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Biomedical subjects

Scott M Williams

Publications and source records attributed to Scott M Williams.

At least 19 recordsLinked to original sources
PubMed2026

Human genetic variation associates with infection by derived Ugandan M. tuberculosis lineage.

BACKGROUND: Several studies have examined host and pathogen genetic influences on tuberculosis (TB) susceptibility separately, but relatively few studied their combined effects. However, host-pathogen interactions or co-evolution may explain the inability to replicate many reported human genetic effects across global populations and provide additional insight into TB risk. In this study, we address such possible interactions by focusing on the outcome of infection with the L4-Uganda M. tuberculosis sub-lineage and human genetic variants as independent variables. This is possible because the L4-Uganda sub-lineage is both restricted to Uganda and nearby locations and is recent there, compared to other more ancestral L4 lineages. METHODS: Our study consisted of 276 culture-confirmed adult TB cases from a long-standing household contact study. We conducted a genome-wide association study, with infection with L4-Uganda versus L4-NonUganda as the outcome. RESULTS: Multiple loci with results suggestive of association (p<10-5) also demonstrated convergent relevant evidence for strain specific infection via: evidence of gene expression in relevant cells and lung tissue, signatures of natural selection, eQTL expression, and CRISPR screens for immunity-related genes. We also replicated previously published host-pathogen interaction effects, demonstrating that effects seen for other sub-lineages were also present for L4-Uganda. CONCLUSIONS: These results provide evidence for host-pathogen co-evolution in TB, consistent with our previous work, and indicate these interactions involve genes highly relevant to the host immune response to Mycobacterium infection.

GWAS↗
PubMed2007

Epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thereby risk for arterial thrombosis. Activation of the renin-angiotensin system has been linked to the production of PAI-1 expression via the angiotensin II type 1 receptor (AT1R). In addition, bradykinin can induce the release of t-PA through a B2 receptor mechanism. In the present study, we aimed to investigate the epistatic effects of polymorphisms in genes from the renin-angiotensin, bradykinin, and fibrinolytic systems on plasma t-PA and PAI-1 levels in a large population-based sample (n=2527). We demonstrated a strong significant interaction within genetic variations of the bradykinin B2 gene (P=0.002) and between ACE and bradykinin B2 (p=0.003) polymorphisms on t-PA levels in females. In males, polymorphisms in the bradykinin B2 and AT1R gene showed the most strong effect on t-PA levels (P=0.006). In both females and males, the bradykinin B2 gene interacted with AT1R gene on plasma PAI-1 levels (P=0.026 and P=0.039, respectively). In addition, the current study found a borderline significant interaction between PAI 4G5G and ACE I/D on plasma t-PA and PAI-1 levels. These results support the idea that the interplay between the renin-angiotensin, bradykinin, and fibrinolytic systems might play an important role in t-PA and PAI-1 biology.

Bradykinin↗
PubMed2006

Ethnic differences in key candidate genes for spontaneous preterm birth: TNF-alpha and its receptors.

OBJECTIVES: Spontaneous preterm birth (PTB) has a significant ethnic disparity with people of African descent having an almost 2-fold higher incidence than those of European descent in the United States. This disparity may be caused by differences in the distribution of genetic risk factors. The objective of this study is to examine genetic differences between African-Americans and European Americans for single nucleotide polymorphisms (SNPs) in candidate genes for PTB. METHODS: We examined patterns of variation in 19 SNPs in 3 candidate genes for preterm birth: TNF-alpha, TNF-receptor 1 and TNF-receptor 2. Allele, genotype and haplotype frequencies were compared between African-Americans (AA) and European-Americans (EA) in cases and controls separately. Both maternal and fetal genotypes were studied, as it is unclear whether one or both of these are important in the etiology of PTB. RESULTS: The vast majority of the SNPs differed significantly between ethnic groups, although there are only a few suggestive results comparing cases and controls within an ethnic group. For TNF-alpha, four of six SNPs; for TNF-R1, 5/6; and for TNF-R2, 6/7 showed significant differences between ethnic groups in either allele and/or genotype frequency. CONCLUSIONS: Our data demonstrate highly significant genetic differences between ethnic groups in genes that may play a role in the risk of PTB.

Adolescent↗
PubMed2006

Elevated male European and female African contributions to the genomes of African American individuals.

