Katharyn M Baca1, Manika Govil2, Joseph M Zmuda3, Hyagriv N Simhan4, Mary L Marazita5, Lisa M Bodnar6. 1. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA. 2. Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA. 3. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 15261, USA. 4. Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, 300 Halket Street, Pittsburgh, PA, 15213, USA; Magee-Womens Research Institute, Pittsburgh, PA, 15213, USA. 5. Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, 15261, USA; Clinical and Translational Science Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA. 6. Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, School of Medicine, University of Pittsburgh, 300 Halket Street, Pittsburgh, PA, 15213, USA; Magee-Womens Research Institute, Pittsburgh, PA, 15213, USA. Electronic address: bodnar@edc.pitt.edu.
Abstract
BACKGROUND: Several candidate genes and genome wide association studies have reported significant associations between vitamin D metabolism genes and 25-hydroxyvitamin D. Few studies have examined these relationships in pregnancy. OBJECTIVE: We evaluated the relationship between maternal allelic variants in three vitamin D metabolism genes and 25-hydroxyvitamin D (25(OH)D) concentration in pregnancy. STUDY DESIGN: In two case-control studies, samples were drawn from women who delivered at Magee Womens Hospital in Pittsburgh, PA from 1999 to 2010 and twelve recruiting sites across the United States from 1959 to 65. For 882 Black and 1796 White pregnant women from these studies, 25(OH)D concentration was measured and single nucleotide polymorphisms (SNPs) were genotyped 50 kilobases up- and down-stream in three genes (VDR, GC, and CYP27B1). Using multivariable linear regression, we estimated the associations between allelic variation of each locus and log-transformed 25(OH)D concentration separately by race and study group. Meta-analysis was used to estimate the association across the four groups for each SNP. RESULTS: Minor alleles of several variants in VDR, GC, and CYP27B1 were associated with differences in log-transformed 25(OH)D concentration compared to the corresponding major alleles [beta, 95% confidence intervals (CI)]. The meta-analysis confirmed the associations for differences in log-transformed 25(OH)D by allelic loci for one intron VDR variant [rs2853559 0.08 (0.02, 0.13), p<0.01] and a variant in the GC flanking region [rs13150174: 0.04 (0.02, 0.07), p<0.01], and a GC missense mutation [rs7041 0.05 (0.01, 0.09), p<0.01]. The meta-analysis also revealed possible associations for SNPs in linkage disequilibrium with variants in the VDR 3-prime untranslated region, another GC missense variant (rs4588), and a variant of the 3-prime untranslated region of CYP27B1. CONCLUSION: We observed associations between VDR, GC, and CYP27B1 variants and maternal 25-hydroxyvitamin D concentration. Our results provide additional support for a possible role of genetic variation in vitamin D metabolism genes on vitamin D status during pregnancy.
BACKGROUND: Several candidate genes and genome wide association studies have reported significant associations between vitamin D metabolism genes and 25-hydroxyvitamin D. Few studies have examined these relationships in pregnancy. OBJECTIVE: We evaluated the relationship between maternal allelic variants in three vitamin D metabolism genes and 25-hydroxyvitamin D (25(OH)D) concentration in pregnancy. STUDY DESIGN: In two case-control studies, samples were drawn from women who delivered at Magee Womens Hospital in Pittsburgh, PA from 1999 to 2010 and twelve recruiting sites across the United States from 1959 to 65. For 882 Black and 1796 White pregnant women from these studies, 25(OH)D concentration was measured and single nucleotide polymorphisms (SNPs) were genotyped 50 kilobases up- and down-stream in three genes (VDR, GC, and CYP27B1). Using multivariable linear regression, we estimated the associations between allelic variation of each locus and log-transformed 25(OH)D concentration separately by race and study group. Meta-analysis was used to estimate the association across the four groups for each SNP. RESULTS: Minor alleles of several variants in VDR, GC, and CYP27B1 were associated with differences in log-transformed 25(OH)D concentration compared to the corresponding major alleles [beta, 95% confidence intervals (CI)]. The meta-analysis confirmed the associations for differences in log-transformed 25(OH)D by allelic loci for one intron VDR variant [rs2853559 0.08 (0.02, 0.13), p<0.01] and a variant in the GC flanking region [rs13150174: 0.04 (0.02, 0.07), p<0.01], and a GC missense mutation [rs7041 0.05 (0.01, 0.09), p<0.01]. The meta-analysis also revealed possible associations for SNPs in linkage disequilibrium with variants in the VDR 3-prime untranslated region, another GC missense variant (rs4588), and a variant of the 3-prime untranslated region of CYP27B1. CONCLUSION: We observed associations between VDR, GC, and CYP27B1 variants and maternal 25-hydroxyvitamin D concentration. Our results provide additional support for a possible role of genetic variation in vitamin D metabolism genes on vitamin D status during pregnancy.
Keywords:
1 alpha-hydroxylase gene; 25-Hydroxy vitamin d; CYP27B1; GC; Genetic variation; VDR; Vitamin D; Vitamin D binding protein gene; Vitamin D deficiency; Vitamin D receptor gene; Vitamin d metabolic loci
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