Department of Neurology, Boston University School of Medicine, Boston, Mass, USA.
Stroke. 2010 Feb;41(2):210-7. doi: 10.1161/STROKEAHA.109.569194. Epub 2009 Dec 31.
Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).
The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.
This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.
先前研究检查与 MRI 定义的脑梗死相关的遗传关联性，得出了不一致的结果。我们研究了无短暂性脑缺血发作或中风病史者的隐匿性 MRI 梗死的遗传变异。我们对包含在心血管衰老遗传学研究（CHARGE）联盟中的 6 项研究中的白种人参与者进行了全基因组关联研究的荟萃分析。
利用 220 万个基因分型和推测的单核苷酸多态性，每个研究使用年龄和性别调整的逻辑回归模型进行 MRI 梗死的横断面全基因组关联分析。在逆方差加权荟萃分析中，将研究特异性发现合并在一起，该分析包括 9401 名平均年龄 69.7 岁的参与者（其中 19.4%有≥1 个 MRI 梗死）。
与 MACRO 结构域包含 2 基因内含子 3 和纤维连接蛋白富含亮氨酸跨膜蛋白 3 基因下游区域的 rs2208454（次要等位基因频率为 20%）的关联最显著。每个次要等位基因的拷贝与较低的 MRI 梗死风险相关（比值比，0.76；95%置信区间，0.68-0.84；P=4.64x10(-7)）。与 rs2208454 处于连锁不平衡（r(2)>0.64）的 22 个其他单核苷酸多态性也有高度提示性关联（P<1.0x10(-5)）。rs2208454 的关联在来自 1822 名白人和 644 名黑人参与者的独立样本中未得到复制，尽管 rs2208454 附近 200kb 内的 4 个单核苷酸多态性与黑人样本的 MRI 梗死相关。
这是第一项关于隐匿性 MRI 梗死的基于社区的全基因组关联研究，揭示了新的关联。尽管未能复制与顶尖单核苷酸多态性的关联，可能是因为效力不足，但黑人样本的结果令人鼓舞，需要进一步进行复制研究。
