000). DNA. Psychological Bulletin, 126(6), 806-828. Porter, L.S., Gil, K.M., Sedway, J.A., Ready, J., Workman, E., and Thompson, R.J., Jr. (1998). Pain and stress in sickle cell disease: An analysis of daily pain records. Interna- tional Journal of Behavioral Medicine, 5, 185-203. Quinn, C.T., and Miller, S.T. (2004). Risk factors and prediction of outcomes in children and adolescents who have sickle cell anemia. Hematology/Oncology Clinics of North America, 18, 1339-1354. Ridley, M. (2003). Nature via nurture: Genes, experience, and what makes us human. New York: Harpers Collins Publishers. Ridley, M. (2004). The biology of human nature. Daedalus, 89-98. Rosenstiel, A.K., and Keefe, F.J. (1983). The use of coping strategies in low back pain pa- tients: Relationship to patient characteristics and current adjustment. Pain, 17, 33-40. Sabastiani, P., Ramoni, M.F., Nolan, V.G., Baldwin, C.T., and Steinberg, M.H. (2005). Ge- netic dissection and prognostic modeling of overt stroke in sickle cell anemia. Nature Genetics, 37(4), 435-440. Segerstrom, S.C., and Miller, G.E. (2004). Psychological stress and the human immune sys- tem: A meta-analytic study of 30 years of inquiry. Psychological Bulletin, 130, 601-630. Smolinski, P.A., Offermann, M.K., Eckman, J.R., and Wick, T.M. (1995). Double-stranded RNA induces sickle erythrocyte adherence to endothelium: A potential role for viral infection in vaso-occlusive pain episodes in sickle cell anemia. Blood, 85(10), 2945- 2950. Snieder, H., Harshfield, G.A., Barbeau, P., Pollock, D.M., Pollock, J.S., and Treiber, F.A. (2002). Dissecting the genetic architecture of the cardiovascular and renal stress re- sponse. Biological Psychology, 61, 73-95. Steinberg, M.H. (2005). Predicting clinical severity in sickle cell anaemia. British Journal of Haematology, 129, 465-481. Steinberg, M.H., and Rodgers, G.P. (2001). Pathophysiology of sickle cell disease: Role of cellular and genetic modifiers. Seminars in Hematology, 38(4), 299-306. Stuart, M.J., and Nagel, R.L. (2004). Sickle-cell disease. The Lancet, 364, 1343-1360. Telen, M.J. (2005). Erythrocyte adhesion receptors: Blood group antigens and related mol- ecules. Transfusion Medicine Reviews, 19, 32-44. Thompson, R.J., Jr., and Gustafson, K.E. (1996). Adaptation to chronic childhood illness. Washington, DC: American Psychological Association Press. Thompson, R.J., Jr., Gil, K.M., Abrams, M.R., and Phillips, G. (1992). Stress, coping and psychological adjustment of adults with sickle cell disease. Journal of Consulting and Clinical Psychology, 60, 433-440.

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309 APPENDIX D Thompson, R.J., Jr., Gil, K.M., Burbach, D.J., Keith, B.R., and Kinney, T.R. (1993a). Psycho- logical adjustment of mothers of children and adolescents with sickle cell disease: The role of stress, coping methods and family functioning. Journal of Pediatric Psychology, 18, 621-637. Thompson, R.J., Jr., Gil, K.M., Burbach, D.J., Keith, B.R., and Kinney, T.R. (1993b). Role of child and maternal processes in the psychological adjustment of children with sickle cell disease. Journal of Consulting and Clinical Psychology, 61, 468-474. Thompson, R.J., Jr., Gil, K.M., Abrams, M.R., and Phillips, G. (1996). Psychological adjust- ment of adults with sickle cell anemia: Stability over 20 months, correlates, and predic- tors. Journal of Clinical Psychology, 52, 253-266. Thompson, R.J., Jr., Armstrong, F.D., Kronenberger, W.G., Scott, D., McCabe, M.A., Smith, B., Radcliffe, J., Colangelo, L., Gallagher, D., Islam, S., and White, E. (1999a). Family functioning, neurocognitive functioning, and behavior problems in children with sickle cell disease. Journal of Pediatric Psychology, 24, 491-498. Thompson, R.J., Jr., Gustafson, K.E., Gil, K.M., Kinney, T.R., and Spock, A. (1999b). Change in the psychological adjustment of children with cystic fibrosis or sickle cell disease and their mothers. Journal of Clinical Psychology in Medical Settings, 6, 373-391. Thompson, R.J., Jr., Gustafson, K.E., Bonner, M.J., and Ware, R.E. (2002). Neurocognitive development of young children with sickle cell disease through three years of age. Jour- nal of Pediatric Psychology, 27, 235-244. Thompson, R.J., Jr., Armstrong, F.D., Link, C.L., Pegelow, C.H., Moser, F., and Wang W.C. (2003). A prospective study of the relationship over time of behavior problems, intellec- tual functions, and family functioning in children with sickle cell disease: A report from the Cooperative Study of Sickle Cell Disease. Journal of Pediatric Psychology, 28, 59-65. Weatherall, D.J. (2001). Phenotype-genotype relationships in monogenic disease: Lessons from the thalassaemias. Nature Reviews Genetics, 2, 245-255. Weiss, S.M. (1987). Behavioral medicine in the trenches. In J. Blumenthal and D. McKee (Eds.), Applications in Behavioral Medicine snd Health Psychology: A Clinician’s Source Book (pp. xvii-xxiii). Sarasota, FL: Professional Resource Exchange. Williams, R.B., Marchuk, D.A., Gadde, K.M., Barefoot, J.C., Grichnik, K., Helms, M.J., et al. (2001). Central nervous system serotonin function and cardiovascular responses to stress. Psychosomatic Medicine, 63(2), 300-305. Wüst, S., Federenko, I.S., Hellhammer, and D.H., Kirschbaum, C. (2000). Genetic factors, perceived chronic stress, and the free cortisol response to awakening. Psychoneuro- endocrinology, 25(7), 707-720. Wüst, S., Federenko, I.S., Van Rossum, E.F.C., Koper, J.W., Kumsta, R., Entringer, S., and Hellhammer, D.H. (2004a). A psychobiological perspective on genetic determinants of hypothalamus-pituitary-adrenal axis activity. New York Academy of Sciences, 1032, 52-62. Wüst, S., Van Rossum, E.F.C., Federenko, I.S., Koper, J.W., Kumsta, R., and Hellhammer, D.H. (2004b). Common polymorphisms in the glucocorticoid receptor gene are associ- ated with adrenocortical responses to psychosocial stress. Journal of Clinical Endocri- nology and Metabolism, 89, 565-673. Zennadi, R., Hines, P.C., DeCastro, L.M., Cartron, J.P., Parise, L.V., and Telen, M.J. (2004). Epinephrine acts through erythroid signaling pathways to activate sickle cell adhesion to endothelium via LW-αvβ3 interactions. Blood, 104, 3774-3781.