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A genome-wide association study identifies risk loci for spirometric measures among smokers of European and African ancestry.
Lutz, SM, Cho, MH, Young, K, Hersh, CP, Castaldi, PJ, McDonald, ML, Regan, E, Mattheisen, M, DeMeo, DL, Parker, M, et al
BMC genetics. 2015;:138
Abstract
BACKGROUND Pulmonary function decline is a major contributor to morbidity and mortality among smokers. Post bronchodilator FEV1 and FEV1/FVC ratio are considered the standard assessment of airflow obstruction. We performed a genome-wide association study (GWAS) in 9919 current and former smokers in the COPDGene study (6659 non-Hispanic Whites [NHW] and 3260 African Americans [AA]) to identify associations with spirometric measures (post-bronchodilator FEV1 and FEV1/FVC). We also conducted meta-analysis of FEV1 and FEV1/FVC GWAS in the COPDGene, ECLIPSE, and GenKOLS cohorts (total n = 13,532). RESULTS Among NHW in the COPDGene cohort, both measures of pulmonary function were significantly associated with SNPs at the 15q25 locus [containing CHRNA3/5, AGPHD1, IREB2, CHRNB4] (lowest p-value = 2.17 × 10(-11)), and FEV1/FVC was associated with a genomic region on chromosome 4 [upstream of HHIP] (lowest p-value = 5.94 × 10(-10)); both regions have been previously associated with COPD. For the meta-analysis, in addition to confirming associations to the regions near CHRNA3/5 and HHIP, genome-wide significant associations were identified for FEV1 on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 9 [DBH] (p-value = 9.69 × 10(-9)) and 19 [CYP2A6/7] (p-value = 3.49 × 10(-8)) and for FEV1/FVC on chromosome 1 [TGFB2] (p-value = 8.99 × 10(-9)), 4 [FAM13A] (p-value = 3.88 × 10(-12)), 11 [MMP3/12] (p-value = 3.29 × 10(-10)) and 14 [RIN3] (p-value = 5.64 × 10(-9)). CONCLUSIONS In a large genome-wide association study of lung function in smokers, we found genome-wide significant associations at several previously described loci with lung function or COPD. We additionally identified a novel genome-wide significant locus with FEV1 on chromosome 9 [DBH] in a meta-analysis of three study populations.
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Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans.
Tang, W, Cushman, M, Green, D, Rich, SS, Lange, LA, Yang, Q, Tracy, RP, Tofler, GH, Basu, S, Wilson, JG, et al
American journal of hematology. 2015;(6):534-40
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Abstract
Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII C) and VWF antigen (VWF :Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, Ile581Thr, P = 5.10 × 10(-7) in EAs and P = 3.88 × 10(-3) in AAs) and VWF rs7962217 (Gly2705Arg,P = 6.30 × 10(-9) in EAs and P = 2.98 × 10(-2) in AAs. Significant associations for FVIII C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P = 8.02 × 10(-10) ), with VWF rs1800380 in AAs (P = 5.62 × 10(-11) ), and with MAT1A rs2236568 in AAs (P51.69 × 10(-6) ). We replicated previously reported associations of FVIII C and VWF Ag with the ABO blood group, VWF rs1063856(Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII C and VWF Ag in both EAs and AAs.
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Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease.
Yu, B, Li, AH, Muzny, D, Veeraraghavan, N, de Vries, PS, Bis, JC, Musani, SK, Alexander, D, Morrison, AC, Franco, OH, et al
Circulation. Cardiovascular genetics. 2015;(2):351-5
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BACKGROUND Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample. METHODS AND RESULTS By conducting whole exome sequencing on 1152 African Americans in the Atherosclerosis Risk in Communities (ARIC) study and focusing on loss-of-function (LoF) variants, we identified 3 novel rare LoF variants in HAL, a gene that encodes histidine ammonia-lyase in the first step of histidine catabolism. These LoF variants had large effects on blood histidine levels (β=0.26; P=1.2×10(-13)). The positive association with histidine levels was replicated by genotyping an independent sample of 718 ARIC African Americans (minor allele frequency=1%; P=1.2×10(-4)). In addition, high blood histidine levels were associated with reduced risk of developing incident CHD with an average of 21.5 years of follow-up among African Americans (hazard ratio=0.18; P=1.9×10(-4)). This finding was validated in an independent sample of European Americans from the Framingham Heart Study (FHS) Offspring Cohort. However, LoF variants in HAL were not directly significantly associated with incident CHD after meta-analyzing results from the CHARGE Consortium. CONCLUSIONS Three LoF mutations in HAL were associated with increased histidine levels, which in turn were shown to be inversely related to the risk of CHD among both African Americans and European Americans. Future investigations on the association between HAL gene variation and CHD are warranted.
