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Genetic variants in the upstream stimulatory factor 1 (USF1) gene are associated with LDL cholesterol levels and incident T2DM in women: results from the MONICA/KORA Augsburg case-cohort study, 1984-2002

C Holzapfel, Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany
J Baumert, Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany
H Grallert, Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany
A Mueller, Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany
B Thorand, Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany
N Khuseyinova, Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
C Herder, Institute for Clinical Diabetes Research, German Diabetes Center, Duesseldorf, Germany
C Meisinger, Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany
H Hauner, Else Kroener-Fresenius-Center for Nutritional Medicine, Technical University of Munich, Munich, Germany
H Wichmann, Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany
W Koenig, Ulm, Germany
T Illig, Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany
N Klopp, Institute of Epidemiology, Helmholtz Center Munich, Munich, Germany

Correspondence: Christina Holzapfel, Email: Christina.Holzapfel{at}helmholtz-muenchen.de

Abstract

Objective: upstream stimulatory factor 1 (USF1) regulates genes of glucose and lipid metabolism. Polymorphisms in the USF1 gene showed association with familial combined hyperlipidemia and lipid parameters. The aim of our study was to examine the associations between USF1 polymorphisms and lipid parameters as well as incident type 2 diabetes mellitus (T2DM) in German Caucasians.

Design: We genotyped eight polymorphisms in the USF1 gene in 2,067 middle-aged (35-74 years) individuals including 498 incident T2DM cases and 1,569 non-cases of the population-based case-cohort study from the MONICA/KORA Augsburg project.

Methods: Six polymorphisms and their haplotypes were analyzed using multivariable linear regression and Cox proportional hazards models.

Results: Polymorphism rs3737787 was inversely associated with incident T2DM in women with decreased risk for female heterozygotes compared to women homozygous for the major allele (HR=0.57; 95%-CI: 0.38-0.87; P=0.008). After correction for multiple testing significance remained. Polymorphisms rs3813609 and rs1556259 were significantly associated with reduction in low density lipoprotein (LDL) cholesterol (pNOM=0.001; pNOM=0.00002) in women. Analyses also indicated associations of haplotypes with LDL cholesterol in women, but the association lost statistical significance after correction for multiple testing. Total serum cholesterol (TC) and high density lipoprotein (HDL) cholesterol were weakly associated (P<0.05) with USF1 polymorphisms in women. No significant associations were found in men.

Conclusions: In this large population-based study statistically significant associations of USF1 polymorphisms with incident T2DM and LDL cholesterol were found in women, but not in men. Genetic variants in the USF1 gene showed weak or no associations with TC, and HDL cholesterol.