von Berg Joanna, McArdle Patrick F, Häppölä Paavo, Haessler Jeffrey, Kooperberg Charles, Lemmens Robin, Pezzini Alessandro, Thijs Vincent, Pulit Sara L, Kittner Steven J, Mitchell Braxton D, de Ridder Jeroen, van der Laan Sander W
Center for Molecular Medicine, Division Laboratories, Pharmacy, and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Oncode Institute, Utrecht, Netherlands.
Front Genet. 2024 Sep 2;15:1392061. doi: 10.3389/fgene.2024.1392061. eCollection 2024.
Large genome-wide association studies (GWASs) using case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing the age at onset (AAO) of ischemic stroke.
Analyses were conducted in a discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with -value <1 x 10 in a sexcombined or sex-stratified analysis using summary data from two additional replication cohorts.
In the women-only meta-analysis, we detected significant evidence for the association of AAO with rs429358, an exonic variant in apolipoprotein E () that encodes for the APOE-Є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29-year earlier stroke AAO (meta -value = 2.48 x 10). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decrease in mortality among APOE-Є4 carriers and have no association to stroke AAO per se. A simulation study showed that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a 2-fold increase in mortality risk would lead to an observed effect of AAO that is comparable to what we found.
In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.
采用病例对照研究设计的大型全基因组关联研究（GWAS）现已确定了数十个与缺血性中风（IS）相关的基因座。作为这些研究的补充，我们采用仅病例设计进行了GWAS，以确定影响缺血性中风发病年龄（AAO）的基因座。
使用线性回归框架在一个由10857例缺血性中风病例组成的发现队列中进行分析。我们使用另外两个重复队列的汇总数据，在性别合并或性别分层分析中对所有P值<1×10⁻⁵的单核苷酸多态性（SNP）进行了荟萃分析。
在仅女性的荟萃分析中，我们检测到显著证据表明AAO与rs429358相关，rs429358是载脂蛋白E（APOE）中的一个外显子变体，编码APOE-ε4等位基因。rs429358:T>C等位基因的每个拷贝与中风发病年龄提前1.29年相关（荟萃分析P值 = 2.48×10⁻⁶）。此前已发现该APOE变体与死亡率增加和缺血性中风发病年龄相关。我们推测，与发病年龄的关联可能反映了一种生存偏倚，这是由于APOE-ε4携带者中与年龄相关的死亡率下降所致，而与中风发病年龄本身并无关联。一项模拟研究表明，与总体死亡率相关的变体确实可能在发病年龄分析中被检测到。死亡率风险增加2倍的变体将导致观察到的发病年龄效应与我们的发现相当。
总之，我们检测到APOE基因座与中风发病年龄之间存在强有力的关联，并通过模拟表明这种关联可能与缺血性中风本身无关，而是与一般的生存偏倚有关。