The differential relative contribution of males and females from Africa and Europe to individual African American genomes is relevant to mapping genes utilizing admixture analysis. The assessment of ancestral population contributions to the four types of genomic DNA (autosomes, X and Y chromosomes, and mitochondrial) with their differing modes of inheritance is most easily addressed in males. A thorough evaluation of 93 African American males for 2,018 autosomal single nucleotide polymorphic (SNP) markers, 121 X chromosome SNPs, 10 Y chromosome haplogroups specified by SNPs, and six haplogroup defining mtDNA SNPs is presented. A distinct lack of correlation observed between the X chromosome and the autosomal admixture fractions supports separate treatment of these chromosomes in admixture-based gene mapping applications. The European genetic contributions were highest (and African lowest) for the Y chromosome (28.46%), followed by the autosomes (19.99%), then the X chromosome (12.11%), and the mtDNA (8.51%). The relative order of admixture fractions in the genomic compartments validates previous studies that suggested sex-biased gene flow with elevated European male and African female contributions. There is a threefold higher European male contribution compared with European females (Y chromosome vs. mtDNA) to the genomes of African American individuals meaning that admixture-based gene discovery will have the most power for the autosomes and will be more limited for X chromosome analysis.

Black or African American↗
PubMed2006

Variations in the alpha2A-adrenergic receptor gene and their functional effects.

BACKGROUND AND OBJECTIVES: The alpha2A-adrenergic receptor (ADRA2A) plays a central role in the regulation of systemic sympathetic activity and hence cardiovascular responses such as heart rate and blood pressure. The objectives of this study were to systematically search for variants in the ADRA2A gene, to define the gene's haplotype structure, and to examine potential functional effects of these variants. METHODS: We examined 5957 base pairs of contiguous sequence of ADRA2A (promoter, exonic, and 3'-flanking region) using polymerase chain reaction to amplify the genomic target, followed by bidirectional sequencing, in 135 healthy subjects (85 white and 50 black subjects). Haplotypes were inferred by use of an expectation-maximization algorithm. Primary (plasma norepinephrine concentration) and secondary (resting heart rate and blood pressure) phenotypes were compared among subjects grouped by individual polymorphisms and haplotypes. RESULTS: We identified 41 variants, including 24 novel variants. On the basis of 9 optimally selected markers, 11 haplotypes in 5 haplotype groups were inferred, representing approximately 99% of the cohort. Two uncommon variants in complete linkage disequilibrium (G>C at -1903 and C>G at -1607, identified in 3 black subjects) were associated with significantly increased plasma norepinephrine concentrations (376.7 +/- 6.1 pg/mL versus 218.4 +/- 95.0 pg/mL, P = .011). There was no other significant association between genetic variants or any of the haplotypes with phenotypes. CONCLUSION: We describe novel variants and the haplotype structure of the ADRA2A gene. Common genetic ADRA2A variants are not important determinants of baseline cardiovascular measures (plasma norepinephrine, heart rate, and blood pressure) in healthy volunteers.

Adult↗
PubMed2006

Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension.

BACKGROUND: Salt-sensitive (SS) hypertension affects >30 million Americans and is often associated with low plasma renin activity. We tested the diagnostic validity of several candidate genes for SS and low-renin hypertension. METHODS: In Japanese patients with newly diagnosed, untreated hypertension (n = 184), we studied polymorphisms in 10 genes, including G protein-coupled receptor kinase type 4 (GRK4), some variations of which are associated with hypertension and impair D1 receptor (D1R)-inhibited renal sodium transport. We used the multifactor dimensionality reduction method to determine the genotype associated with salt sensitivity (> or =10% increase in blood pressure with high sodium intake) or low renin. To determine whether the GRK4 genotype is associated with impaired D1R function, we tested the natriuretic effect of docarpamine, a dopamine prodrug, in normotensive individuals with or without GRK4 polymorphisms (n = 18). RESULTS: A genetic model based on GRK4 R65L, GRK4 A142V, and GRK4 A486V was 94.4% predictive of SS hypertension, whereas the single-locus model with only GRK4 A142V was 78.4% predictive, and a 2-locus model of GRK4 A142V and CYP11B2 C-344T was 77.8% predictive of low-renin hypertension. Sodium excretion was inversely related to the number of GRK4 variants in hypertensive persons, and the natriuretic response to dopaminergic stimulation was impaired in normotensive persons having > or =3 GRK4 gene variants. CONCLUSIONS: GRK4 gene variants are associated with SS and low-renin hypertension. However, the genetic model predicting SS hypertension is different from the model for low renin, suggesting genetic differences in these 2 phenotypes. Like low-renin testing, screening for GRK4 variants may be a useful diagnostic adjunct for detection of SS hypertension.

