Australian Centre for Precision Health, Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia.
Australian Centre for Precision Health, Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia; South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia; Department of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
EBioMedicine. 2020 Sep;59:102954. doi: 10.1016/j.ebiom.2020.102954. Epub 2020 Aug 17.
The three main alleles of the APOE gene (ε4, ε3 and ε2) carry differential risks for conditions including Alzheimer's disease (AD) and cardiovascular disease. Due to their clinical significance, we explored disease associations of the APOE genotypes using a hypothesis-free, data-driven, phenome-wide association study (PheWAS) approach.
We used data from the UK Biobank to screen for associations between APOE genotypes and over 950 disease outcomes using genotype ε3ε3 as a reference. Data was restricted to 337,484 white British participants (aged 37-73 years).
After correction for multiple testing, PheWAS analyses identified associations with 37 outcomes, representing 18 distinct diseases. As expected, ε3ε4 and ε4ε4 genotypes associated with increased odds of AD (p ≤ 7.6 × 10), hypercholesterolaemia (p ≤ 7.1 × 10) and ischaemic heart disease (p ≤ 2.3 × 10), while ε2ε3 provided protection for the latter two conditions (p ≤ 3.7 × 10) compared to ε3ε3. In contrast, ε4-associated disease protection was seen against obesity, chronic airway obstruction, type 2 diabetes, gallbladder disease, and liver disease (all p ≤ 5.2 × 10) while ε2ε2 homozygosity increased risks of peripheral vascular disease, thromboembolism, arterial aneurysm, peptic ulcer, cervical disorders, and hallux valgus (all p ≤ 6.1 × 10). Sensitivity analyses using brain neuroimaging, blood biochemistry, anthropometric, and spirometric biomarkers supported the PheWAS findings on APOE associations with respective disease outcomes.
PheWAS confirms strong associations between APOE and AD, hypercholesterolaemia, and ischaemic heart disease, and suggests potential ε4-associated disease protection and harmful effects of the ε2ε2 genotype, for several conditions.
National Health and Medical Research Council of Australia.
APOE 基因的三个主要等位基因（ε4、ε3 和 ε2）对包括阿尔茨海默病（AD）和心血管疾病在内的多种疾病的风险具有不同的影响。由于其具有临床意义，我们采用无假设、数据驱动的表型全基因组关联研究（PheWAS）方法探索了 APOE 基因型与疾病的关联。
我们使用英国生物库的数据，以 APOE 基因型 ε3ε3 为参照，在 337484 名白种英国人（年龄 37-73 岁）中筛查 APOE 基因型与 950 多种疾病结果之间的关联。
经多重检验校正后，PheWAS 分析鉴定出与 37 种疾病结果相关的关联，代表 18 种不同的疾病。如预期的那样，ε3ε4 和 ε4ε4 基因型与 AD（p≤7.6×10）、高胆固醇血症（p≤7.1×10）和缺血性心脏病（p≤2.3×10）的发病风险增加相关，而 ε2ε3 则为后两种疾病提供了保护（p≤3.7×10），与 ε3ε3 相比。相比之下，ε4 与肥胖症、慢性气道阻塞、2 型糖尿病、胆囊疾病和肝病（均 p≤5.2×10）的保护性疾病相关，而 ε2ε2 纯合子增加了外周血管疾病、血栓栓塞、动脉动脉瘤、消化性溃疡、颈椎疾病和拇囊炎（均 p≤6.1×10）的风险。使用脑神经影像学、血液生化、人体测量和肺功能生物标志物进行的敏感性分析支持 PheWAS 关于 APOE 与相应疾病结果关联的发现。
PheWAS 证实 APOE 与 AD、高胆固醇血症和缺血性心脏病之间存在强烈关联，并表明 ε4 与多种疾病相关的潜在保护性疾病和 ε2ε2 基因型的有害影响。
澳大利亚国家健康与医学研究委员会。
