Apolipoprotein E4 reduces risk of diabetic nephropathy in patients with NIDDM

Kimura, Hideki; Suzuki, Yuichi; Gejyo, Fumitake; Karasawa, R; Miyazaki, Ryunosuke; Suzuki, Shuhei; Arakawa, Masaaki

doi:10.1053/ajkd.1998.v31.pm9531184

Cited by 81 publications

(60 citation statements)

References 19 publications

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“…However, several studies, even in Japanese subjects with type 2 diabetes, did not confirm this association (12-15). Kimura et al (12) did not find the association between the ⑀2 carriers and ESRD in a total of 178 Japanese patients with type 2 diabetes. Also, Hadjadj et al (15) examined 494 subjects with type 1 diabetes and various stages of DN and found that the distribution of the APOE genotypes did not differ according to the stage of DN.…”

Section: Discussionmentioning

confidence: 91%

“…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).…”

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confidence: 99%

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

et al. 2003

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OBJECTIVE -The aim of this study is to clarify the conflicting results of the ⑀2/⑀3/⑀4 APOE polymorphism as a risk factor on diabetic nephropathy by a cohort study. RESEARCH DESIGN AND METHODS-A total of 429 Japanese subjects with type 2 diabetes and with normoalbuminuria (n ϭ 299) or with microalbuminuria (n ϭ 130) were enrolled in a prospective observational follow-up study during 1995-1998 and followed until 2001 (for at least 3 years). The endpoint was the occurrence of a renal event defined as the progression to a higher stage of diabetic nephropathy.RESULTS -During the study (the mean follow-up period: 4.4 Ϯ 1.0 years), 31 of 429 subjects progressed: 21 from normoalbuminuria to microalbuminuria and 10 from microalbuminuria to overt proteinuria. The allele frequency of the APOE polymorphism was significantly different between the progressors and the nonprogressors. Eight of 42 ⑀2 carriers (19%) progressed, whereas 23 of 387 noncarriers (6%) progressed with a relative risk of 3.2 (95% CI 1.5-6.7). When subjects were stratified by renal status at baseline, each relative risk for the progression in the ⑀2 carriers was 2.7 (0.99 -7.4) in those with normoalbuminuria and 4.2 (1.3-13.3) in those with microalbuminuria. Furthermore, when analyzed only in subjects with normoalbuminuria and short duration of diabetes (Ͻ15 years) at baseline, the risk in the ⑀2 carriers became higher to 3.2 (1.2-8.8).CONCLUSIONS -Our follow-up study indicates that the ⑀2 allele of the APOE polymorphism is a prognostic risk factor for both the onset and the progression of diabetic nephropathy in Japanese type 2 diabetes. Diabetes Care 26:2416 -2420, 2003D iabetic nephropathy (DN) associated with type 2 diabetes is a leading cause of end-stage renal disease (ESRD) in Japan and the U.S. (1,2). Although long-standing hyperglycemia is an important risk factor for the development of DN, epidemiologic and family studies suggest that genetic susceptibility to this complication is also required (3). The abnormalities of lipid metabolism have been proposed as one plausible mechanism in the pathogenesis of the development of DN (4). Thus, the genes encoding components of this pathway that regulate lipid metabolism can be considered as candidate genes susceptible to DN (5).Apolipoprotein E (apoE) is a 299-amino acid glycoprotein that plays a central role in lipid metabolism. ApoE is well known to consist of three common isoforms (E2, E3, E4) encoded by three alleles (⑀2, ⑀3, ⑀4) in exon 4 of the apoE gene (APOE) (6). The lipid profiles or atherogenic factors are, in part, determined by this genetic variation of APOE (6). Carriers of apoE4 have higher plasma levels of total cholesterol and low-density lipoprotein cholesterol than carriers of apoE2 or apoE3 homozygotes (6). On the other hand, the binding of apoE2 to lipoprotein receptors is defective in comparison with that of E3 or E4 and results in delayed clearance of triglyceride (TG)-rich lipoprotein.Recently, this ⑀2/⑀3/⑀4 polymorphism of APOE has been investigated for the association with DN ...

