Apo E genotype, diabetes, and peripheral arterial disease in older men: the Honolulu Asia-aging study

The epsilon4 allele of the gene coding for apolipoprotein (apo) E is associated with an atherogenic lipid profile that has been linked to increased risk of coronary artery disease (CAD). Apo E genotype may also be associated with peripheral arterial disease (PAD). If present, this association may be modified by diabetes, which is also associated with dyslipidemia that predisposes to macrovascular disease. Observable associations between both ApoE genotype and diabetes with PAD may be confounded by smoking, a potent PAD risk factor that is unrelated to lipids. From 1991 to 1993, apo E genotypes (2/3, 3/3, 3/4), PAD (defined as ankle-brachial index [ABI] <0.9), diabetes (prevalent and newly-diagnosed), and smoking history (ever/never) were determined for 3,161 Japanese-American men aged 71-93. Data on hypertension and other potential confounders were also collected. Logistic regression was used to determine odds ratios (OR) between groups cross-categorized by apo E genotype and diabetes with prevalence of PAD, within strata of smoking. In each smoking stratum, non-diabetic apo epsilon3/3 carriers were considered the reference. Among ever-smokers, there was no association between apo E and PAD, regardless of diabetes status. Among never-smokers there appeared to be both apo E- and diabetes effects on PAD prevalence. Compared to the non-diabetic epsilon3/3 group, the ORS of PAD were 2.3 (1.2-4.4) and 2.0 (1.1-3.4) for epsilon3/3 newly-diagnosed and epsilon3/3 prevalent diabetic subjects, respectively. Associations were stronger among diabetic individuals in the epsilon3/4 group: the ORS were 3.0 (1.1-8.8) and 4.1 (1.9-8.7) for epsilon3/4 newly-diagnosed and epsilon3/4prevalent diabetic subjects, respectively. Despite associations whose pattern and magnitude suggested interaction between apo E genotype and diabetes on PAD prevalence among never-smokers, formal testing of this interaction did not reach statistical significance. Our finding of an apo E-PAD association among never-smokers may result from the effects of an apo epsilon4-related atherogenic lipid profile on peripheral arteries. Further studies are needed to clarify the potential mediating role of diabetes on the apo E-PAD association.