Asian People↗
PubMed2006

Multilocus interactions at maternal tumor necrosis factor-alpha, tumor necrosis factor receptors, interleukin-6 and interleukin-6 receptor genes predict spontaneous preterm labor in European-American women.

OBJECTIVE: We hypothesize that genetic variations (single nucleotide polymorphisms-SNPs) in the tumor necrosis factor-alpha (TNF-alpha), TNF receptors (TNFRI and TNFRII), interleukin-6 (IL-6) and IL-6 receptor (IL-6R) genes predict high-risk status for spontaneous preterm birth (sPTB) in European-American women. In this study we examine the allelic and genotypic variations and the gene-gene interactions in the TNF-alpha, TNFRs, IL-6, and IL-6R genes in maternal DNA samples by using a case-control model. STUDY DESIGN: Maternal DNA from cases of sPTB after preterm labor (n = 101) and controls (normal term labor and delivery) (n = 321) were genotyped for SNPs in the TNF-alpha (6), TNFRI (6), TNFRII (7), IL-6 (5), and IL-6R (3) loci. SNPs were tested for both allele and genotype differences (cases vs controls) with the use of standard genetic epidemiologic methods. Multilocus interaction was assessed with multifactor dimensionality reduction analysis (MDR) to test all single and multilocus combinations for the ability to predict sPTB. RESULTS: Few significant allelic and genotypic associations were detected between cases and controls in maternal DNA. Single locus analysis documented independent association of SNPs at -7294 (allele and genotype) of TNFRI and 24660 (genotype) TNFRII loci with sPTB. MDR revealed a significant 3 locus model that includes SNPs -3448 of TNF-alpha, -7227 of IL-6, and 33314 of IL-6R. This interactive model allowed the successful prediction of pre- to low-risk genotypes is 3.50 (95% CI 2.52-4.87, P < .001). CONCLUSION: This is the first report to document a multilocus interaction in sPTB that predicts 65.2% of the cases in a European-American sample. Although putatively significant associations with sPTB were seen at a few single locus sites in TNFRI and TNFRII, they were not as predictive as the 3-locus model produced by MDR, suggesting the use of multilocus analyses in gene association studies of complex disease such as sPTB.

Adult↗
PubMed2006

Angiotensinogen promoter sequence variants in essential hypertension.

BACKGROUND: Essential hypertension is a complex multifactorial disease caused by ill-defined genetic factors. The angiotensinogen (AGT) gene has been implicated as a risk factor in essential hypertension. METHODS: To assess the role of AGT in hypertension, we evaluated two polymorphisms (A-6G and C-20A) in the 5' region of the gene that have been shown to have a role in transcriptional regulation. A total of 463 subjects were studied: 243 African Americans (26 male and 34 female normotensives, 66 male and 117 female hypertensives) and 220 whites (35 male and 60 female normotensives, 55 male and 70 female hypertensives). African American and white subjects were examined individually, as significant differences in allele and genotype frequencies were observed between these two cohorts. RESULTS: White female hypertensives and normotensives differed significantly in genotype frequency at C-20A (P = .02). No other single site comparisons were significantly different between hypertensives and normotensives in either the white or African American samples. Haplotype frequencies in white males also differed significantly between phenotypic classes (P = .05). To evaluate the data further, we assessed all polymorphic sites simultaneously by the examination of multisite interaction and determined the single best genetic model for each population. A model that included both sites and gender correctly predicted hypertension status in the white population 59.1% of the time (P = .039). The model generated for the African American population was not significant. CONCLUSIONS: Our results suggest that a complex set of genetic factors interact with gender to predispose whites to hypertension.

Adenine↗
PubMed2006

Interaction among 5,10 methylenetetrahydrofolate reductase, plasminogen activator inhibitor and endothelial nitric oxide synthase gene polymorphisms predicts the severity of coronary artery disease in Turkish patients.

