APOE gene polymorphisms and their association with ischemic heart disease risk: a narrative review with implications for South Asian populations

Abstract Ischemic heart disease (IHD) is the leading cause of death worldwide and arises from a complex interplay of genetic, environmental, and lifestyle factors. Apolipoprotein E (ApoE), encoded by the APOE gene on chromosome 19q13.3, is a central regulator of lipid metabolism and one of the most extensively studied genetic determinants of cardiovascular risk. The three major APOE isoforms, ε2, ε3, and ε4, defined by the rs429358 and rs7412 single nucleotide polymorphisms, exert distinct effects on low-density lipoprotein cholesterol (LDL-C) levels, atherosclerotic plaque formation, and vascular inflammation. This review aimed to synthesise current evidence on APOE polymorphisms and their association with IHD, with particular attention to South Asian and Pakistani populations. A narrative literature search was conducted in PubMed, Scopus, and Google Scholar for studies published between 1990 and 2024, using the terms APOE polymorphism, ischemic heart disease, coronary artery disease, apolipoprotein E SNP, and cardiovascular genetics. The APOE ε4 allele was consistently associated with elevated total cholesterol and LDL-C levels, increased atherosclerotic burden, and higher IHD risk across multiple populations, whereas the ε2 allele was generally protective, with the notable exception of rare ε2/ε2 homozygotes who may develop type III hyperlipoproteinemia. Promoter-region polymorphisms, including rs405509, rs769446, and rs449647, were found to further modulate APOE expression and may independently influence lipid profiles and plaque stability. In a premature coronary artery disease cohort, the ε3/ε4 genotype (18.9% versus 10.2% in controls; p = 0.001) and the ε4 allele (11.1% versus 7.0%; p = 0.007) were significantly more frequent in patients than controls. South Asian populations, including Pakistanis, exhibited a lower ε4 allele frequency than Western populations yet remained disproportionately susceptible to IHD, suggesting that additional genetic and environmental factors substantially contribute to regional cardiovascular risk. APOE polymorphisms are important modulators of IHD risk through their effects on lipid metabolism, inflammation, and endothelial function. Although incorporating APOE genotyping into risk stratification holds promise, current evidence—particularly the absence of large-scale, longitudinal data in Pakistani populations—does not yet justify its routine clinical use for personalised prevention. Adequately powered, population-specific genotyping studies linked to long-term clinical outcomes are therefore needed before such applications can be realised.