Suggestive evidence of associations between liver X receptor β polymorphisms with type 2 diabetes mellitus and obesity in three cohort studies: HUNT2 (Norway), MONICA (France) and HELENA (Europe)

Springer Science and Business Media LLC - Tập 11 - Trang 1-11 - 2010
Karianne Solaas1,2, Vanessa Legry3, Kjetil Retterstol4,5, Paul R Berg6, Kirsten B Holven2, Jean Ferrières7, Philippe Amouyel3, Sigbjorn Lien6, Javier Romeo8, Jara Valtueña9, Kurt Widhalm10, Jonatan R Ruiz11, Jean Dallongeville3, Serena Tonstad12, Helge Rootwelt13, Bente Halvorsen14, Marit S Nenseter14, Kare I Birkeland1,15, Per M Thorsby16, Aline Meirhaeghe3, Hilde I Nebb2
1Department of Endocrinology, Oslo University Hospital, Aker, Oslo, Norway
2Department of Nutrition, Faculty of Medicine, University of Oslo, Oslo, Norway
3INSERM, U744; Institut Pasteur de Lille, Univ. Lille Nord de France; UDSL, Lille, France
4The Lipid Clinic, Oslo University Hospital, Rikshospitalet, Oslo, Norway
5Norwegian Medical Agency, Oslo, Norway
6Centre for Integrative Genetics, The Norwegian University of Life Sciences, Aas, Norway
7Department of Cardiology, Toulouse University School of Medicine, Rangueil Hospital, Toulouse, France
8Immunonutrition group, Department of Metabolism and Nutrition, Institute Frio-ICTAN, Spanish Scientific Research Council, Madrid, Spain
9Facultad de Ciencias de la Actividad Fisica y del Deporte- INEF, Universidad Politécnica de Madrid, Madrid, Spain
10Department of Paediatrics, Division of Clinical Nutrition and Prevention, Medical University of Vienna, Vienna, Austria
11Unit for Preventive Nutrition, Department of Biosciences and Nutrition at NOVUM, Karolinska Institutet, Stockholm, Sweden
12Department of Preventive Medicine, Oslo University Hospital, Ulleval, Oslo, Norway
13Department of Medical Biochemistry, Oslo University Hospital, Rikshospitalet, Oslo, Norway
14Research Institute for Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
15Faculty of Medicine, University of Oslo, Norway
16The Hormone Laboratory, Oslo University Hospital, Aker, Oslo, Norway

Tóm tắt

The liver X receptors (LXR) α and β regulate lipid and carbohydrate homeostasis and inflammation. Lxrβ -/- mice are glucose intolerant and at the same time lean. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRβ and risk of type 2 diabetes mellitus (T2DM), obesity and related traits in 3 separate cohort studies. Twenty LXRβ SNPs were identified by sequencing and genotyped in the HUNT2 adult nested case-control study for T2DM (n = 835 cases/1986 controls). Five tag-SNPs (rs17373080, rs2695121, rs56151148, rs2303044 and rs3219281), covering 99.3% of the entire common genetic variability of the LXRβ gene were identified and genotyped in the French MONICA adult study (n = 2318) and the European adolescent HELENA cross-sectional study (n = 1144). In silico and in vitro functionality studies were performed. We identified suggestive or significant associations between rs17373080 and the risk of (i) T2DM in HUNT2 (OR = 0.82, p = 0.03), (ii) obesity in MONICA (OR = 1.26, p = 0.05) and (iii) overweight/obesity in HELENA (OR = 1.59, p = 0.002). An intron 4 SNP (rs28514894, a perfect proxy for rs17373080) could potentially create binding sites for hepatic nuclear factor 4 alpha (HNF4α) and nuclear factor 1 (NF1). The C allele of rs28514894 was associated with ~1.25-fold higher human LXRβ basal promoter activity in vitro. However, no differences between alleles in terms of DNA binding and reporter gene transactivation by HNF4α or NF1 were observed. Our results suggest that rs17373080 in LXRβ is associated with T2DM and obesity, maybe via altered LXRβ expression.

Tài liệu tham khảo

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