BACKGROUND: Genetic factors play a role in the onset of coronary artery disease. The objective of our study is to evaluate the single locus and combined effects of three different genetic polymorphisms (methylenetetrahydrofolate reductase C677T polymorphism, plasminogen activator inhibitor 4G/5G polymorphism, and endothelial nitric oxide synthase 3-27 base pairs repeat polymorphism) on the presence and extent of coronary artery disease in patients with early-onset coronary artery disease. MATERIALS AND METHODS: DNA samples were obtained from 102 consecutive patients with symptoms resulting from early-onset coronary artery disease documented by coronary angiography. The severity of coronary artery disease in patients was stratified into three groups as one, two, or three-vessel coronary artery disease. The control group was selected from older subjects with a recent and negative cardiac work-up. Information on standard risk factors was collected. Multifactor dimensionality reduction analysis was performed to seek a model of coronary artery disease based on these three genetic polymorphisms. RESULTS: Single-locus effects of the three polymorphisms were not significantly related to the presence or severity of coronary artery disease. When gene-gene interactions were studied, however, the severity of disease was related to the frequency of high-risk alleles, yet advanced analysis did not detect a significant genetic model for coronary artery disease in these patients based on these three genetic polymorphisms. CONCLUSION: These three genetic polymorphisms are susceptibility loci and genotypes of these genes are neither necessary nor sufficient for the coronary artery disease to occur, but coexistence of high-risk alleles may increase the severity of coronary artery disease.

Alleles↗
PubMed2006

Genomics, nutrition, obesity, and diabetes.

PURPOSE: To present evidence of genetic and environmental interactions as they relate to nutrition, diabetes, and obesity. METHODS: A review of seminal literature related to genetics, obesity, and diabetes. FINDINGS: Multifactorial interactions are important in the development of nutrition-related disorders, but the challenge remains to explain how these interactions are expressed. Treating subpopulations of people might be important and useful to some extent at present, but in the future treating people of given genetic predispositions and other personal and environmental factors will have greater effects on quality-of-life indicators and life expectancies. CONCLUSIONS: Individualization coupled with multifactorial interactions will lead to new and more effective preventive and treatment modalities of nutrition-related disorders. With obesity and diabetes, genomics will bridge the traditional use of diet, exercise, and weight reduction with other environmental factors, ultimately leading to healthier lives.

Diabetes Mellitus↗
PubMed2006

Potential differences in breast cancer risk factors based on CYP1A1 MspI and African-American-specific genotypes.

OBJECTIVES: Recent studies show that an Mspl polymorphism in the 3'-noncoding region of the CYP1A1 gene is associated with breast cancer in African-American women but not in Caucasian women. In addition, an African-American-specific (AAS) polymorphism is located in intron 7 of this gene. We hypothesized that the AAS polymorphism may partially account for this race-specific association and that different environmental risk factor profiles are a function of genotype status. We studied both CYP1A1 polymorphisms to determine if African-American women with these variants have breast cancer risk factor profiles that are different from those of other African-American women. METHODS: A case-control analysis was conducted. Cases were 304 African-American patients pathologically diagnosed with breast cancer from 1995 to 1998 who lived in three Tennessee counties. Controls were 305 African-American women without breast cancer, selected through random-digit dialing and frequency matched to cases by age and county. Information on risk factors was collected through telephone interviews. Tumor tissue samples were collected for CYP1A1 genotyping. There were 215 and 188 cases with the Mspl and AAS polymorphisms measured respectively. RESULTS: Our study results suggest that some risk factors for breast cancer are dependent upon CYP1A1 genotype. Specifically, low intakes of folate, methionine, vitamin C, and vitamin E appear to increase the risk of breast cancer in individuals with the AAS variant: the odds ratio (OR) estimates and 95% confidence intervals were 2.10 and 0.99-4.44 for folate, 1.96 and 0.91-4.23 for methionine, 2.13 and 1.00-4.53 for vitamin C, and 2.43 and 1.12-5.25 for vitamin E. Such associations are stronger for tumors with both AAS and MspI polymorphisms: the OR estimates increased to >6.00 for all these variables except for vitamin C. CONCLUSIONS: This study found that methyl-deficient diets and antioxidant vitamins may be related to the risk of breast cancer as a function of the Mspl and AAS genotpyes. Our results are preliminary because of a small number of cases with polymorphisms at both sites, but they indicate the need for large-scale epidemiologic studies of both African-American and Caucasian women that include genotype information from controls with more detailed information on risk factors.

