Kathiresan Sekar, Larson Martin G, Vasan Ramachandran S, Guo Chao-Yu, Gona Philimon, Keaney John F, Wilson Peter W F, Newton-Cheh Christopher, Musone Stacy L, Camargo Amy L, Drake Jared A, Levy Daniel, O'Donnell Christopher J, Hirschhorn Joel N, Benjamin Emelia J
Framingham Heart Study, Framingham, MA 01702-5827, USA.
Circulation. 2006 Mar 21;113(11):1415-23. doi: 10.1161/CIRCULATIONAHA.105.591271. Epub 2006 Mar 13.
Serum C-reactive protein (CRP) level is a heritable complex trait that predicts incident cardiovascular disease. We investigated the clinical and genetic sources of interindividual variability in serum CRP.
We studied serum CRP in 3301 Framingham Heart Study (FHS) participants (mean age 61 years, 53% women). Twelve clinical covariates explained 26% of the variability in CRP level, with body mass index alone explaining 15% (P<0.0001) of the variance. To investigate the influence of genetic variation at the CRP gene on CRP levels, we first constructed a dense linkage disequilibrium map for common single-nucleotide polymorphisms (SNPs) spanning the CRP locus (1 SNP every 850 bases, 26 kilobase [kb] genomic region). Thirteen CRP SNPs were genotyped in 1640 unrelated FHS participants with measured CRP levels. After adjustment for clinical covariates, 9 of 13 SNPs were associated with CRP level (P<0.05). To account for correlation among SNPs, we conducted forward stepwise selection among all 13 SNPs; a triallelic SNP (rs3091244) remained associated with CRP level (stepwise P<0.0001). The triallelic SNP (C-->T-->A; allele frequencies 62%, 31%, and 7%), located in the promoter sequence, explained 1.4% of total serum CRP variation; haplotypes harboring the minor T and A alleles of this SNP were associated with higher CRP level (haplotype P=0.0002 and 0.004).
In our community-based sample, clinical variables explained 26% of the interindividual variation in CRP, whereas a common triallelic CRP SNP contributed modestly. Studies of larger samples are warranted to assess the association of genetic variation in CRP and risk of cardiovascular disease.
血清C反应蛋白（CRP）水平是一种可遗传的复杂性状，可预测心血管疾病的发生。我们研究了血清CRP个体间变异的临床和遗传来源。
我们对3301名弗雷明汉心脏研究（FHS）参与者（平均年龄61岁，53%为女性）的血清CRP进行了研究。12个临床协变量解释了CRP水平变异的26%，仅体重指数就解释了15%（P<0.0001）的方差。为了研究CRP基因的遗传变异对CRP水平的影响，我们首先构建了一个密集的连锁不平衡图谱，用于跨越CRP基因座的常见单核苷酸多态性（SNP）（每850个碱基1个SNP，26千碱基[kb]基因组区域）。在1640名CRP水平已测的无关FHS参与者中对13个CRP SNP进行了基因分型。在调整临床协变量后，13个SNP中有9个与CRP水平相关（P<0.05）。为了考虑SNP之间的相关性，我们在所有13个SNP中进行了向前逐步选择；一个三等位基因SNP（rs3091244）仍与CRP水平相关（逐步P<0.0001）。该三等位基因SNP（C→T→A；等位基因频率分别为62%、31%和7%）位于启动子序列中，解释了血清CRP总变异的1.4%；携带该SNP次要T和A等位基因的单倍型与较高的CRP水平相关（单倍型P=0.0002和0.004）。
在我们基于社区的样本中，临床变量解释了CRP个体间变异的26%，而一个常见的三等位基因CRP SNP贡献较小。有必要对更大样本进行研究，以评估CRP基因变异与心血管疾病风险的关联。
