Center for Genomic Medicine, Massachusetts General Hospital, Boston.
Stroke Unit, IRCCS Mondino Foundation, Pavia, Italy.
JAMA Neurol. 2019 Apr 1;76(4):480-491. doi: 10.1001/jamaneurol.2018.4519.
Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations.
To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) ε4 alleles, the most potent genetic risk factor for ICH.
DESIGN, SETTING, AND PARTICIPANTS: This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study.
Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies.
In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE ε2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE ε4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE ε4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE ε2 and ε4 did not show an association with nonlobar ICH risk in any race/ethnicity.
APOE ε4 and ε2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
脑出血 (ICH) 的遗传研究主要集中在白种参与者身上，但遗传风险可能因非白人群体中不同的非遗传共同暴露而有所不同或被掩盖。跨种族分析风险可能会阐明遗传在不同人群中ICH 风险中的作用。
评估种族/族裔间 ICH 风险的既定差异与载脂蛋白 E (APOE) ε4 等位基因风险的可变性之间的关联，APOE ε4 等位基因是 ICH 最强的遗传风险因素。
设计、设置和参与者：本项原发性 ICH 的病例对照研究对 APOE 等位基因状态与 ICH 风险的关联进行了荟萃分析，应用基于种族/族裔的两阶段聚类方法，并按促成研究进行分层。采用倾向评分分析来模拟 APOE 与种族/族裔组中高血压负担的关联。原发性 ICH 病例和对照是从美国 3 家医院和人群为基础的研究以及国际中风遗传联盟的 8 个欧洲研究地点收集的。参与者于 1999 年 1 月 1 日至 2017 年 12 月 31 日入组。继发性 ICH 患者被排除在入组之外。在每个参与的研究中，对照都在区域内进行匹配。
临床变量是在每个地点的结构化访谈中系统获得的。所有研究都对 APOE 基因型进行了中心检测。
共纳入 13124 名参与者（7153 名[54.5%]男性，中位[四分位数间距]年龄为 66[56-76]岁）。在白种参与者中，APOE ε2（比值比[OR]，1.49；95%置信区间[CI]，1.24-1.80；P<0.001）和 APOE ε4（OR，1.51；95%CI，1.23-1.85；P<0.001）与脑叶 ICH 风险相关；然而，在自我认定的西班牙裔和黑人参与者中，没有发现关联。在对高血压负担进行倾向评分匹配后，APOE ε4 与西班牙裔（OR，1.14；95%CI，1.03-1.28；P=0.01）而非黑人（OR，1.02；95%CI，0.98-1.07；P=0.25）参与者的脑叶 ICH 风险相关。APOE ε2 和 ε4 与任何种族/族裔的非脑叶 ICH 风险均无关联。
APOE ε4 和 ε2 等位基因似乎通过种族/族裔差异对脑叶 ICH 风险有不同的影响，这种关联在白种人中得到了证实，但只有在对高血压的额外负担进行倾向评分匹配后，才能在西班牙裔人群中表现出来；需要进一步的研究来探索在有 ICH 风险的代表性人群中，APOE 等位基因与因种族/族裔而异的环境暴露之间的相互作用。