Adult↗
PubMed2006

The gender-specific role of polymorphisms from the fibrinolytic, renin-angiotensin, and bradykinin systems in determining plasma t-PA and PAI-1 levels.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) directly influence thrombus formation and degradation and thus risk for arterial thrombosis. We report here results from a genetic analysis of plasma t-PA and PAI-1 levels in a large population-based sample from the PREVEND study in Groningen, the Netherlands (n = 2,527). We measured polymorphisms from genes of the fibrinolytic system, the renin-angiotensin system (RAS), and the bradykinin system. We found that males had higher levels of natural-log transformed t-PA, and PAI-1 (P < 0.01) compared to females. When stratifying females by menopausal status, PAI-1 levels were only significantly different between pre-menopausal females and males (p < 0.001). Furthermore, we found that age, body mass index, and waist-to-hip ratio were significant predictors of t-PA and PAI-1 in both females and males, and that the regression relationships between these factors and plasma t-PA and PAI-1 were dependent on gender. In addition, we found that the PAI-1 4G/5G polymorphism was a significant predictor of PAI-1 levels in both females and males, that the angiotensin II type I receptor A1166C was a significant predictor of t-PA and PAI-1 levels in females, and that the bradykinin receptor B2 58CT polymorphism was a significant predictor of t-PA levels in females. In conclusion, this large population-based study showed that t-PA and PAI-1 levels are determined by several demographic and genetic factors involved in the fibrinolytic, RAS and bradykinin system. In addition, the results support the idea that the biology of t-PA and PAI-1 is different between females and males.

Adult↗
PubMed2006

Data simulation software for whole-genome association and other studies in human genetics.

Genome-wide association studies have become a reality in the study of the genetics of complex disease. This technology provides a wealth of genomic information on patient samples, from which we hope to learn novel biology and detect important genetic and environmental factors for disease processes. Because strategies for analyzing these data have not kept pace with the laboratory methods that generate the data it is unlikely that these advances will immediately lead to an improved understanding of the genetic contribution to common human disease and drug response. Currently, no single analytical method will allow us to extract all information from a whole-genome association study. Thus, many novel methods are being proposed and developed. It will be vital for the success of these new methods, to have the ability to simulate datasets consisting of polymorphisms throughout the genome with realistic linkage disequilibrium patterns. Within these datasets, we can embed genetic models of disease whereby we can evaluate the ability of novel methods to detect these simulated effects. This paper describes a new software package, genomeSIM, for the simulation of large-scale genomic data in population based case-control samples. It allows for single SNP, as well as gene-gene interaction models to be associated with disease risk. We describe the algorithm and demonstrate its utility for future genetic studies of whole-genome association.

Algorithms↗
PubMed2005

Endothelial NO synthase polymorphisms and postural tachycardia syndrome.

Postural tachycardia syndrome (POTS) is a heterogeneous disorder characterized by an excessive rise in heart rate and symptoms consistent with cerebral hypoperfusion in the upright position. NO produced by endothelial NO synthase is a significant factor in the regulation of blood flow. Genetic polymorphisms in the promoter region (T-786C) and exon 7 (E298D) of the NO synthase isoform 3 gene affect enzyme activity and have been associated with a number of cardiovascular diseases. Because some findings in POTS suggest aberrant NO-mediated functions, we postulated that the variant genotypes of these polymorphisms may increase the risk of developing POTS and correlate with more severe symptoms. We genotyped 136 patients with POTS (mean age 32.2+/-9.9 years; 46 men and 90 women) from Nashville, Tenn, and Vienna, Austria, and compared them with 191 healthy volunteers (mean age 29.1+/-8.0 years; 127 men and 64 women). Participants also underwent orthostatic testing with blood pressure, heart rate, and plasma norepinephrine measurements while supine and upright. The frequencies of the -786CC and 298DD genotypes were significantly lower in patients with POTS than in control subjects (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.14 to 0.57; P=0.001 for -786CC; and OR, 0.44; 95% CI, 0.21 to 0.91; P=0.033 for 298DD). According to 2-locus genotype analyses, patients with -786CC and 298EE or 298ED experienced the largest changes in heart rate and plasma norepinephrine with standing. These results indicate that NO may influence the development of POTS and the severity of POTS symptoms.

Adolescent↗
PubMed2005

Susceptibility and modifier genes in Portuguese transthyretin V30M amyloid polyneuropathy: complexity in a single-gene disease.

