背景:维生素D缺乏在非洲血统个体中更为常见,可能与不良健康结局有关。维生素D结合蛋白(VDBP)调节生物活性维生素D的浓度。
目的:我们在非洲血统个体中进行了VDBP和25-羟维生素D的全基因组关联研究(GWAS)。
方法:数据来自南部社区队列研究(SCCS)的2,602名非洲裔美国成年人和来自英国生物库的6,934名非洲或加勒比海血统成年人。血清VDBP浓度仅在SCCS中可用,并通过使用多克隆人VDBPELISA试剂盒进行测量。两个研究样品的血清25-羟基维生素D浓度通过使用DiasorinLiason测量,化学发光免疫测定法。通过使用Illumina或Affymetrix平台对参与者进行全基因组覆盖的单核苷酸多态性(SNP)基因分型。通过使用包括P值<5×10-8且在前导SNP的250kbps内的所有变体的正向逐步线性回归模型进行精细映射分析。
结果:我们在SCCS人群中确定了4个与VDBP浓度显著相关的位点:rs7041(每个等位基因β=0.61μg/mL,SE=0.05,P=1.4×10-48)和rs842998(每个等位基因β=0.39μg/mL,SE=0.03,P=4.0×10-31)在GC中,rs8427873(每个等位基因β=0.31μg/mL,SE=0.04,P=3.0×10-14)靠近GC和rs11731496(每个等位基因β=0.21μg/mL,SE=0.03,P=3.6×10-11)在GC和NPFFR2之间。在条件分析中,其中包括上述SNP,只有rs7041仍然显着(P=4.1×10-21)。GC中的SNPrs4588是唯一的GWAS鉴定的与25-羟基维生素D浓度相关的SNP。在英国生物银行参与者中:每个等位基因β=-0.11μg/mL,SE=0.01,P=1.5×10-13;在SCCS中:每个等位基因β=-0.12μg/mL,SE=0.06,P=2.8×10-02)。rs7041和rs4588是影响VDBP与25-羟基维生素D结合亲和力的功能性SNP。
结论:我们的结果与先前在欧洲血统人群中进行的研究一致,显示GC,直接编码VDBP的基因,将是重要的VDBP和25-羟基维生素D的浓度。目前的研究扩展了我们对不同人群维生素D遗传学的认识。
Vitamin D deficiency is more common among African-ancestry individuals and may be associated with adverse health outcomes. Vitamin D binding protein (VDBP) regulates concentrations of biologically active vitamin D.
We conducted genome-wide association study (GWAS) of VDBP and 25-hydroxyvitamin D among African-ancestry individuals.
Data were collected from 2,602 African American adults from the Southern Community Cohort Study (SCCS) and 6,934 African- or Caribbean-ancestry adults from the UK Biobank. Serum VDBP concentrations were available only in the SCCS and were measured by using the Polyclonal Human VDBP ELISA kit. Serum 25-hydroxyvitamin D concentrations for both study samples were measured by using Diasorin Liason, a chemiluminescent immunoassay. Participants were genotyped for single nucleotide polymorphisms (SNPs) with genome-wide coverage by using Illumina or Affymetrix platforms. Fine-mapping analysis was performed by using forward stepwise linear regression models including all variants with P value < 5 × 10-8 and within 250 kbps of a lead SNP.
We identified 4 loci notably associated with VDBP concentrations in the SCCS population: rs7041 (per allele β = 0.61 μg/mL, SE = 0.05, P = 1.4 × 10-48) and rs842998 (per allele β = 0.39 μg/mL, SE = 0.03, P = 4.0 × 10-31) in GC, rs8427873 (per allele β = 0.31 μg/mL, SE = 0.04, P = 3.0 × 10-14) near GC and rs11731496 (per allele β = 0.21 μg/mL, SE = 0.03, P = 3.6 × 10-11) in between GC and NPFFR2. In conditional analyses, which included the above-mentioned SNPs, only rs7041 remained notable (P = 4.1 × 10-21). SNP rs4588 in GC was the only GWAS-identified SNP associated with 25-hydroxyvitamin D concentration. Among UK Biobank participants: per allele β = -0.11 μg/mL, SE = 0.01, P = 1.5 × 10-13; in the SCCS: per allele β = -0.12 μg/mL, SE = 0.06, P = 2.8 × 10-02). rs7041 and rs4588 are functional SNPs that influence the binding affinity of VDBP to 25-hydroxyvitamin D.
Our results were in line with previous studies conducted in European-ancestry populations, showing that GC, the gene that directly encodes for VDBP, would be important for VDBP and 25-hydroxyvitamin D concentrations. The current study extends our knowledge of the genetics of vitamin D in diverse populations.