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). - Archive ouverte HAL Access content directly
Journal Articles BMC Medical Genetics Year : 2010

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).

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Kjetil Retterstol
  • Function : Author
  • PersonId : 909773
Paul Berg
  • Function : Author
  • PersonId : 909774
Kirsten Holven
  • Function : Author
  • PersonId : 909775
Jean Ferrières
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  • PersonId : 909776
Sigbjorn Lien
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  • PersonId : 909777
Javier Romeo
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  • PersonId : 909778
Kurt Widhalm
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  • PersonId : 909780
Jonatan Ruiz
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  • PersonId : 909781
Serena Tonstad
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  • PersonId : 909782
Helge Rootwelt
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  • PersonId : 909783
Bente Halvorsen
  • Function : Author
  • PersonId : 909784
Marit Nenseter
  • Function : Author
  • PersonId : 909785
Kare Birkeland
  • Function : Author
  • PersonId : 909786
Per Thorsby
  • Function : Author
  • PersonId : 909787
Hilde Nebb
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  • PersonId : 909788

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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.
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inserm-00622786 , version 1 (12-09-2011)

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Karianne Solaas, Vanessa Legry, Kjetil Retterstol, Paul Berg, Kirsten Holven, et al.. 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).. BMC Medical Genetics, 2010, 11 (1), pp.144. ⟨10.1186/1471-2350-11-144⟩. ⟨inserm-00622786⟩
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