Department of Endocrinology, Oslo University Hospital, Aker, Oslo, Norway.
BMC Med Genet. 2010 Oct 12;11:144. doi: 10.1186/1471-2350-11-144.
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.
肝 X 受体（LXR）α 和 β 调节脂质和碳水化合物的稳态和炎症。Lxrβ⁻/⁻ 小鼠不耐受葡萄糖，同时也偏瘦。我们旨在评估 LXRβ 中的单核苷酸多态性（SNP）与 3 项独立队列研究中 2 型糖尿病（T2DM）、肥胖和相关特征的风险之间的关联。
通过对 HUNT2 成人巢式病例对照 T2DM 研究（n=835 例病例/1986 例对照）进行测序和基因分型，确定了 20 个 LXRβSNP。通过对法国 MONICA 成人研究（n=2318 例）和欧洲青少年 HELENA 横断面研究（n=1144 例）中的 5 个标签 SNP（rs17373080、rs2695121、rs56151148、rs2303044 和 rs3219281）进行基因分型，这些 SNP 涵盖了 LXRβ 基因整个常见遗传变异的 99.3%。进行了计算机模拟和体外功能研究。
我们发现 rs17373080 与（i）HUNT2 中 T2DM 的风险之间存在提示性或显著关联（OR=0.82，p=0.03），（ii）MONICA 中肥胖的风险（OR=1.26，p=0.05），以及（iii）HELENA 中超重/肥胖的风险（OR=1.59，p=0.002）。内含子 4 SNP（rs28514894，与 rs17373080 完全一致）可能为肝核因子 4α（HNF4α）和核因子 1（NF1）创造结合位点。rs28514894 的 C 等位基因与体外人 LXRβ 基础启动子活性增加约 1.25 倍相关。然而，在 HNF4α 或 NF1 的 DNA 结合和报告基因转录激活方面，等位基因之间没有差异。
我们的结果表明，LXRβ 中的 rs17373080 与 T2DM 和肥胖有关，可能是通过改变 LXRβ 的表达。