Familial amyloid polyneuropathy type I is an autosomal dominant disorder caused by mutations in the transthyretin (TTR) gene; however, carriers of the same mutation exhibit variability in penetrance and clinical expression. We analyzed alleles of candidate genes encoding non-fibrillar components of TTR amyloid deposits and a molecule metabolically interacting with TTR [retinol-binding protein (RBP)], for possible associations with age of disease onset and/or susceptibility in a Portuguese population sample with the TTR V30M mutation and unrelated controls. We show that the V30M carriers represent a distinct subset of the Portuguese population. Estimates of genetic distance indicated that the controls and the classical-onset group were furthest apart, whereas the late-onset group appeared to differ from both. Importantly, the data also indicate that genetic interactions among the multiple loci evaluated, rather than single-locus effects, are more likely to determine differences in the age of disease onset. Multifactor dimensionality reduction indicated that the best genetic model for classical onset group versus controls involved the APCS gene, whereas for late-onset cases, one APCS variant (APCSv1) and two RBP variants (RBPv1 and RBPv2) are involved. Thus, although the TTR V30M mutation is required for the disease in Portuguese patients, different genetic factors may govern the age of onset, as well as the occurrence of anticipation.

Adult↗
PubMed2005

Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis.

Epistasis plays an important role in the genetic architecture of common human diseases and can be viewed from two perspectives, biological and statistical, each derived from and leading to different assumptions and research strategies. Biological epistasis is the result of physical interactions among biomolecules within gene regulatory networks and biochemical pathways in an individual such that the effect of a gene on a phenotype is dependent on one or more other genes. In contrast, statistical epistasis is defined as deviation from additivity in a mathematical model summarizing the relationship between multilocus genotypes and phenotypic variation in a population. The goal of this essay is to review definitions and examples of biological and statistical epistasis and to explore the relationship between the two. Specifically, we present and discuss the following two questions in the context of human health and disease. First, when does statistical evidence of epistasis in human populations imply underlying biomolecular interactions in the etiology of disease? Second, when do biomolecular interactions produce patterns of statistical epistasis in human populations? Answers to these two reciprocal questions will provide an important framework for using genetic information to improve our ability to diagnose, prevent and treat common human diseases. We propose that systems biology will provide the necessary information for addressing these questions and that model systems such as bacteria, yeast and digital organisms will be a useful place to start.

Animals↗
PubMed2005

Variation in the alpha2B-adrenergic receptor gene (ADRA2B) and its relationship to vascular response in vivo.

The alpha2B-adrenergic receptor (ADRA2B) plays an important role in vasoconstriction and blood pressure regulation. One common variant in the ADRA2B gene (del 301--303) has been identified, and results in markedly decreased receptor desensitization in vitro but does not alter vascular sensitivity in vivo. Therefore, we fully characterized genetic variations in ADRA2B and related them to phenotype in vivo. We examined 5812 bp of contiguous sequence of ADRA2B (promoter, exonic, and 3'-untranslated region; 3'-UTR) using the polymerase chain reaction to amplify the genomic target followed by bidirectional sequencing (n=68). Haplotypes were inferred using an expectation maximization algorithm. Vasoconstriction in response to increasing doses of the highly selective alpha2-adrenergic receptor agonist, dexmedetomidine (0.01--1000 ng/min) was measured in the dorsal hand vein using a linear variable differential transformer. The dose that produced 50% (ED50) of maximum venoconstriction (Emax) was determined for each subject from the individual dose--response curves. ED50 and Emax were compared in subjects with and without variant alleles and haplotypes of interest. We identified 24 variable sites, 12 in the promoter region, five in the coding region (including two previously described as non-synonymous variants) and seven in the 3'-UTR region. Four haplotypes were inferred, representing approximately 95% of the cohort. One haplotype, characterized by two single nucleotide polymorphisms in the promoter region, and one in the 3'-UTR, occurred in seven of 38 African-Americans, and was associated with a lower Emax, 61.3% [95% confidence interval (CI) 39.5--83.0, n=7] compared to 78.1% (CI 73.8--82.5) in wild-types (n=61) (P=0.02). There was no association between the nine common variants and dexmedetomidine ED50. We have described novel variants and haplotypes of the ADRA2B gene. These do not alter sensitivity to a selective alpha2-adrenergic receptor agonist but some may decrease maximal venoconstriction in vivo.

Adolescent↗