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Evidence for threshold effects of 25-hydroxyvitamin D on glucose tolerance and insulin resistance in black and white obese postmenopausal women.
Sorkin, JD, Vasaitis, TS, Streeten, E, Ryan, AS, Goldberg, AP
The Journal of nutrition. 2014;(5):734-42
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We identified normal vs. abnormal 25-hydroxyvitamin D [25(OH)D] concentrations by examining the relation of 25(OH)D to non-bone-related measures (plasma glucose, insulin resistance, lipids, blood pressure, fitness, obesity, and regional adiposity) and asking whether there is a 25(OH)D concentration above and below which the relation between 25(OH)D and outcome changes. We examined the relation between 25(OH)D and outcome by race to see whether race-specific normal ranges are needed, and we examined the role of insulin-like growth factor-1 (IGF-1) in modulating the relation between 25(OH)D and outcome. In a cross-sectional study of 239 overweight and obese, sedentary postmenopausal women without diabetes (83 black, 156 white), outcome measures included plasma lipids, glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), IGF-1, parathyroid hormone (PTH), aerobic fitness, body composition, subcutaneous abdominal and visceral fat, and blood pressure. We identified threshold effects in the association between 25(OH)D and these variables using piecewise linear regressions. We found that 25(OH)D was inversely related to fasting glucose, fasting and 2-h insulin, HOMA-IR, visceral abdominal fat, percentage fat, PTH, and triglycerides. Evidence for a threshold effect of 25(OH)D was found for 2-h glucose, 2-h insulin, fasting insulin, and HOMA-IR. There was no evidence suggesting the need for race-specific normal 25(OH)D concentrations. IGF-1 modulated the relation between 25(OH)D and outcome but only below, and not above, a threshold 25(OH)D concentration. Our findings suggest a threshold effect of 25(OH)D on glucose-insulin metabolism such that 25(OH)D ≥ ∼26 μg/L (65.0 pmol/L) supports normal glucose homeostasis and that the same cut point defining normal 25(OH)D concentration can be used in black and white women. This study was registered at clinicaltrials.gov as NCT01798030.
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CYP3A4*22 and CYP3A5*3 are associated with increased levels of plasma simvastatin concentrations in the cholesterol and pharmacogenetics study cohort.
Kitzmiller, JP, Luzum, JA, Baldassarre, D, Krauss, RM, Medina, MW
Pharmacogenetics and genomics. 2014;(10):486-91
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OBJECTIVE Simvastatin is primarily metabolized by CYP3A4. A combined CYP3A4/5 genotype classification, combining the decrease-of-function CYP3A4*22 and the loss-of-function CYP3A5*3, has recently been reported. We aim to determine whether CYP3A4*22 and CYP3A5*3 alleles are associated with increased plasma concentrations of simvastatin lactone (SV) and simvastatin acid (SVA). This is the first report evaluating associations between in-vivo simvastatin concentrations and CYP3A4*22, alone or in a combined CYP3A4/5 genotype-defined classification. PARTICIPANTS AND METHODS Genotypes and simvastatin concentrations were determined for 830 participants (555 Whites and 275 African-Americans) in the Cholesterol and Pharmacogenomics clinical trial with 40 mg/day simvastatin for 6 weeks. Concentrations were determined in 12-h postdose samples. Associations between simvastatin concentrations and CYP3A4*22 and CYP3A5*3 alleles were tested separately and in a combined CYP3A4/5 genotype-defined classification system. RESULTS In Whites, CYP3A4*22 carriers (n=42) had 14% higher SVA (P=0.04) and 20% higher SV (P=0.06) compared with noncarriers (n=513). CYP3A5*3 allele status was not significantly associated with SV or SVA in Whites. In African-Americans, CYP3A4*22 carriers (n=8) had 170% higher SV (P<0.01) than noncarriers (n=267), but no significant difference was detected for SVA. African-American CYP3A5 nonexpressors (n=28) had 33% higher SV (P=0.02) than CYP3A5 expressors (n=247), but no significant difference was detected for SVA. For both races, SV appeared to decrease across the rank-ordered combined CYP3A4/5 genotype-defined groups (poor, intermediate, and extensive metabolizers); however, similar trends were not observed for SVA. CONCLUSION Genetic variation in CYP3A4 was associated with plasma simvastatin concentrations in self-reported Whites. Genetic variations in CYP3A4 and CYP3A5 were associated with plasma simvastatin concentrations in self-reported African-Americans.
