APOE gene variants shape heart disease risk, but South Asia tells a different story

Ischemic heart disease remains the leading cause of death worldwide, and a newly published narrative review argues that one of the most intensively studied genes in cardiovascular medicine, APOE, still holds unresolved answers for some of the world’s most affected populations. Writing in the Egyptian Journal of Medical Human Genetics, researchers Anam Ijaz and Shabana synthesized evidence from studies published between 1990 and 2024, drawing on roughly 80 records identified in PubMed, Scopus, and Google Scholar, of which 53 were retained as the primary evidence base. Their central conclusion is double-edged: the APOE ε4 allele is a consistent and mechanistically well-understood driver of heart disease risk across European, American, and Asian cohorts, yet South Asian populations, including Pakistanis, carry it less often than Europeans while suffering a disproportionate share of the disease.

The APOE gene sits on chromosome 19 at position 19q13.3 and encodes a 299-amino-acid glycoprotein that serves as the primary ligand for low-density lipoprotein receptors on liver cells, mediating the clearance of atherogenic lipoproteins from the bloodstream. Three major protein isoforms, ApoE2, ApoE3, and ApoE4, arise from two single nucleotide polymorphisms within exon 4: rs429358, which substitutes an arginine for cysteine at position 112, and rs7412, which substitutes a cysteine for arginine at position 158. The haplotype combinations of these two variants produce the ε2, ε3, and ε4 alleles and six possible genotypes, each with markedly different consequences for lipid metabolism.

The molecular details matter because they explain why the isoforms behave so differently. In the ε2 isoform, the Arg158Cys substitution disrupts a critical electrostatic interaction with aspartate 154, reducing ApoE2’s affinity for the LDL receptor by 50- to 100-fold relative to ApoE3. The immediate result is slower hepatic clearance of remnant lipoproteins, which typically lowers LDL cholesterol through compensatory receptor upregulation but can paradoxically cause type III hyperlipoproteinemia in the rare homozygous ε2/ε2 individuals, estimated at roughly 1 percent of the population, substantially raising cardiovascular risk in that small group. In the ε4 isoform, the Cys112Arg substitution does not impair receptor binding at all; instead, it shifts the protein’s lipoprotein preference. Whereas ApoE2 and ApoE3 preferentially associate with HDL particles, ApoE4 binds LDL and very-low-density lipoprotein through trans-domain interactions between arginine 61 and glutamate 255, promoting accelerated VLDL processing, downregulation of hepatic LDL receptors, and ultimately elevated circulating LDL cholesterol, the central driver of atherosclerosis.

Quantitative differences in protein levels add a further layer. Plasma ApoE concentrations follow a clear genotype hierarchy, highest in E2/E2 homozygotes and falling progressively by 29, 34, 43, 46, and 49 percent across the 2/3, 2/4, 3/3, 3/4, and 4/4 genotypes respectively. The ε2-defining rs7412 variant is associated with elevated ApoE levels, while the ε4-defining rs429358 variant is linked to significantly lower concentrations, an effect the review reports with a beta coefficient of −0.352 and a p-value of 8.73 × 10−12. Because higher circulating ApoE correlates with more efficient lipoprotein clearance, these genotype-driven differences are mechanistically relevant to disease risk.

The clinical evidence is most striking in a Chinese cohort study of premature coronary artery disease. The ε3/ε4 genotype appeared in 18.9 percent of patients versus 10.2 percent of age- and sex-matched controls, a difference the authors reported at p = 0.001, and the ε4 allele frequency was likewise elevated at 11.1 percent versus 7.0 percent, p = 0.007. Logistic regression identified ε3/ε4 carriage as an independent risk factor alongside body mass index of 24.0 kg/m² or above, smoking, and elevated total cholesterol. Consistent with the allele’s lipid phenotype, controls carrying ε2 in the same study had significantly higher HDL cholesterol, 1.42 versus 1.22 mmol/L at p = 0.011, and lower LDL cholesterol, 2.03 versus 2.46 mmol/L at p < 0.001, than ε3-homozygous controls. Earlier work, including the European Atherosclerosis Research Study, documented a dose-response relationship between the number of ε4 alleles and coronary heart disease risk in young European adults, an effect amplified by traditional risk factors.

The review also highlights promoter-region variants that modulate APOE expression independently of the canonical isoform system. The rs405509 T/T genotype reduces APOE transcription and has been associated with impaired cholesterol efflux from macrophage foam cells and altered inflammatory responses, both of which influence plaque stability. The rs769446 variant has been shown to modulate expression bidirectionally, and in a Korean population study its minor C allele was protective against normal-tension glaucoma, illustrating the pleiotropic reach of this locus. Together with rs449647, these promoter SNPs may influence lipid profiles and plaque biology in ways not captured by ε2/ε3/ε4 genotyping alone, a point the authors stress as an underexplored dimension of cardiovascular genetics.

