Serum 25-hydroxyvitamin D and risk of venous thromboembolism: the Atherosclerosis Risk in Communities (ARIC) Study.
ABSTRACT: Some evidence suggests that an inadequate vitamin D level may increase the risk for atherosclerotic cardiovascular disease. Whether a low vitamin D level plays a role in venous thromboembolism (VTE), that is, venous thrombosis and pulmonary embolism, is largely unexplored.We tested prospectively, in the Atherosclerosis Risk in Communities (ARIC) cohort, whether the serum level of 25-hydroxyvitamin D (25[OH]D) is inversely associated with VTE incidence, and whether it partly explains the African American excess of VTE in the ARIC Study.We measured 25(OH)D by using mass spectroscopy in stored samples of 12 752 ARIC Study participants, and followed them over a median of 19.7 years (1990-1992 to 2011) for the incidence of VTE (n = 537).The seasonally adjusted 25(OH)D level was not associated with VTE incidence. In a model adjusted for age, race, sex, hormone replacement therapy, and body mass index, the hazard ratios of VTE across 25(OH)D quintiles 5 (high) to 1 (low) were: 1 (ref.), 0.84 (95% confidence interval [CI] 0.65-1.08), 0.88 (95% CI 0.68-1.13), 1.04 (95% CI 0.78-1.38), and 0.90 (95% CI 0.64-1.27). The lowest 25(OH)D quintile contained 59% African Americans, whereas the highest quintile contained 7% African Americans. However, lower 25(OH)D levels explained little of the 63% greater VTE risk of African Americans over whites in this cohort.A low 25(OH)D level was not a risk factor for VTE in this prospective study. However, the totality of the literature (three studies) suggests that a low 25(OH)D level might modestly increase VTE risk in whites, but this needs further confirmation.
Project description:Elevated plasma concentrations of coagulation factor XI may increase risk of venous thromboembolism (VTE), but prospective data are limited. We studied prospectively the associations of plasma factor XI and a key F11 genetic variant with incident VTE in whites and African-Americans. We measured factor XI in 16,299 participants, initially free of VTE, in two prospective population cohorts. We also measured the F11 single nucleotide polymorphism rs4241824, which a genome-wide association study had linked to factor XI concentration. During follow-up, we identified 606 VTEs. The age, race, sex, and study-adjusted hazard ratio of VTE increased across factor XI quintiles (P?<?0.001 for trend), and the hazard ratio was 1.51 (95% CI 1.16, 1.97) for the highest versus lowest quintile overall, and was 1.42 (95% CI 1.03, 1.95) in whites and 1.72 (95% CI 1.08, 2.73) in African-Americans. In whites, the F11 variant was associated with both factor XI concentration and VTE incidence (1.15-fold greater incidence of VTE per risk allele). In African-Americans, these associations were absent. In conclusion, this cohort study documented that an elevated plasma factor XI concentration is a risk factor for VTE over extended follow-up, not only in whites but also in African-Americans. In whites, the association of the F11 genetic variant with VTE suggests a causal relation, but we did not observe this genetic relation in African-Americans.
Project description:<h4>Background and aims</h4>Low serum 25-hydroxyvitamin D (25(OH)D) is associated with higher nonalcoholic fatty liver disease (NAFLD) risk in studies of mainly white participants. Significant racial/ethnic differences exist in serum 25(OH)D and NAFLD prevalence questioning extending this association to other racial/ethnic groups. We tested whether the association between serum 25(OH)D and NAFLD vary by race/ethnicity.<h4>Methods and results</h4>This was a cross-sectional analysis from the Multi-Ethnic Study of Atherosclerosis (MESA) that included 3484 participants (44% male; 38.4% Whites, 27.8% African-Americans, 23.5% Hispanics, and 10.3% Chinese-Americans) who had serum 25(OH)D and upper abdominal CT images available at baseline. Serum 25(OH)D was measured by high-performance liquid chromatography-tandem mass spectrometry. NAFLD was identified if liver-to-spleen Hounsfield-Unit ratio was <1. Whites had the highest 25(OH)D level and African-Americans had the lowest level (mean ± SD: 29.5 ± 10.4 vs.19.9 ± 9.1, respectively). Six hundred and eleven (17.5%) participants had NAFLD; Hispanics had the highest prevalence (26.2%) followed by Chinese-Americans (19.8%), Whites (15.8%) and African-Americans (11.7%), P < 0.0001. In adjusted model, the association of 25(OH)D with NAFLD differed by race/ethnicity (P < 0.0001). Negative association was only evident in Causations (OR (95% CI):1.23 (1.03, 1.47) per 1 SD lower serum 25(OH)D). For other racial/ethnic groups, BMI, triglycerides, diabetic status and/or smoking, but not serum 25(OH)D, were common independent risk factors for NAFLD.<h4>Conclusions</h4>The negative association between serum 25(OH)D and NAFLD in Whites may not be broadly generalizable to other racial/ethnic groups. Modifiable risk factors including BMI, triglycerides, diabetic status and/or smoking associate with NAFLD risk in non-white racial/ethnic groups beyond 25(OH)D.
