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)
11 páginas, 3 figuras, 4 tablas.-- et al. ; [Background]: 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. [Methods]: 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. [Results]: 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. [Conclusions]: Our results suggest that rs17373080 in LXRβ is associated with T2DM and obesity, maybe via altered LXRβ expression. ; The work was supported by the Norwegian Research Council [grant number 101114/310] 'to [KS] and [MSN]'; South-Eastern Norway Regional Health Authority [grant number AUS 2007-25] 'to [KS]'; the Institut Pasteur de Lille 'to [VL]'; the Institut National de la Santé et de la Recherche Médicale (INSERM); the Conseil Régional du Nord-Pas de Calais, ONIVINS; the Parke-Davis Laboratory, the Mutuelle Générale de l'Education Nationale (MGEN); the Groupe Fournier, the Réseau National de Santé Publique; the Direction Générale de la Santé, the Institut Pasteur de Lille; and the Unité d'Evaluation du Centre Hospitalier et Universitaire de Lille. The HELENA Study was funded by the European Union's Sixth RTD Framework Programme [grant number Contract FOOD-CT-2005-007034]; Universidad Politécnica de Madrid [grant number CH/018/2008]; Axis- Shield Diagnostics Ltd (Oslo, Norway); Abbot Científica S.A. (Spain); the Spanish Ministry of Education [EX-2007-1124], and Cognis GmbH (Germany). The present study was part of CRESCENDO (Consortium for Research into Nuclear Receptors in Development and Aging) funded by the Commission's Sixth Framework Programme [grant number LSHM-CT- 2005-018652] ; Peer reviewed