TY - JOUR
T1 - Suggestive evidence of associations between liver X receptor β polymorphisms with type 2 diabetes mellitus and obesity in three cohort studies
T2 - HUNT2 (Norway), MONICA (France) and HELENA (Europe)
AU - Solaas, Karianne
AU - Legry, Vanessa
AU - Retterstol, Kjetil
AU - Berg, Paul R.
AU - Holven, Kirsten B.
AU - Ferrières, Jean
AU - Amouyel, Philippe
AU - Lien, Sigbjorn
AU - Romeo, Javier
AU - Valtueña, Jara
AU - Widhalm, Kurt
AU - Ruiz, Jonatan R.
AU - Dallongeville, Jean
AU - Tonstad, Serena
AU - Rootwelt, Helge
AU - Halvorsen, Bente
AU - Nenseter, Marit S.
AU - Birkeland, Kare I.
AU - Thorsby, Per M.
AU - Meirhaeghe, Aline
AU - Nebb, Hilde I.
N1 - Funding Information:
The HUNT2 Study is collaboration between the HUNT Research Centre, Faculty of Medicine, Norwegian University of Science and Technology, Norwegian Institute of Public Health, and Nord-Trøndelag County Council. We thank Nina Gjerlaugsen and Kristil Kindem Sundsaasen for excellent laboratory work. We thank Dr R. Gronostajski (Buffalo, NY, USA) for providing us with the NF1 expression vectors. 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].
PY - 2010/10/12
Y1 - 2010/10/12
N2 - 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.
AB - 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.
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U2 - 10.1186/1471-2350-11-144
DO - 10.1186/1471-2350-11-144
M3 - Article
C2 - 20939869
SN - 1471-2350
VL - 11
JO - BMC Medical Genetics
JF - BMC Medical Genetics
IS - 1
M1 - 144
ER -