在群体结构中利用基因组学和流行病学研究对炎症相关基因变异和C反应蛋白进行多祖先分析。
Multiancestral analysis of inflammation-related genetic variants and C-reactive protein in the population architecture using genomics and epidemiology study.
作者信息
Kocarnik Jonathan M, Pendergrass Sarah A, Carty Cara L, Pankow James S, Schumacher Fredrick R, Cheng Iona, Durda Peter, Ambite José Luis, Deelman Ewa, Cook Nancy R, Liu Simin, Wactawski-Wende Jean, Hutter Carolyn, Brown-Gentry Kristin, Wilson Sarah, Best Lyle G, Pankratz Nathan, Hong Ching-Ping, Cole Shelley A, Voruganti V Saroja, Bůžkova Petra, Jorgensen Neal W, Jenny Nancy S, Wilkens Lynne R, Haiman Christopher A, Kolonel Laurence N, Lacroix Andrea, North Kari, Jackson Rebecca, Le Marchand Loic, Hindorff Lucia A, Crawford Dana C, Gross Myron, Peters Ulrike
出版信息
Circ Cardiovasc Genet. 2014 Apr;7(2):178-88. doi: 10.1161/CIRCGENETICS.113.000173. Epub 2014 Mar 12.
BACKGROUND
C-reactive protein (CRP) is a biomarker of inflammation. Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) associated with CRP concentrations and inflammation-related traits such as cardiovascular disease, type 2 diabetes mellitus, and obesity. We aimed to replicate previous CRP-SNP associations, assess whether these associations generalize to additional race/ethnicity groups, and evaluate inflammation-related SNPs for a potentially pleiotropic association with CRP.
METHODS AND RESULTS
We selected and analyzed 16 CRP-associated and 250 inflammation-related GWAS SNPs among 40 473 African American, American Indian, Asian/Pacific Islander, European American, and Hispanic participants from 7 studies collaborating in the Population Architecture using Genomics and Epidemiology (PAGE) study. Fixed-effect meta-analyses combined study-specific race/ethnicity-stratified linear regression estimates to evaluate the association between each SNP and high-sensitivity CRP. Overall, 18 SNPs in 8 loci were significantly associated with CRP (Bonferroni-corrected P<3.1×10(-3) for replication, P<2.0×10(-4) for pleiotropy): Seven of these were specific to European Americans, while 9 additionally generalized to African Americans (1), Hispanics (5), or both (3); 1 SNP was seen only in African Americans and Hispanics. Two SNPs in the CELSR2/PSRC1/SORT1 locus showed a potentially novel association with CRP: rs599839 (P=2.0×10(-6)) and rs646776 (P=3.1×10(-5)).
CONCLUSIONS
We replicated 16 SNP-CRP associations, 10 of which generalized to African Americans and/or Hispanics. We also identified potentially novel pleiotropic associations with CRP for two SNPs previously associated with coronary artery disease and/or low-density lipoprotein-cholesterol. These findings demonstrate the benefit of evaluating genotype-phenotype associations in multiple race/ethnicity groups and looking for pleiotropic relationships among SNPs previously associated with related phenotypes.
背景
C反应蛋白（CRP）是一种炎症生物标志物。全基因组关联研究（GWAS）已鉴定出与CRP浓度以及心血管疾病、2型糖尿病和肥胖等炎症相关性状相关的单核苷酸多态性（SNP）。我们旨在重复先前的CRP-SNP关联，评估这些关联是否适用于其他种族/族裔群体，并评估炎症相关SNP与CRP的潜在多效性关联。
方法与结果
我们从参与基因组学和流行病学群体结构（PAGE）研究的7项研究中的40473名非裔美国人、美洲印第安人、亚太岛民、欧裔美国人和西班牙裔参与者中选择并分析了16个与CRP相关的SNP和250个与炎症相关的GWAS SNP。固定效应荟萃分析结合了各研究特定种族/族裔分层的线性回归估计值，以评估每个SNP与高敏CRP之间的关联。总体而言，8个基因座中的18个SNP与CRP显著相关（复制的Bonferroni校正P<3.1×10⁻³，多效性的P<2.0×10⁻⁴）：其中7个仅在欧裔美国人中出现，而9个另外适用于非裔美国人（1个）、西班牙裔（5个）或两者（3个）；1个SNP仅在非裔美国人和西班牙裔中出现。CELSR2/PSRC1/SORT1基因座中的两个SNP与CRP显示出潜在的新关联：rs599839（P=2.0×10⁻⁶）和rs646776（P=3.1×10⁻⁵）。
结论
我们重复了16个SNP-CRP关联，其中10个适用于非裔美国人和/或西班牙裔。我们还确定了先前与冠状动脉疾病和/或低密度脂蛋白胆固醇相关的两个SNP与CRP的潜在新多效性关联。这些发现证明了在多个种族/族裔群体中评估基因型-表型关联以及寻找先前与相关表型相关的SNP之间的多效性关系的益处。
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