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Common genetic variants associated with resting oxygenation in chronic obstructive pulmonary disease.
McDonald, ML, Cho, MH, Sørheim, IC, Lutz, SM, Castaldi, PJ, Lomas, DA, Coxson, HO, Edwards, LD, MacNee, W, Vestbo, J, et al
American journal of respiratory cell and molecular biology. 2014;(5):678-87
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Hypoxemia is a major complication of chronic obstructive pulmonary disease (COPD) that correlates with disease prognosis. Identifying genetic variants associated with oxygenation may provide clues for deciphering the heterogeneity in prognosis among patients with COPD. However, previous genetic studies have been restricted to investigating COPD candidate genes for association with hypoxemia. To report results from the first genome-wide association study (GWAS) of resting oxygen saturation (as measured by pulse oximetry [Spo2]) in subjects with COPD, we performed a GWAS of Spo2 in two large, well characterized COPD populations: COPDGene, including both the non-Hispanic white (NHW) and African American (AA) groups, and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We identified several suggestive loci (P < 1 × 10(-5)) associated with Spo2 in COPDGene in the NHW (n = 2810) and ECLIPSE (n = 1758) groups, and two loci on chromosomes 14 and 15 in the AA group (n = 820) from COPDGene achieving a level of genome-wide significance (P < 5 × 10(-8)). The chromosome 14 single-nucleotide polymorphism, rs6576132, located in an intergenic region, was nominally replicated (P < 0.05) in the NHW group from COPDGene. The chromosome 15 single-nucleotide polymorphisms were rare in subjects of European ancestry, so the results could not be replicated. The chromosome 15 region contains several genes, including TICRR and KIF7, and is proximal to RHCG (Rh family C glyocoprotein gene). We have identified two loci associated with resting oxygen saturation in AA subjects with COPD, and several suggestive regions in subjects of European descent with COPD. Our study highlights the importance of investigating the genetics of complex traits in different racial groups.
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Clinical utility of visceral adipose tissue for the identification of cardiometabolic risk in white and African American adults.
Katzmarzyk, PT, Heymsfield, SB, Bouchard, C
The American journal of clinical nutrition. 2013;(3):480-6
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BACKGROUND Visceral adipose tissue (VAT) has been identified as a harmful fat depot, and sex and race differences in VAT have been reported in white and African Americans. OBJECTIVES We determined the clinical utility of VAT in the identification of individuals at elevated cardiometabolic risk in white and African American adults and compared the clinical utility with measures obtained by using dual-energy X-ray absorptiometry (DXA) and anthropometric measures. DESIGN The sample included 429 white women, 311 African American women, 406 white men, and 100 African American men who were 18-74 y of age. VAT was measured by using computed tomography, fat mass (FM) and percentage of body fat were measured by using DXA, and waist circumference (WC) and BMI were assessed. Receiver operating characteristic curves were used to compare the utility of measures in the identification of participants in the upper quintile of a continuous score derived from principal components analysis of fasting glucose, HDL cholesterol, triglycerides, and blood pressure. RESULTS The clinical utility of measures varied across sex-by-race groups. In the overall sample, the areas under the curve were significantly higher for VAT and WC in comparison with the other indicators. Identified VAT thresholds were higher in white men (140 cm(2)) and women (141 cm(2)) than in African American men (82 cm(2)) and women (97 cm(2)). CONCLUSIONS VAT and WC showed greater clinical utility than did other obesity measures. Because of the complexity of measuring VAT, the use of WC is recommended for the identification of adults with elevated cardiometabolic risk factors. The Pennington Center Longitudinal Study was registered at clinicaltrials.gov as NCT00959270.
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Loss of control eating in African-American and Caucasian youth.
