Association of Apolipoprotein ε2 Allele With Diabetic Nephropathy in Caucasian Subjects With IDDM

Abstract

Epidemiological and family studies imply that genetic factors are important in the etiology of diabetic nephropathy in subjects with IDDM (1,2). Vascular disease is characteristic of nephropathy, and lipoproteins are important determinants of atherosclerosis. Apolipoprotein E (apoE) is a major protein constituent of lipoproteins, mediating hepatic lipoprotein uptake and reverse cholesterol transport. ApoE occurs as three isoproteins: E3 with normal function, E2 with reduced affinity, and E4 with increased affinity for the apoE receptor. These are encoded by three codominant alleles e2, E3, and e4. This polymorphism has an influence on lipid levels, the E2 isoform being associated with lower cholesterol but higher triglyceride levels compared with the E3 isoform, and the E4 isoform being associated with higher cholesterol but lower triglyceride levels (3). There is also an association with vascular disease in diabetic and nondiabetic populations (3,4). Preliminary data suggest that this triallelic polymorphism may be associated with genetic susceptibility to diabetic nephropathy (5). The aim of this study was thus to determine the role of the apoE gene polymorphism in a large cohort of IDDM patients with and without diabetic nephropathy.Four patient cohorts were examined: IDDM patients with diabetic nephropathy (nephropathy group, n = 252), IDDM patients with long duration of disease and no nephropathy (long-duration non-nephropathy group [LDNN], n = 197), a Received for publication 7 April 1997 and accepted in revised form 22 October 1997. apoE, apolipoprotein E; LDNN, long-duration non-nephropathy; UA/UC, urinary albumin/creatinine. background population of recently diagnosed patients with IDDM (sporadic diabetic group, n = 270), and nondiabetic control patients (nondiabetic group, n = 346). The criteria used to classify patients has been described previously in detail (6). Presence of hypertension, and retinopathy were inclusion criteria in the nephropathy cohort. DNA was extracted from peripheral blood leukocytes by the Nucleon method (Scotlab, Paisley, Scotland, U.K.). ApoE genotyping was performed by the method of Crook et al. (7).The distribution of alleles and genotypes were compared between the groups by x 2 analysis. A probability of <1 in 20 (P < 0.05) was taken to be significant. Odds ratios were determined by the logit method (Woolfs analysis). Statistical analysis was performed using the statistical package SPSS.No significant difference was seen between the nephropathy and LDNN groups in age at diagnosis of diabetes, duration of diabetes, mean HbA lc , and serum cholesterol at time of venesection. The nephropathy group had a significantly higher proportion of men (P < 0.01), systolic and diastolic blood pressure (P < 0.001), proportion on antihypertensive therapy (P < 0.01), and serum creatinine (P < 0.001). Allele frequencies between the nondiabetic group and the sporadic group (Table 1) were almost identical (x 2 = 0.886, P = 0.642). There was, however, significant heterogeneity in allele frequen...

Genetic Factors in Diabetic Nephropathy

“…Several studies (72)(73)(74) concluded that the ApoE4 isoform is associated with protection from type 2 DN in both white and Japanese individuals. Hsu et al (70) corroborated this finding, demonstrating that the frequency of the 4 allele is decreased in type 2 diabetes and chronic kidney disease and revealing association between the 2 allele and chronic kidney disease, a result that is consistent with several older studies of type 1 DN in white individuals (75,76) and one of type 2 DN in Japanese individuals (77). In contrast, an equal number of studies (78 -80) failed to find any association between 2 and type 2 DN or microvascular complications associated with type 2 diabetes.…”

Differences in HDL-cholesterol:apoA-I + apoA-II ratio and apoE phenotype with albuminuric status in Type I diabetic patients

“…Two previous studies (n = 162 and 252) did, however, find an association [17,19]. Two out of three studies in patients with Type II (non-insulin-dependent) diabetes mellitus found that the e2 allele was associated with increased risk of nephropathy [31,39,40].…”

“…Because the e2 allele is associated with an increased concentration of triglyceride [15,16] it is a candidate gene for the development of nephropathy. Three small studies in Type I diabetic patients have found conflicting evidence on whether the e2 allele is a risk factor for nephropathy [17,18,19]. Therefore in this study we also examined whether the e2 allele is associated with albuminuria, cross-sectionally and prospectively.…”

APOE Polymorphism and the Progression of Diabetic Nephropathy in Japanese Subjects With Type 2 Diabetes

“…Recently, this ⑀2/⑀3/⑀4 polymorphism of APOE has been investigated for the association with DN in subjects with both type 1 and type 2 diabetes using a case-control comparison, but the findings were inconclusive (7)(8)(9)(10)(11)(12)(13)(14)(15). Very recently, we reported that the ⑀2 allele of APOE increases the risk of DN in type 1 diabetes in a large number of case-control comparisons and a family-based study called the transmission/disequilibrium test (16).…”