Apolipoprotein E genetic polymorphism, remnant lipoproteins, and nephropathy in type 2 diabetic patients

Eto, Masashi; Saito, Mieko; Okada, Mizuho; Kume, Yoshie; Kawasaki, Fumiko; Matsuda, Masafumi; Yoneda, Masaya; Matsuki, Michihiro; Takigami, Shigeru; Kaku, Kohei

doi:10.1053/ajkd.2002.34502

Cited by 76 publications

(52 citation statements)

References 39 publications

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“…One possibility is the lipid abnormalities related to the APOE polymorphism. Recently, Eto et al (22) reported that remnant lipoproteins associated with the ⑀2 allele may have an important role in the development of DN. Although we did not measure the remnant lipoproteins in our study, this hypothesis must be confirmed in a longitudinal study.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

et al. 2003

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“…Previous genetic studies implicated polymorphisms in two other genes that affect important components of lipid metabolism: the apoE and apoB genes (14,15). Numerous models of metabolic syndrome and diabetes (mice fed high-fat diets, leptin impaired db/db and ob/ob mice, streptozotocin-treated rats) display upregulated lipogenic genes and develop glomerular and tubular lipid deposits (16 -19).…”

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confidence: 99%

Lipotoxicity in Diabetic Nephropathy

Murea

Freedman²,

Parks³

et al. 2010

Clinical Journal of the American Society of Nephrology

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Cellular toxicity mediated by lipids (lipotoxicity) has been implicated in the pathophysiology of metabolic syndrome and diabetes mellitus. Genetic analyses now implicate lipotoxicity in susceptibility to type 2 diabetes mellitus-associated nephropathy (T2DN), a pathway that had previously been unexplored. A genome-wide association study in Japanese patients identified a single nucleotide polymorphism in the acetyl-CoA carboxylase ␤ (ACACB) gene associated with T2DN. Replication analyses suggest that this same polymorphism may be a diabetic nephropathy risk allele in other ethnic groups. The ACACB gene (also called ACC2 or acetyl-CoA carboxylase 2) plays a critical role in intracellular fatty acid (FA) oxidation. This manuscript reviews the physiology of FA metabolism and adverse cellular effects that can result from dysregulation of this process. It is hypothesized that glomerular and tubular dysfunction can be induced by increases in intracellular FA concentrations, a process that may be enabled by genetic risk variants. This novel glucolipotoxicity hypothesis in T2DN warrants further investigation. Clin J Am Soc Nephrol 5: 2373-2379, 2010. doi: 10.2215 O ver the last decade, dysregulated fatty acid (FA) oxidation has been implicated as an effector pathway in the pathophysiology of metabolic syndrome, atherosclerosis, cardiomyopathy, and diabetes mellitus (1). An imbalance between circulating and cytosolic FA levels resulting in excessive intracellular accumulation of FAs and their derivatives (diacylglycerol, ceramides) underlies the spectrum of insulin-deficient states, including insulin resistance in metabolic syndrome, insulin resistance and relative insulin deficiency in type 2 diabetes (T2D), and absolute insulin deficiency in type 1 diabetes (T1D) (2).Diabetic nephropathy (DN) is a serious complication that develops in a significant yet limited proportion of patients with T1D and T2D. Glycemic control and genetic predisposition have been explored as major pathogenic determinants. To determine how DN develops, the long-held theory that glomerular and tubular toxicity result from hyperglycemia (glucotoxicity) has been evaluated extensively at the molecular level for contributing factors, including generation of advanced glycation end products; activation of protein kinase C, TGF␤-Smad, and mitogen-activated protein kinase pathways; enhanced production of reactive oxygen species; increased extracellular matrix deposition, and increased tubulointerstitial fibrosis (3,4). Despite these investigations, the renal pathology in animal models of glucotoxicity does not reliably replicate what occurs in human DN, and specific factors that cause, propagate, or predict DN remain elusive.DN is believed to be a complex polygenic trait; that is, the clinical and histopathologic phenotype depends on alleles in multiple genes. On the basis of this hypothesis, scientists have taken full advantage of unbiased genetic studies as human genome-wide association studies have been used in large diabetic cohorts. Although several ...

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“…29 Case-control studies with similar results also exist. 1,15,30,44 Additionally, the single histopathological study conducted by Guan et al 13 also found an association between diabetes-related glomerulopathy and APO E2. On the other hand, some other studies found no relationship between APO E2 and DN.…”

Section: Discussionmentioning

confidence: 95%

“…In addition to these, effects of other genetic factors may also be influential. 13,30,48 The possible effect mechanism of APO E2 gene polymorphism on DN is not yet clear. Despite the lack of evidence, an increase in APO E2 and lipoproteinrich triglycerides and their traces may be related to DN development.…”

Section: Discussionmentioning

confidence: 99%

“…APO E gene polymorphism is closely related to a disruption in lipid metabolism 28 and is thus claimed to play a role in the development of DN despite similarly inconclusive research results. 13,[29][30][31] Our aim in this study was to study the relationship of AGT M235T and APO E gene polymorphism with DN in Turkish patients of Type 2 diabetes, and to compare genotype and allele distributions among DN patients, normoalbuminuria Type 2 diabetes patients, and healthy controls.…”

Section: Introductionmentioning

confidence: 99%

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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 E genetic polymorphism, remnant lipoproteins, and nephropathy in type 2 diabetic patients

Cited by 76 publications

References 39 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

Lipotoxicity 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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