Keebler Mary E, Deo Rahul C, Surti Aarti, Konieczkowski David, Guiducci Candace, Burtt Noel, Buxbaum Sarah G, Sarpong Daniel F, Steffes Michael W, Wilson James G, Taylor Herman A, Kathiresan Sekar
Massachusetts General Hospital, Boston, MA 02115, USA.
Circ Cardiovasc Genet. 2010 Aug;3(4):358-64. doi: 10.1161/CIRCGENETICS.109.914267. Epub 2010 Jun 22.
Genome-wide association studies in cohorts of European descent have identified novel genomic regions as associated with lipids, but their relevance in African Americans remains unclear.
We genotyped 8 index single nucleotide polymorphisms (SNPs) and 488 tagging SNPs across 8 novel lipid loci in the Jackson Heart Study, a community-based cohort of 4605 African Americans. For each trait, we calculated residuals adjusted for age, sex, and global ancestry and performed multivariable linear regression to detect genotype-phenotype association with adjustment for local ancestry. To explore admixture effects, we conducted stratified analyses in individuals with a high probability of 2 African ancestral alleles or at least 1 European allele at each locus. We confirmed 2 index SNPs as associated with lipid traits in African Americans, with suggestive association for 3 more. However, the effect sizes for 4 of the 5 associated SNPs were larger in the European local ancestry subgroup compared with the African local ancestry subgroup, suggesting that the replication is driven by European ancestry segments. Through fine-mapping, we discovered 3 new SNPs with significant associations, 2 with consistent effect on triglyceride levels across ancestral groups: rs636523 near DOCK7/ANGPTL3 and rs780093 in GCKR. African linkage disequilibrium patterns did not assist in narrowing association signals.
We confirm that 5 genetic regions associated with lipid traits in European-derived populations are relevant in African Americans. To further evaluate these loci, fine-mapping in larger African American cohorts and/or resequencing will be required.
在欧洲裔人群队列中开展的全基因组关联研究已确定了与血脂相关的新基因组区域，但这些区域在非裔美国人中的相关性仍不明确。
我们在杰克逊心脏研究中对4605名非裔美国人的社区队列中的8个新血脂位点的8个索引单核苷酸多态性（SNP）和488个标签SNP进行了基因分型。对于每个性状，我们计算了经年龄、性别和总体祖先调整后的残差，并进行多变量线性回归以检测在调整局部祖先后的基因型-表型关联。为了探究混合效应，我们在每个位点具有两个非洲祖先等位基因或至少一个欧洲等位基因的高概率个体中进行了分层分析。我们确认了2个索引SNP与非裔美国人的血脂性状相关，另有3个存在提示性关联。然而，与非洲局部祖先亚组相比，5个相关SNP中的4个在欧洲局部祖先亚组中的效应大小更大，这表明这种复制是由欧洲祖先片段驱动的。通过精细定位，我们发现了3个具有显著关联的新SNP，其中2个在不同祖先群体中对甘油三酯水平具有一致的影响：DOCK7/ANGPTL3附近的rs636523和GCKR中的rs780093。非洲连锁不平衡模式无助于缩小关联信号范围。
我们证实，在欧洲裔人群中与血脂性状相关的5个基因区域在非裔美国人中也具有相关性。为了进一步评估这些位点，需要在更大的非裔美国人队列中进行精细定位和/或重测序。
