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Genome-wide association study of 25(OH) Vitamin D concentrations in Punjabi Sikhs: Results of the Asian Indian diabetic heart study.

ABSTRACT: Vitamin D deficiency is implicated in multiple disease conditions and accumulating evidence supports that the variation in serum vitamin D (25(OH)D) levels, including deficiency, is under strong genetic control. However, the underlying genetic mechanism associated with vitamin 25(OH)D concentrations is poorly understood. We earlier reported a very high prevalence of vitamin D deficiency associated with an increased risk for type 2 diabetes and obesity in a Punjabi Sikh diabetic cohort as part of the Asian Indian diabetic heart study (AIDHS). Here we have performed the first genome-wide association study (GWAS) of serum 25(OH)D on 3538 individuals from this Punjabi Sikh population. Our discovery GWAS comprised of 1387 subjects followed by validation of 24 putative SNPs (P<10(-4)) using an independent replication sample (n=2151) from the same population by direct genotyping. A novel locus at chromosome 20p11.21 represented by rs2207173 with minor allele frequency (MAF) 0.29, [?=-0.13, p=4.47×10(-9)] between FOXA2 and SSTR4 was identified to be associated with 25(OH)D levels. Another suggestive association signal at rs11586313 (MAF 0.54) [?=0.90; p=1.36×10(-6)] was found within the regulatory region of the IVL gene on chromosome 1q21.3. Additionally, our study replicated 3 of 5 known GWAS genes associated with 25(OH)D concentrations including GC (p=0.007) and CYP2R1 (p=0.019) reported in Europeans and the DAB1 (p=0.003), reported in Hispanics. Identification of novel association signals in biologically plausible regions with 25(OH)D metabolism will provide new molecular insights on genetic drivers of vitamin D status and its implications in health disparities.

SUBMITTER: Sapkota BR

PROVIDER: S-EPMC4769937 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Genome-wide association study of 25(OH) Vitamin D concentrations in Punjabi Sikhs: Results of the Asian Indian diabetic heart study.

Sapkota Bishwa R BR Hopkins Ruth R Bjonnes Andrew A Ralhan Sarju S Wander Gurpreet S GS Mehra Narinder K NK Singh Jai Rup JR Blackett Piers R PR Saxena Richa R Sanghera Dharambir K DK

The Journal of steroid biochemistry and molecular biology 20151215

Vitamin D deficiency is implicated in multiple disease conditions and accumulating evidence supports that the variation in serum vitamin D (25(OH)D) levels, including deficiency, is under strong genetic control. However, the underlying genetic mechanism associated with vitamin 25(OH)D concentrations is poorly understood. We earlier reported a very high prevalence of vitamin D deficiency associated with an increased risk for type 2 diabetes and obesity in a Punjabi Sikh diabetic cohort as part of ...[more]

PMID: 26704534

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Project description:BackgroundEvidence has accumulated for the association between low vitamin D serum concentrations and mental health disorders in both children and adults. We performed a cross-sectional analysis in a population-based sample of children and adolescents to detect associations between 25(OH)-vitamin D serum [25(OH)D] concentrations and scores of the five Strengths and Difficulties Questionnaire (SDQ) subscales and the total difficulties score in different age groups (age ?3-<12 years and ?12-<18 years).Methods9068 participants of the population-based, nation-wide German Health Interview and Examination Survey for Children and Adolescents (KIGGS) with information on mental health status assessed by the SDQ and 25(OH)D levels were included in the analysis. For statistical analysis we used linear regression models stratified by gender based on different adjustment sets. For the younger subsample the analysis was additionally adjusted for the frequency of playing outside. We compared the associations based on parent- and self-ratings of the SDQ for children and adolescents aged ?12-<18 years.ResultsWe found inverse associations between 25(OH)D concentrations and the subscales emotional problems, peer relationship problems and the total difficulties score in both genders after adjustment for potential confounders. The strongest associations were observed in the older subsample for parent-ratings in boys and self-ratings in girls. In the younger subsample the associations were less strong and no longer evident after adjustment for potential confounders such as migration background, socioeconomic status and frequency of playing outside.ConclusionBased on the large-scale cross-sectional study in a German population-based sample of children and adolescents we detected inverse associations between 25(OH)D concentrations and both parent- and self-rated SDQ scores of the total difficulties scale and different subscales with the strongest association in the subsample aged ?12-<18 years for both genders. Migration background and socioeconomic status were detected as relevant confounders. Further studies-particularly in countries with comparatively low mean 25(OH)D concentrations-in childhood and adolescence are warranted. Longitudinal studies are also necessary to infer direction of effects. Finally, RCTs in children and adolescents are required to determine whether Vitamin D is beneficial for mental health.