Project description:ESSENTIALS: There is little prospective information on genetic risk scores to predict venous thromboembolism (VT). Community based cohort followed a median of 22.6 years for VT occurrence. A 5-SNP risk score identified whites at risk of VT, but not African Americans. The utility of genetic risk scores for VT is yet to be established.Case-control studies have created genetic risk scores of single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) and documented their ability to predict VTE, but prospective data are lacking.To test the ability of a genetic risk score to predict VTE incidence in a prospective study, particularly in African Americans.We computed a previously proposed genetic risk score, based on five established VTE SNPs in the F5, F2, ABO, FGG, and F11 genes, in 9520 whites and 3049 African Americans initially free of VTE. We followed them a median of 22.6 years for VTE occurrence (n = 380 events in whites and n = 187 in African Americans).In whites, the five-SNP weighted genetic risk score ranged from 0 to 5.8, and VTE risk increased 1.41-fold (95% confidence interval [CI] 1.27-fold to 1.56-fold) per allele increment. In African Americans, the weighted genetic risk score ranged from 0 to 4.6 and the hazard ratio per risk allele was 1.14 (95% CI 0.94-1.38), with adjustment for 10 principal components of ancestry. The area under the receiver operating characteristic curve for 20-year prediction of VTE from the weighted genetic risk score was 0.59 (95% CI 0.56-0.63) in whites and 0.56 (95% CI 0.51-0.61) in African Americans. Adding non-genetic factors increased the area under the curve to 0.67 in whites and to 0.66 in African Americans.Higher values for a five-SNP genetic risk score helped identify white adults at risk of VTE. The genetic risk score did not identify future VTE occurrence in African Americans.
Project description:INTRODUCTION:African Americans have a higher incidence of venous thromboembolism (VTE) than European descent individuals. However, the typical genetic risk factors in populations of European descent are nearly absent in African Americans, and population-specific genetic factors influencing the higher VTE rate are not well characterized. METHODS:We performed a candidate gene analysis on an exome-sequenced African American family with recurrent VTE and identified a variant in Protein S (PROS1) V510M (rs138925964). We assessed the population impact of PROS1 V510M using a multicenter African American cohort of 306 cases with VTE compared to 370 controls. Additionally, we compared our case cohort to a background population cohort of 2203 African Americans in the NHLBI GO Exome Sequencing Project (ESP). RESULTS:In the African American family with recurrent VTE, we found prior laboratories for our cases indicating low free Protein S levels, providing functional support for PROS1 V510M as the causative mutation. Additionally, this variant was significantly enriched in the VTE cases of our multicenter case-control study (Fisher's Exact Test, P = 0.0041, OR = 4.62, 95% CI: 1.51-15.20; allele frequencies - cases: 2.45%, controls: 0.54%). Similarly, PROS1 V510M was also enriched in our VTE case cohort compared to African Americans in the ESP cohort (Fisher's Exact Test, P = 0.010, OR = 2.28, 95% CI: 1.26-4.10). CONCLUSIONS:We found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case-control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population-specific genetic risk factor for VTE in African Americans.
Project description:Plasma D-dimer is a useful clinical test for acute venous thromboembolism (VTE), and concentrations remain higher in VTE patients after treatment than in controls. Yet, evidence is limited on whether higher basal D-dimer concentrations in the general population are associated with greater risk of first VTE.To assess the prospective association between D-dimer and incident VTE over a long follow-up.We measured plasma D-dimer in 12,097 participants, initially free of VTE, in the Atherosclerosis Risk in Communities Study. Over a median follow-up of 17years, we identified 521 VTEs. We calculated hazard ratios of VTE using proportional hazards regression.The age, race, and sex adjusted hazard ratios of VTE across quintiles of D-dimer were 1, 1.5, 1.8, 2.1, and 3.2 (p for trend <0.0001). For the first 10years of follow-up, the hazard ratio for the highest versus lowest quintile was 3.5, and was 2.9 after 10years. In both whites and African Americans, VTE risk remained strongly associated with D-dimer after further adjustment for diabetes, body mass index, kidney function, and several thrombophilia genetic markers. D-dimer was associated with both unprovoked and provoked VTE, but more strongly with unprovoked.A higher basal level of plasma D-dimer in the general population, presumably reflecting a predisposition to thrombosis, is a strong, long-term risk factor for a first VTE.
