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Polymorphisms in the Ghrelin Gene Are Associated with Serum High-Density Lipoprotein Cholesterol Level and not with Type 2 Diabetes Mellitus in Koreans

Department of Internal Medicine (H.J.C., Y.M.C., M.K.M., H.C.J., S.Y.K., H.K.L., K.S.P.), Seoul National University College of Medicine, Seoul 110-744, Korea; Genome Research Center for Diabetes and Endocrine Disease (Y.M.C., M.K.M., H.H.C., H.C.J., S.Y.K., H.K.L., K.S.P.), Clinical Research Institute, Seoul National University Hospital, Seoul 110-744, Korea; and Department of Genetic Epidemiology (H.D.S.), SNP Genetics, Inc., Seoul 153-803, Korea

Address all correspondence and requests for reprints to: Kyong Soo Park, M.D., Ph.D., Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea. E-mail: kspark{at}snu.ac.kr.

Context: Ghrelin is known to play a role in glucose metabolism and in ß-cell function. There are controversies regarding the role of ghrelin polymorphisms in diabetes and diabetes-related phenotypes.

Objective: The objective of this study was to examine polymorphisms of the ghrelin gene in a Korean cohort and investigate associations between them and susceptibility to type 2 diabetes and its related phenotypes.

Design and Patients: The ghrelin gene was sequenced to identify polymorphisms in 24 DNA samples. Common variants were then genotyped in 760 type 2 diabetic patients and 641 nondiabetic subjects. Genetic associations with diabetes-related phenotypes were also analyzed.

Results: Nine polymorphisms were identified, and four common polymorphisms [g.–1500C>G, g.–1062G>C, g.–994C>T, g.+408C>A (Leu72Met)] were genotyped in a larger study. The genotype distributions of these four common polymorphisms in type 2 diabetes patients were similar to those of normal nondiabetic controls. However, these four common polymorphisms were variably associated with several diabetes-related phenotypes, such as high-density lipoprotein (HDL) cholesterol, fasting plasma glucose, and homeostasis model assessment of insulin resistance. In particular, subjects harboring g.–1062C were associated with a lower serum HDL cholesterol level after adjusting for other variables (P = 0.0004 or 0.01 after Bonferroni correction for 24 tests).

Conclusion: The aforementioned four common polymorphisms in the ghrelin gene were not found to be significantly associated with susceptibility to type 2 diabetes mellitus in the Korean population. However, the common polymorphism g.–1062G>C in the promoter region of the ghrelin gene was found to be significantly associated with serum HDL cholesterol levels.