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Serum gamma-glutamyl transferase and risk of type 2 diabetes in the general Korean population: a Mendelian randomization study.

Accepted version
Peer-reviewed

Type

Article

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Authors

Lee, Youn Sue 
Cho, Yoonsu 
Davey Smith, George 
Relton, Caroline L 

Abstract

Elevated gamma-glutamyl transferase (GGT) levels are associated with higher risk of type 2 diabetes in observational studies, but the underlying causal relationship is still unclear. Here, we tested a hypothesis that GGT levels have a causal effect on type 2 diabetes risk using Mendelian randomization. Data were collected from 7640 participants in a South Korean population. In a single instrumental variable (IV) analysis using two stage least squares regression with the rs4820599 in the GGT1 gene region as an instrument, one unit of GGT levels (IU/L) was associated with 11% higher risk of type 2 diabetes (odds ratio (OR) = 1.11, 95% confidence interval (CI): 1.04 to 1.19). In a multiple IV analysis using seven genetic variants that have previously been demonstrated to be associated with GGT at a genome-wide level of significance, the corresponding estimate suggested a 2.6% increase in risk (OR = 1.026, 95% CI: 1.001 to 1.052). In a two-sample Mendelian randomization analysis using genetic associations with type 2 diabetes taken from a trans-ethnic GWAS study of 110 452 independent samples, the single IV analysis confirmed an association between the rs4820599 and type 2 diabetes risk (P-value = 0.04); however, the estimate from the multiple IV analysis was compatible with the null (OR = 1.007, 95% CI: 0.993 to 1.022) with considerable heterogeneity between the causal effects estimated using different genetic variants. Overall, there is weak genetic evidence that GGT levels may have a causal role in the development of type 2 diabetes.

Description

Keywords

Adult, Asian People, Diabetes Mellitus, Type 2, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Polymorphism, Single Nucleotide, Republic of Korea, gamma-Glutamyltransferase

Journal Title

Hum Mol Genet

Conference Name

Journal ISSN

0964-6906
1460-2083

Volume Title

25

Publisher

Oxford University Press (OUP)
Sponsorship
Medical Research Council (MR/L003120/1)
Medical Research Council (G0800270)
Wellcome Trust (100114/Z/12/Z)
British Heart Foundation (None)
British Heart Foundation (None)
Medical Research Council (MC_UU_00002/7)
Basic Science Research Program through the National research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2015R1A2A1A15054758 to M.J.S.); Medical Research Council Integrative Epidemiology Unit to G.D.S., C.L.R. and S.Y.S. Medical Research Council Integrative Epidemiology Unit (MC_UU_12013/1 and 2); Wellcome Trust 100114 to S.B.; A Post-Doctoral Research Fellowship from the Oak Foundation to S.Y.S.