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

Abstract

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 ...

Effect of polymorphisms of the MTHFR and APOE genes on susceptibility to diabetes and severity of diabetic retinopathy in Brazilian patients

“…This positive association of allele ε2/ APOE with DM2 is in agreement with data from the literature, which points to the involvement of allele ε2/APOE in the occurrence of DM2 (33) or in diabetic nephropathy (34)(35)(36). We could speculate that our positive results were due to the simultaneous occurrence of DM and nephropathy; however, the frequency of the ε2/APOE allele was similar (ε2 = 13/190 = 6.8%) in patients with and without nephropathy (ε2 = 7/112 = 6.1%), implying that the higher frequency of the ε2/APOE allele might be primarily related to DM2.…”

Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression

“…Functional PRKCB1 promoter variants have been shown to be associated with diabetic nephropathy and albuminuria, 60,61 mediated by increased renal oxidative stress, production of fibrotic cytokines such as TGFb, and consequently increased glomerular permeability. [29][30][31] Also of interest is the potential gene-gene interaction with APOE e2 alleles, which contribute to the development and progression of diabetic nephropathy 62,63 and are preferentially transmitted to autistic children in our sample. 64 A potential parallel between 'leaky kidney' and 'leaky gut' syndromes is suggested by an in vitro study demonstrating that PKCb and calcium are both necessary for oxidative stress to yield abnormal permeability in monolayers of human intestinal Caco-2 cells.…”

Polymorphisms of the Protein Kinase C-β Gene (PRKCB1) Accelerate Kidney Disease in Type 2 Diabetes Without Overt Proteinuria

“…RESEARCH DESIGN AND METHODS -The subjects were recruited from among the participants at the outpatient clinic of the Department of Medicine, Shiga University of Medical Science (9). During 1996 -1998, patients clinically diagnosed as having type 2 diabetes in accordance with World Health Organization criteria were examined with multiple measurements of urinary AER and estimated GFR in 24-h urine sample collection in the initial 2 years (baseline period).…”