The population-level picture is where the review’s argument becomes most provocative. In European populations, ε4 is described as one of the strongest known genetic risk factors for ischemic heart disease, with a population attributable risk comparable to hypertension, and North American GWAS data have confirmed rs429358 as a top-ranked associated SNP. In Asian populations, by contrast, ε4 frequency is generally lower, yet carriers retain elevated risk, suggesting the allele’s pathogenic mechanisms are conserved across ethnic groups even as dietary and lifestyle factors modulate its penetrance. Pakistan exemplifies the paradox: the age-standardised incidence of cardiovascular disease stands at 918.18 per 100,000, well above the global rate of 684.33, and cardiovascular deaths doubled from 170,000 to 340,000 between 1990 and 2019, while ischemic heart disease mortality reaches 410 per 100,000.

Within Pakistan, the available studies are small but convergent. A case-control study of the Pashtun ethnic group in Khyber Pakhtunkhwa, involving 200 myocardial infarction cases and 100 controls, found the ε4-defining rs429358 variant significantly associated with myocardial infarction, with an odds ratio of 2.11 and a 95 percent confidence interval of 1.25 to 2.43. A larger angiographic study of 672 genotyped Pakistani patients found ε4 carriers significantly over-represented among those with severe coronary stenosis of 70 percent or more compared with mild stenosis below 30 percent, at 22.8 versus 13.0 percent, p = 0.01, and reported an odds ratio of 2.16 with a confidence interval of 1.29 to 3.79. A further study of 623 Pakistani subjects, 219 without and 404 with coronary heart disease, confirmed the isoform-specific lipid pattern, with each ε2 allele lowering and each ε4 allele raising LDL cholesterol. Comparative data indicate the ε4 allele is markedly less frequent in Pakistani cohorts, at 2.5 to 9.1 percent, than in Northern European populations at roughly 14 percent, and the ε2 allele is frequently rare or absent, yet its pathogenic effect persists despite the low frequency.

Ethnic heterogeneity within Pakistan complicates the picture further. The country comprises Punjabi, Pashtun, Sindhi, Muhajir, and Baloch populations alongside Kashmiri and other groups, and APOE data are not uniformly available across them. In the ethnic Kashmiri population, the ε4 allele was more frequent in coronary artery disease patients than controls, 0.20 versus 0.11, with ε3/ε3 predominant and ε2 comparatively rare at roughly 0.06 to 0.075. Notably, the ε4 frequency among Kashmiri controls, about 11 percent, is considerably higher than estimates from general healthy Pakistani samples of around 2.5 percent, indicating meaningful inter-ethnic variation. Critically, the authors report that no dedicated APOE and ischemic heart disease studies have yet been conducted in the Punjabi majority or in the Sindhi, Baloch, or Muhajir populations, a gap they describe as significant given the evident heterogeneity between the Pashtun and Kashmiri groups.

The review is explicit about its own limits and about what its findings do not yet license. As a narrative rather than systematic review, it is subject to non-systematic evidence selection and potential selection bias, and its conclusions should be regarded as hypothesis-generating. The underlying Pakistani studies range from roughly 100 to 700 participants, are geographically concentrated, predominantly cross-sectional, and seldom adjust for the full spectrum of confounders. The authors therefore conclude that incorporating APOE genotyping into routine clinical risk stratification is not yet justified, particularly in the absence of large-scale longitudinal data in Pakistani populations, and they frame genotype-guided strategies, such as earlier lipid-lowering intervention for ε4 carriers, as biologically plausible hypotheses requiring prospective validation rather than current recommendations. Their priority research directions include a large-scale Pakistani cardiovascular genetics biobank with linked longitudinal outcomes, characterisation of promoter haplotypes in South Asian cohorts, investigation of gene-environment interactions with diet, air pollution, and tobacco, and evaluation of whether ethnicity-calibrated polygenic risk scores outperform European-derived scores in South Asian cardiovascular prediction.

Subject of Research: APOE gene polymorphisms and their association with ischemic heart disease risk, with a focus on South Asian populations

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

Article References: Ijaz, A., & Shabana (2026). APOE gene polymorphisms and their association with ischemic heart disease risk: a narrative review with implications for South Asian populations. Egyptian Journal of Medical Human Genetics, 27(1), Article 90. https://doi.org/10.1186/s43042-026-00921-w

Image Credits: AI Generated

DOI: 10.1186/s43042-026-00921-w

Keywords: APOE, ischemic heart disease, genetics, lipid metabolism, rs429358, rs7412, Pakistan, South Asia, cardiovascular risk, LDL cholesterol, polymorphism, narrative review