Association Between Gene Variants In Vitamin D Metabolic Pathway And Plasma 25(OH)D Level Among Pregnant Women In First Trimester

Backgrounds and objectivesVitamin D deficiency is a worldwide health problem affecting more than 1 billion individuals.Vitamin D deficiency is associated with many musculoskeletal disorders and non-musculoskeletal disorders.Women have less outdoor activities compare with men and often take sun protection;and the demand for Vitamin D significantly increases among pregnant women.Therefore,Vitamin D deficiency is more common in pregnant women.Vitamin D deficiency or insufficiency may be associated with pregnancy complications and adverse pregnancy outcomes,including preeclampsia,gestational diabetes mellitus and preterm birth,and may even increase the risk of cancer,diabetes,inflammatory diseases,allergic disease,and neurodegenerative diseases in offspring after birth.25(OH)D is a generally accepted as the best indicator of vitamin D status.Many enviromental factors including season,latitude,intake of Vitamin D,and also genetic factors have all been previously reported to influence plasma 25(OH)D levels.The genetic contribution to variance in vitamin D levels has been investigated in several twin and family studies.Estimates for the heritability of vitamin D levels vary between 23%and 80%.Previous studies have identified single nucleotide polymorphisms(SNPs)in the Vitamin D metabolic pathway genes,such as NADSYN1,DHCR7,GC,CYP2R1 and VDR,are significantly associated with alteration in plasma 25(OH)D level.However,the studis are mostly among general adults and their results are inconsistent.The association between the Vitamin D pathway genetic variations and plasma 25(OH)D hasn't been systematically explored among pregnant women.Therefore,this study was conducted in Zhoushan maternal and child health hospital.We explored the associations of SNPs in the Vitamin D pathway genes including NADSYN1,DHCR7,GC,CYP2R1,CYP3A4,CYP27A1,CYP27B1,LRP2,CYP24A1,VDR with early pregnant plasma 25(OH)D in a cross-sectional study,aiming to provide scientific basis for the reasonable supplementation of vitamin D for pregnant women.Materials and MethodsWe took Zhoushan Maternal and Child Health Hospital as the research field.In the prospective cohort,participants' social-demographic characteristics,life behavior,height and weight were obtained through epidemiological investigation questionnaires,by face-to-face interview,and blood samples were collected at three timepoints after informed consent.759 pregnant women deliverd in this cohort from August 2011 to April 2014 were selected for this study.The plasma 25(OH)D concentration and the selected SNPs genotype of white blood cell samples were measured.A high performance liquid chromatography tandem mass spectrometry was used to detect plasma 25(OH)D levels.Genotyping for the selected genetic polymorphisms was performed using MassARRAY system method.Multiple statistical methods including linear regression,crossover analysis,Generalized Multifactor Dimensionality Reduction(GMDR)analysis were applied to explore the major and interactive effects of the SNPs of Vitamin D pathway genes and enviromental factors on plasma 25(OH)D level.Results A total of 759 pregnant women were recruited for this investigation.The mean age of the participants was 28.30±3.06 years old and the mean gestational age was 11.51±0.63 weeks.The blood samples of 168,192,195,and 204 women were collected in spring,summer,autumn,and winter,respectively.The mean plasma 25(OH)D concentration was 15.64±6.52 ng/mL.Vitamin D deficiency(25(OH)D<20 ng/mL)was present in 78.13%of the women.Only 21.87%of the population had 25(OH)D ? 20 ng/mL.Linear regression model was used to explore the association between SNPs and 25(OH)D level.Of the 49 SNPs assessed,10 SNPs were significantly associated with plasma 25(OH)D level.In the analysis of SNPs of GC gene,after the adjustment of age,prepregnant BMI,season of blood sampling and physical activity,the plasma 25(OH)D of individuals with rs 16846876 AT and TT genotypes on average respectively lowered 1.22 ng/mL and 2.72 ng/mL,in comparison with that of the individuals with rs16846876 AA genotype(P=O.0121,P = 0.0006).Compared with the rsl7467825 AA genotype,individuals with rsl7467825 GA and GG genotypes had lower 25(OH)D(?=-1.95,P<0.001;?=-2.88,P = 0.0003).Associations of the genotype of rs2282679,rs3755967,rs2298850,rs4588,which is in strong LD with rsl7467825,showed a similar pattern of association of rs17467825.Besides,compared with the rs7041 AA genotype,plasma 25(OH)D of individuals with rs7041 CA and CC genotypes were 1.80 ng/mL and 2.30 ng/mL higher,respectively(P =0.0002;P =0.0123).Compared with the rsl155563 TT genotype,individuals with CC genotype presented,on average,lower levels of 25(OH)D(?=-1.80,P =0.0104).However,individuals with rs2298849 GG genotype had higher levels of 25(OH)D,compared with the AA genotype(?=1.44,P=0.0423).In the analysis of SNPs of CYP3A4 gene,we found that individuals with rs2242480 TT genotype had higher levels of 25(OH)D,compared with the CC genotype(?>=2.48,P =0.0081).In the haplotype analysis of GC gene,after the adjustment of confounders,we found that the haplotype ATAGGCTG(? =2.17,P =0.0041),ATATGCTG(? =1.47,P=0.0110),ACATTCTG(?=3.08,P =0.0001),ATATTTCA(?=1.99,P =0.0092)were associated with a significantly higher level of plasma 25(OH)D when compared with the most common haplotype TTGTGTCA.In the haplotype analysis of LRP2 gene,when compared with the most common haplotype TCCCGCA,haplotype TCCCCTG significantly associated with lower levels of plasma 25(OH)D(?=-1.55,P =0.0462).No significant associations between haplotype of other genes and plasma 25(OH)D were observed.Additionally,we found that rs933994-CYP27A1 and rs2246709-CYP3A4 polymorphisms and the season of blood sampling might exert joint effects on plasma 25(OH)D levels.Besides,complex gene-gene interactions between vitamin D pathway gene polymorphisms was found according to the results of crossover analysis.In GMDR analysis,interaction of rs7041-GC?rsl155563-GC,rs1562902-CYP2R1 rs2209314-CYP24A1 polymorphisms yielded the highest testing accuracy for the prediction of plasma 25(OH)D levelsConclusionsIn pregnant women,SNPs in vitamin D metabolic pathway genes were significantly associate with early pregnant plasma 25(OH)D level.The most significantly related gene is GC.Vitamin D metabolic pathway genes and the season of blood sampling might exert joint effects on plasma 25(OH)D.Further studies in the pregnant women with larger sample size are warranted to validate those findings.