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Section: Discussionmentioning

confidence: 91%

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confidence: 99%

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

et al. 2003

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“…This may be due in part to the small sample size used in all but one study (70). 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).…”

Section: Additional Candidate Genes Of Interestmentioning

confidence: 99%

Genetic Factors in Diabetic Nephropathy

Freedman

Bostrom

Daeihagh

et al. 2007

Clinical Journal of the American Society of Nephrology

173

125

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Several genes that predispose to type 2 diabetes have recently been identified. In addition to the recognized and powerful effects of environmental factors, there is abundant evidence in support of genetic susceptibility to the microvascular complication of nephropathy in individuals with both type 1 and type 2 diabetes. Familial aggregation of phenotypes such as end-stage renal disease, albuminuria, and chronic kidney disease have routinely been reported in populations throughout the world, and heritability estimates for albuminuria and glomerular filtration rate demonstrate strong contributions of inherited factors. Recent genome-wide linkage scans have identified several chromosomal regions that likely contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under these linkage peaks. These complimentary approaches have demonstrated that polymorphisms in the carnosinase 1 gene on chromosome 18q, the adiponectin gene on 3q, and the engulfment and cell motility gene on 7p are likely associated with susceptibility to diabetic nephropathy. Additional genes that seem to be of importance in renal phenotypes include manganese superoxide dismutase and angiotensin 1-converting enzyme, with nitric oxide synthase implicated in albuminuria. This article reviews the inherited aspects of diabetic kidney disease with particular emphasis on recently implicated genes and pathways. It seems likely that the risk for diabetes-associated kidney disease is magnified by inheriting risk alleles at several susceptibility loci, in the presence of hyperglycemia.Clin J Am Soc Nephrol 2: 1306 -1316, 2007. doi: 10.2215/CJN.02560607 I t was previously thought that individuals who had diabetes and developed progressive diabetic nephropathy (DN) and/or ESRD were simply exposed to long durations of diabetes with relatively poor glycemic control. In other words, all individuals with diabetes were assumed to be at essentially equivalent risk for developing nephropathy, allowing for differences in their ambient serum glucose concentration. In support of the concept that exposure to a hyperglycemic environment led to DN (often with coexisting obesity, metabolic syndrome, hypertension, and hyperlipidemia), clinical trials have conclusively demonstrated that improving glycemic control delays and, in some cases, may prevent the subsequent development of albuminuria, DN, and macrovascular complications such as coronary artery disease (1,2). The concept that select individuals with diabetes were at differential risk for developing nephropathy on the basis of familial aggregation of kidney disease was initially reported in 1989 but has only recently gained broad acceptance among nephrologists and diabetologists (3). Familial Aggregation of DNThe notion that genetic factors contribute to any complex disease rests on the demonstration of familial aggregation. Familial clustering of nephropathy could result from shared genes, environmental exposures, or their combination.After repeated demonstra...

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“…On the other hand, some other studies found no relationship between APO E2 and DN. 6,42,45,46 Conversely, Boizel et al 47 claimed that the risk for DN was lower with APO E2 than it was with E3 and E4. In another study conducted with a Turkish population, Ilhan et al 31 claimed that there might be a relationship between APO E4 isoform and DN.…”

Section: Discussionmentioning

confidence: 99%

Association of the Angiotensinogen M235T and APO E Gene Polymorphisms in Turkish Type 2 Diabetic Patients with and without Nephropathy

et al. 2011

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Background: Diabetic nephropathy (DN) is a leading cause of diabetes-related morbidity and mortality. The aim of this study was to evaluate the relationship of AGT M235T and apoprotein E (APO E) gene polymorphism with DN in Turkish patients of Type 2 diabetes, and to compare genotype and allele distributions among DN patients, non-DN patients, and healthy controls. Methods: AGT M235T and APO E genotype and allele analysis were performed in 111 DN patients, 108 non-DN patients, 106 healthy control subjects for APO E genotype, and 100 for AGT M235T genotype polymorphism. APO E and AGT M235T genotype were determined by RFLP-PCR. Results: The frequencies of APO E ε2/3, ε 3/3, ε 3/4 genotypes were 22.7%, 60%, 60%, respectively, among DN patients and 6.6%, 80%, 10.4%, respectively (p < 0.001), in the non-DN patients. The frequencies of AGT M235T MM, MT, TT genotypes among the same groups were 17%, 46%, 37% and 21%, 63%, 16%, respectively (p < 0.02). Having the ε2/3 genotype and TT genotype increased the risk for DN nephropathy [4.8-fold (95% CI: 1.94-11.67), 2.9-fold (95% CI: 1.27-6.69), respectively]. Conclusion: Our study has shown that AGT M235T TT genotype and APO E ε 2/3 genotype may be linked to a risk for DN among Turkish population.

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Apolipoprotein E4 reduces risk of diabetic nephropathy in patients with NIDDM

Cited by 81 publications

References 19 publications

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

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

Genetic Factors in Diabetic Nephropathy

Association of the Angiotensinogen M235T and APO E Gene Polymorphisms in Turkish Type 2 Diabetic Patients with and without Nephropathy

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