Project description:ContextThe optimal measure of vitamin D status is unknown.ObjectiveTo directly measure circulating free 25-hydroxyvitamin D [25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans.DesignCross-sectional analysis.SettingSeven academic sites.PatientsA total of 1661 adults: healthy (n = 279), prediabetic (n = 479), outpatients (n = 714), cirrhotic (n = 90), pregnant (n = 20), nursing home resident (n = 79).InterventionsMerge research data on circulating free 25(OH)D (directly-measured immunoassay), total 25(OH)D (liquid chromatography/tandem mass spectrometry), D-binding protein [DBP; by radial (polyclonal) immunodiffusion assay], albumin, creatinine, intact parathyroid hormone, and DBP haplotype.Main outcome measuresDistribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed-effects modeling incorporating clinical condition, DBP haplotype with sex, race, estimated glomerular filtration rate (eGFR), body mass index (BMI), and other covariates).ResultsFree 25(OH)D was 4.7 ± 1.8 pg/mL (mean ± SD) in healthy persons and 4.3 ± 1.9 pg/mL in outpatients, with levels of 0.5 to 8.1 pg/mL and 0.9 to 8.1 pg/mL encompassing 95% of healthy persons and outpatients, respectively. Free 25(OH)D was higher in patients with cirrhosis (7.1 ± 3.0 pg/mL; P < 0.0033) and nursing home residents (7.9 ± 2.1 pg/mL; P < 0.0033) than in other groups and differed between whites and blacks (P < 0.0033) and between DBP haplotypes (P < 0.0001). Mixed-effects modeling of relationships between free and total 25(OH)D identified clinical conditions (patients with cirrhosis > nursing home residents > patients with prediabetes > outpatients > pregnant women) and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race, or DBP haplotype.ConclusionsTotal 25(OH)D, health condition, race, and DBP haplotype affected free 25(OH)D, but only health conditions and BMI affected relationships between total and free 25(OH)D. Clinical importance of free 25(OH)D needs to be established in studies assessing outcomes.

Project description:Background: Cardiovascular disease (CVD) risk factors are associated with low serum 25 hydroxyvitamin D (25(OH)D) concentrations in observational studies; however, clinical trial findings are inconsistent. Objective: We assessed the effect of vitamin D supplementation and increased serum 25(OH)D concentrations on CVD risk factors in a systemic review and meta-analysis of randomized controlled trials (RCTs). Design: MEDLINE, CINAHL, EMBASE, and Google Scholar were searched for RCTs that evaluated vitamin D supplementation and cardiovascular outcomes [blood pressure, parathyroid hormone (PTH), serum high-sensitivity C-reactive protein (hs-CRP), total cholesterol, high and low density lipoprotein (HDL and LDL, respectively), triglycerides, peak wave velocity (PWV) and Augmentation Index (AI)] from 1992 through 2017. Meta-analysis was based on a random-effects model and inverse variance method to calculate standardized mean difference (SMD) as effect sizes, followed by a leave-one-out method for sensitivity analysis. Risk of publication bias was assessed using Cochrane checklist and Begg funnel plots. The systematic review is registered as CRD42015025346. Results: We identified 2341 studies from which 81 met inclusion criteria. The meta-analysis indicated a significant reduction in systolic blood pressure (SMD = -0.102 ± 0.04 mmHg, 95% confidence interval (CI), -0.20 to -0.03), diastolic blood pressure (SMD = -0.07 ± 0.03 mmHg, 95% CI, -0.14 to -0.006), serum PTH (SMD = -0.66 ± 0.08 ng/L, 95% CI, -0.82 to -0.49), hs-CRP (SMD = -0.20 ± 0.07 mg/L, 95% CI, -0.34 to -0.06), total cholesterol (SMD = -0.15 ± 0.06 mmol/L, 95% CI, -0.25 to -0.04), LDL (SMD = -0.10 ± 0.05 mmol/L, 95% CI, -0.20 to -0.003), triglycerides (SMD = -0.12 ± 0.06 mmol/L, 95% CI, -0.23 to -0.003) and a significant increase in HDL (SMD = 0.09 ± 0.04 mmol/L, 95% CI, 0.00 to 0.17) with vitamin D supplementation. These findings remained significant in sensitivity analyses for blood pressure, lipid profile, serum PTH, and serum hs-CRP. There was no significant effect of vitamin D supplementation on PWV (SMD = -0.20 ± 0.13 m/s, 95% CI, -0.46 to 0.06, p = 0.14) and AI (SMD = -0.09 ± 0.14%, 95% CI, -0.37 to 0.19, p = 0.52) for vitamin D supplemented groups. Conclusion: These findings suggest that vitamin D supplementation may act to protect against CVD through improving risk factors, including high blood pressure, elevated PTH, dyslipidemia, and inflammation.

Dataset Information

Genome-wide association study of 25(OH) Vitamin D concentrations in Punjabi Sikhs: Results of the Asian Indian diabetic heart study.

Publications

Genome-wide association study of 25(OH) Vitamin D concentrations in Punjabi Sikhs: Results of the Asian Indian diabetic heart study.

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