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Diabetes Care 26:2416-2420, 2003
© 2003 by the American Diabetes Association, Inc.

Pathophysiology/Complications
Original Article

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

Results of a prospective observational follow-up study

Shin-ichi Araki, MD, PHD, Daisuke Koya, MD, PHD, Tetsuya Makiishi, MD, Toshiro Sugimoto, MD, PHD, Motohide Isono, MD, PHD, Ryuichi Kikkawa, MD, PHD, Atsunori Kashiwagi, MD, PHD and Masakazu Haneda, MD, PHD

From the Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan

Address correspondence and reprint requests to Masakazu Haneda, MD, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan. E-mail: haneda{at}belle.shiga-med.ac.jp

OBJECTIVE—The aim of this study is to clarify the conflicting results of the {epsilon}2/{epsilon}3/{epsilon}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 = 299) or with microalbuminuria (n = 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 ± 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 {epsilon}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 {epsilon}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 (<15 years) at baseline, the risk in the {epsilon}2 carriers became higher to 3.2 (1.2–8.8).

CONCLUSIONS—Our follow-up study indicates that the {epsilon}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.

Abbreviations: AER, albumin excretion rate • apoE, apolipoprotein E • dBP, diastolic blood pressure • DN, diabetic nephropathy • ESRD, end-stage renal disease • sBP, systolic blood pressure • TG, triglyceride


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