Project description:BACKGROUND:Recent studies suggest that potassium levels may differ by race. The basis for these differences and whether associations between potassium levels and adverse outcomes differ by race are unknown. STUDY DESIGN:Observational study. SETTING & PARTICIPANTS:Associations between race and potassium level and the interaction of race and potassium level with outcomes were investigated in the Racial and Cardiovascular Risk Anomalies in Chronic Kidney Disease (RCAV) Study, a cohort of US veterans (N=2,662,462). Associations between African ancestry and potassium level were investigated in African Americans in the Atherosclerosis Risk in Communities (ARIC) Study (N=3,450). PREDICTORS:Race (African American vs non-African American and percent African ancestry) for cross-sectional analysis; serum potassium level for longitudinal analysis. OUTCOMES:Potassium level for cross-sectional analysis; mortality and end-stage renal disease for longitudinal analysis. RESULTS:The RCAV cohort was 18% African American (N=470,985). Potassium levels on average were 0.162mmol/L lower in African Americans compared with non-African Americans, with differences persisting after adjustment for demographics, comorbid conditions, and potassium-altering medication use. In the ARIC Study, higher African ancestry was related to lower potassium levels (-0.027mmol/L per each 10% African ancestry). In both race groups, higher and lower potassium levels were associated with mortality. Compared to potassium level of 4.2mmol/L, mortality risk associated with lower potassium levels was lower in African Americans versus non-African Americans, whereas mortality risk associated with higher levels was slightly greater. Risk relationships between potassium and end-stage renal disease were weaker, with no difference by race. LIMITATIONS:No data for potassium intake. CONCLUSIONS:African Americans had slightly lower serum potassium levels than non-African Americans. Consistent associations between potassium levels and percent African ancestry may suggest a genetic component to these differences. Higher and lower serum potassium levels were associated with mortality in both racial groups.
Project description:African-Americans generally have lower circulating levels of 25 hydroxyvitamin D [25(OH)D] than Whites, attributed to skin pigmentation and dietary habits. Little is known about the genetic determinants of 25(OH)D levels nor whether the degree of African ancestry associates with circulating 25(OH)D.With the use of a panel of 276 ancestry informative genetic markers, we estimated African and European admixture for a sample of 758 African-American and non-Hispanic White Southern Community Cohort Study participants. For African-Americans, cut points of <85%, 85% to 95%, and >or=95% defined low, medium, and high African ancestry, respectively. We estimated the association between African ancestry and 25(OH)D and also explored whether vitamin D exposure (sunlight, diet) had varying effects on 25(OH)D levels dependent on ancestry level.The mean serum 25(OH)D levels among Whites and among African-Americans of low, medium, and high African ancestry were 27.2, 19.5, 18.3, and 16.5 ng/mL, respectively. Serum 25(OH)D was estimated to decrease by 1.0 to 1.1 ng/mL per 10% increase in African ancestry. The effect of high vitamin D exposure from sunlight and diet was 46% lower among African-Americans with high African ancestry than among those with low/medium ancestry.We found novel evidence that the level of African ancestry may play a role in clinical vitamin D status.This is the first study to describe how 25(OH)D levels vary in relation to genetic estimation of African ancestry. Further study is warranted to replicate these findings and uncover the potential pathways involved.
Project description:Low circulating 25-hydroxyvitamin D [25(OH)D] is prevalent in African Americans, but predictors of vitamin D status are understudied compared to Caucasian populations.We investigated whether certain environmental and genetic factors are predictors of circulating 25(OH)D in 989 elderly African Americans participating in the Health, Aging, and Body Composition (Health ABC) Study.Regression analysis estimated the cross-sectional association of nongenetic (environmental) factors with 25(OH)D. Single nucleotide polymorphisms (SNPs) associated with 25(OH)D in Caucasian genome-wide association studies (GWASs) were analyzed for association with serum 25(OH)D, including analyses of all imputed SNPs in identified genomic regions. Genome-wide complex trait analysis (GCTA) evaluated the association of all (genome-wide) genotyped SNPs with serum 25(OH)D in the Health ABC Study with replication in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort.Gender, study site, season of blood draw, body mass index, dietary supplement use, dairy and cereal consumption, Healthy Eating Index score, and walking >180 min/wk were associated with 25(OH)D (P < 0.05), jointly explaining 25% of the variation in circulating 25(OH)D. Multivitamin supplement use was the strongest predictor of circulating 25(OH)D, and supplement users had a 6.3-μg/L higher serum 25(OH)D concentration compared with nonusers. Previous GWAS-identified gene regions were not replicated in African Americans, but the nonsynonymous rs7041 SNP in group-specific component (vitamin D binding protein) was close to significance thresholds (P = 0.08), and there was evidence for an interaction between this SNP and use of multivitamin supplements in relation to serum 25(OH)D concentration (P = 0.04). Twenty-three percent (95% CI: 0%, 52%) of the variation in serum 25(OH)D was explained by total genetic variation in a pooled GCTA of 2087 Health ABC Study and MESA African-American participants, but population substructure effects could not be separated from other genetic influences.Modifiable dietary and lifestyle predictors of serum 25(OH)D were identified in African Americans. GCTA confirms that a proportion of 25(OH)D variability is attributable to genetic variation, but genomic regions associated with the 25(OH)D phenotype identified in prior GWASs of European Americans were not replicated in the Health ABC Study in African Americans.
