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Effect of Hepatic Lipase –514CT Polymorphism and Its Interactions With Apolipoprotein C3 –482CT and Apolipoprotein E Exon 4 Polymorphisms on the Risk of Nephropathy in Chinese Type 2 Diabetic Patients

¹ Department of Medicine and Therapeutics, Chinese University of Hong Kong, Shatin, Hong Kong
² Department of Human Genetics, Roche Molecular Systems, Alameda, California
³ Roche Center for Medical Genomics, F. Hoffmann-La Roche, Basel, Switzerland

Address correspondencereprint requests to Prof. Juliana C.N. Chan, Department of MedicineTherapeutics, Chinese University of Hong Kong, Shatin, Hong Kong. E-mail: jchan{at}cuhk.edu.hk

OBJECTIVE—Triglyceride-rich lipoprotein particles may promote the progression of diabetic nephropathy. Patients with diabetic nephropathy have increased plasma triglycerides and reduced activity of hepatic lipase (HL), which hydrolyzes triglycerides. We hypothesized that the HL –514CT polymorphism, which reduces HL expression, and its interactions with polymorphisms in apolipoprotein (apo) E and apoC3 increase the risk of diabetic nephropathy.

RESEARCH DESIGN AND METHODS—In a case-control study involving 374 Chinese type 2 diabetic patients with and 392 without diabetic nephropathy, we genotyped the HL –514CT, apoE exon 4, and apoC3 –482CT polymorphisms.

RESULTS—HL –514T–containing genotypes (T+) were associated with diabetic nephropathy (OR = 1.7, P = 0.0009). Adjustment by multiple logistic regression for hypertension, triglycerides, sex, non-HDL cholesterol, BMI, smoking, and alcohol intake did not diminish the association (OR = 1.8, P = 0.003). The association between HL T+ genotypes and diabetic nephropathy appeared stronger in diabetic patients with apoC3 –482 non-TT genotypes (OR = 1.9, P = 0.003) or apoE 2 or 4 alleles (OR = 2.2, P = 0.005). Subjects with HL TT exhibited trends toward increased triglyceride and non-HDL cholesterol levels compared with CC carriers.

CONCLUSIONS—HL T+ genotypes might increase the risk of developing diabetic nephropathy by slowing clearance of triglyceride-rich remnant lipoproteins. In concert with other risk factors (e.g., hyperglycemia), lipid abnormalities may damage the kidneys and endothelium, where reduced binding sites for lipases may precipitate a vicious cycle of dyslipidemia, proteinuria, and nephropathy.

Abbreviations: ACR, albumin-to-creatinine ratio • AER, albumin excretion rate • apo, apolipoprotein • FPG, fasting plasma glucose • HL, hepatic lipase • WHR, waist-to-hip ratio

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