Department of Genetics, University of North Carolina, 5112 Genetic Medicine Building, Chapel Hill, NC 27599-7264, USA.
Inflammation. 2012 Apr;35(2):574-83. doi: 10.1007/s10753-011-9348-y.
Recent genome-wide association studies have related several genetic loci, including C-reactive protein (CRP), hepatocyte nuclear factor 1 homeobox (HNF1A), and genetic variations in the leptin receptor (LEPR), to circulating CRP levels in populations of European ancestry. The genetic effects in other populations and across varying levels of exposure to a pathogenic environment, an important environmental factor associated with CRP, remain to be determined. We tested 2,073,674 single-nucleotide polymorphisms (SNPs) for association with plasma CRP (limited to ≤10 mg/L) in 1,709 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey. The strongest evidence of association was observed with variants at CRP (rs876537, P = 1.4 × 10(-9)) and HNF1A (rs7305618, P = 1.0 × 10(-8)). Among other previously reported CRP-associated loci, the apolipoprotein E ε4 haplotype was associated with decreased CRP level (P = 7.1 × 10(-4)), and modest association was observed with LEPR (rs1892534, P = 0.076), with direction of effects consistent with previous studies. The strongest signal at a locus not previously reported mapped to a gene desert region on chromosome 6q16.1 (rs1408282, P = 2.9 × 10(-6)). Finally, we observed nominal evidence of interaction with exposure to a pathogenic environment for top main effect SNPs at HNF1A (rs7305618, P = 0.031), LEPR (rs1892535, P = 0.030) and 6q16.1 (rs1408282, P = 0.046). Our findings demonstrate convincing evidence that genetic variants in CRP and HNF1A contribute to plasma CRP in Filipino women and provide the first evidence that exposure to a pathogenic environment may modify the genetic influence at the HNF1A, LEPR, and 6q16.1 loci on plasma CRP level.
最近的全基因组关联研究已经将几个遗传位点与循环 CRP 水平相关联，包括 C 反应蛋白（CRP）、肝细胞核因子 1 同源盒（HNF1A）和瘦素受体（LEPR）的遗传变异，这些遗传位点存在于欧洲血统的人群中。在其他人群中和在不同程度接触致病环境（与 CRP 相关的重要环境因素）的情况下，遗传效应仍有待确定。我们在来自 Cebu 纵向健康和营养调查的 1709 名菲律宾无亲缘关系女性中，检测了与血浆 CRP（限制在≤10mg/L）相关的 2073674 个单核苷酸多态性（SNP）。与 CRP（rs876537，P=1.4×10(-9))和 HNF1A(rs7305618，P=1.0×10(-8))相关的最强证据。在其他先前报道的 CRP 相关基因座中，载脂蛋白 E ε4 单倍型与 CRP 水平降低相关（P=7.1×10(-4))，并且与 LEPR(rs1892534，P=0.076)存在适度相关性，效应方向与先前研究一致。在一个先前未报道的基因座上的最强信号映射到染色体 6q16.1 上的一个基因荒漠区域(rs1408282，P=2.9×10(-6))。最后，我们观察到在 HNF1A(rs7305618，P=0.031)、LEPR(rs1892535，P=0.030)和 6q16.1(rs1408282，P=0.046)的主要效应 SNP 与致病环境暴露之间存在名义上的相互作用证据。我们的研究结果表明，CRP 和 HNF1A 的遗传变异在菲律宾女性的血浆 CRP 中具有令人信服的证据，并提供了第一个证据，表明致病环境的暴露可能会改变 HNF1A、LEPR 和 6q16.1 基因座对血浆 CRP 水平的遗传影响。