Project description:BACKGROUND:In observational studies, low 25-hydroxyvitamin D (25(OH)D) has been associated with increased risk of coronary heart disease (CHD), and this association may vary by race. Racial differences in the frequency of vitamin D binding protein (DBP) single nucleotide polymorphisms (SNPs) might account for similar bioavailable vitamin D in blacks despite lower mean 25(OH)D. We hypothesized that the associations of low 25(OH)D with CHD risk would be stronger among whites and among persons with genotypes associated with higher DBP levels. METHODS:We measured 25(OH)D by mass spectroscopy in 11,945 participants in the ARIC Study (baseline 1990-1992, mean age 57 years, 59% women, 24% black). Two DBP SNPs (rs7041; rs4588) were genotyped. We used adjusted Cox proportional hazards models to examine the association of 25(OH)D with adjudicated CHD events through December 2011. RESULTS:Over a median of 20 years, there were 1230 incident CHD events. Whites in the lowest quintile of 25(OH)D (<17 ng/ml) compared to the upper 4 quintiles had an increased risk of incident CHD (HR 1.28, 95% CI 1.05-1.56), but blacks did not (1.03, 0.82-1.28), after adjustment for demographics and behavioral/socioeconomic factors (p-interaction with race = 0.22). Results among whites were no longer significant after further adjustment for potential mediators of this association (i.e. diabetes, hypertension). There was no statistically significant interaction of 25(OH)D with the DBP SNPs rs4588 (p = 0.92) or rs7041 (p = 0.87) in relation to CHD risk. CONCLUSIONS:Low 25(OH)D was associated with incident CHD in whites, but no interactions of 25(OH)D with key DBP genotypes was found.
Project description:OBJECTIVES:Vitamin D status has been hypothesized to protect against development of early age-related macular degeneration (AMD) via its anti-inflammatory properties and its possible beneficial influence on blood pressure control. We investigated the association between vitamin D status and prevalent early AMD in a community-based cohort. DESIGN:This was a cross-sectional study. SETTING:This was a secondary data analysis of already existing data from the Atherosclerosis Risk in Communities Study (ARIC) cohort collected from 1990 to 1995. PARTICIPANTS:There were 9,734 (7,779 Caucasians, 1,955 African American) ARIC participants (aged 46 to 70 at visit 2 [1990-1992]) with 25(OH)D data available at visit 2, AMD assessment at visit 3 (1993-1995), and complete covariate data. MEASUREMENTS:Vitamin D status was assessed with serum 25-hydroxyvitamin D (25(OH)D) concentrations from bloods drawn at visit 2. Prevalent, early AMD (n=511) was assessed at visit 3 (1993-95) with nonmydriatic retinal photographs of one randomly chosen eye. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for early AMD by categories of 25(OH)D in nmol/L (deficient <30, inadequate 30-<50, and two categories of adequate status: 50-<75 and ?75). Linear trend was estimated using continuous 25(OH)D concentrations. ORs were adjusted for age, race, and smoking status. We further adjusted for hypertension status to examine if vitamin D status influenced early AMD via its effects on blood pressure. Exploratory analyses of effect modification by age, sex, race and high risk genotypes [Y402H complement factor H (CFH) rs1061170 and the A69S age-related maculopathy susceptibility 2 (ARMS2) rs10490924 polymorphisms] were conducted. RESULTS:The prevalence of early AMD was 5%, and 5% of participants were vitamin D deficient. The adjusted OR (95% CIs) for early AMD among those with adequate (?75 nmol/L) compared to deficient (<30 nmol/L) vitamin D status was 0.94 (0.59-1.50), p-trend=0.86. Further adjustment for hypertension status did not influence results (OR [95% CI]=0.95 [0.59-1.52], p-trend=0.84). Results did not vary significantly by age, race, sex, early AMD subtype (soft drusen or retinal pigment epithelium depigmentation), or ARMS2 genotype. Results did not vary significantly by CFH genotype in African Americans. The p for multiplicative interaction between 25(OH)D and CFH genotype was 0.06 in Caucasians, but OR [95% CIs] for AMD by vitamin D status were similar in each CFH genotype and not statistically significant. CONCLUSIONS:Vitamin D status was not associated with early AMD in this cohort sample.