Cassidy, OL, Matheson, B, Osborn, R, Vannucci, A, Kozlosky, M, Shomaker, LB, Yanovski, SZ, Tanofsky-Kraff, M
Eating behaviors. 2012;(2):174-8
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Loss of control (LOC) eating, a disinhibited eating behavior shown to predict excessive weight gain in youth, has been reported by African-American children and adolescents. Yet, little is known about how LOC-eating manifests in this population. To investigate potential racial differences in LOC-eating, the Eating Disorder Examination was administered to 185 non-Hispanic African-American and Caucasian youth ages 8-17 y. Objective eating was assessed at two test meals during which youth ate ad libitum from a multi-item lunchtime food array. African-American and Caucasian youth reported a similar prevalence of LOC episodes (24.2% vs. 28.9%, p=.75). Yet, accounting for sex, age, fat-free mass, percent fat mass, height, and socioeconomic status, African-Americans consumed more total energy at both laboratory meals (1608±57 kcal vs. 1362±44 kcal; p<.001). Furthermore, African-American youth reporting LOC consumed the most total energy across both meals (1855±104 kcal) compared to African-Americans without LOC (1524±60 kcal), Caucasians with LOC (1278±68 kcal), and Caucasians without LOC (1399±46 kcal; p<.001). Future research is required to examine whether LOC-eating contributes to the high rates of obesity in African-American youth.
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Predictors of long-term weight loss in adults with modest initial weight loss, by sex and race.
Svetkey, LP, Ard, JD, Stevens, VJ, Loria, CM, Young, DY, Hollis, JF, Appel, LJ, Brantley, PJ, Kennedy, BM, Kumanyika, SK, et al
Obesity (Silver Spring, Md.). 2012;(9):1820-8
Abstract
Effective weight management interventions could reduce race-sex disparities in cardiovascular disease (CVD), yet little is known about factors associated with successful weight loss maintenance in race-sex subgroups. In the Weight Loss Maintenance trial (WLM), overweight/obese (BMI 25-45 kg/m(2)) adults who lost ≥4 kg in a 6-month behavioral weight loss intervention (phase I) were randomized into one of three 30-month maintenance interventions (phase II). To investigate predictors in subgroups, randomized groups were combined for this analysis. Of 1,685 phase I participants, 1,032 (61%) entered phase II, including 12% black men (BM), 26% black women (BW), 25% white men (WM), and 37% white women (WW). Weight change over the 36-month study ranged from -2.3% (95% confidence interval = -3.1 to -1.5%) in BW to -4.5% (95% confidence interval = -5.7 to -4.0%) in WM, the result of differential weight loss during phase I. Within race, men lost significantly more weight than women, but within sex group, weight loss did not differ significantly between races. Although participants regained weight during phase II, regain did not differ by race-sex group, and mean weight at the end of the study was significantly lower than phase I entry weight for each subgroup. In regression models, phase I weight loss predicted overall 36-month weight loss in all race-sex groups. Healthy dietary pattern at entry, improvement in dietary pattern, or both were predictive in three of four race-sex groups. Few other variables other than initial weight loss and dietary pattern were predictive. Future research should identify additional modifiable influences on long-term maintenance after a modest weight loss.
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Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African-American and European-American patients on warfarin.
Limdi, NA, McGwin, G, Goldstein, JA, Beasley, TM, Arnett, DK, Adler, BK, Baird, MF, Acton, RT
Clinical pharmacology and therapeutics. 2008;(2):312-21
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The association of CYP2C9 and VKORC1 1173C/T genotype and risk of hemorrhage among African Americans and European Americans is presented. This association was evaluated using Cox proportional hazard regression with adjustment for demographics, comorbidity, and time-varying covariates. Forty-four major and 203 minor hemorrhages occurred over 555 person-years among 446 patients (60.6+/-15.6 years, 50% men, 227 African Americans). The variant CYP2C9 genotype conferred an increased risk for major (hazard ratio (HR) 3.0; 95% confidence interval (CI): 1.1-8.0) but not minor (HR 1.3; 95% CI: 0.8-2.1) hemorrhage. The risk of major hemorrhage was 5.3-fold (95% CI: 0.4-64.0) higher before stabilization of therapy, 2.2-fold (95% CI: 0.7-6.5) after stabilization, and 2.4-fold (95% CI: 0.8-7.4) during all periods when anticoagulation was not stable. The variant VKORC1 1173C/T genotype did not confer a significant increase in risk for major (HR 1.7; 95% CI: 0.7-4.4) or minor (HR 0.8; 95% CI: 0.5-1.3) hemorrhage. The variant CYP2C9 genotype is associated with an increased risk of major hemorrhage, which persists even after stabilization of therapy.