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).

Abstract

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.

• Authors: Karianne Solaas, Vanessa Legry, Kjetil Retterstol, Paul R Berg, Kirsten B Holven, Jean Ferrières, Philippe Amouyel, Sigbjorn Lien, Javier Romeo, Jara Valtueña, Kurt Widhalm, Jonatan R Ruiz, Jean Dallongeville, Serena Tonstad, Helge Rootwelt, Bente Halvorsen, Marit S Nenseter, Kare I Birkeland, Per M Thorsby, Aline Meirhaeghe, Hilde I Nebb
• Journal: BMC medical genetics (BMC Med Genet) Vol. 11 Pg. 144 (Oct 12 2010) ISSN: 1471-2350 [Electronic] England
• PMID: 20939869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HNF4A protein, human
• Hepatocyte Nuclear Factor 4
• Liver X Receptors
• NFI Transcription Factors
• NR1H3 protein, human
• Nr1h3 protein, mouse
• Orphan Nuclear Receptors

Topics

• Adolescent
• Adult
• Aged
• Alleles
• Binding Sites
• Cohort Studies
• Diabetes Mellitus, Type 2 (genetics)
• Europe
• Female
• France
• Genetic Predisposition to Disease
• Genotype
• Hepatocyte Nuclear Factor 4 (metabolism)
• Humans
• Introns
• Liver X Receptors
• Male
• Middle Aged
• NFI Transcription Factors (metabolism)
• Norway
• Obesity (genetics)
• Orphan Nuclear Receptors (genetics)
• Polymorphism, Single Nucleotide
• Sequence Analysis, DNA