Association between liver X receptor α gene polymorphisms and risk of metabolic syndrome in French populations

Abstract

Context:The metabolic syndrome is a complex and multifactorial disorder often associated with type 2 diabetes mellitus and cardiovascular diseases. The liver X receptor a (NR1H3) plays numerous roles in metabolic pathways involved in metabolic syndrome. Objective: In the search for susceptibility genes to metabolic syndrome, we hypothesized that common genetic variation in NR1H3 gene influences metabolic syndrome susceptibility. Design: Two large French population-based studies (n ¼ 1130 and 1160) including overall 664 individuals with and 1626 individuals without metabolic syndrome were genotyped for three polymorphisms (rs12221497, rs11039155 and rs2279239) of NR1H3. Results: We found that the À6A allele of rs11039155 was consistently associated with a 30% reduction in risk of metabolic syndrome in the two independent population samples (adjusted OR (95% CI) ¼ 0.68 (0.53-0.86), P ¼ 0.001 for the combined sample). Moreover, it was associated with an increase in plasma HDL-cholesterol concentrations (P ¼ 0.02 for the combined sample). Neither rs12221497 nor rs11039155, both polymorphisms located in the 5 0 region of NR1H3, had significant influence on NR1H3 and ATP-binding cassette transporter A1 (ABCA1) gene expression in primary human macrophages. Conclusions: These results suggest that NR1H3 plays an important role in the HDL-cholesterol metabolism and in the genetic susceptibility to metabolic syndrome.

Retinoid X Receptor Heterodimer Variants and Cardiovascular Risk Factors

“…Recently, LXR gene polymorphisms were reported to be associated with metabolic syndrome in two large populations 134) . They genotyped 3 SNPs, and found that only the A allele of c.-6G A polymorphism was associated with a 30% reduction in the risk of metabolic syndrome and an increase in plasma HDL-C 134) .…”

“…They genotyped 3 SNPs, and found that only the A allele of c.-6G A polymorphism was associated with a 30% reduction in the risk of metabolic syndrome and an increase in plasma HDL-C 134) . Human primary macrophages were analyzed for their mRNA levels of LXR and ABCA1 as a target of LXR , but no significant differences were confirmed.…”

Genetic Variation in Liver X Receptor Alpha and Risk of Ischemic Vascular Disease in the General Population

“…The minor allele frequency (16%) and the genotype distribution of Ϫ115GϾA in both our studies (Table 3) were very similar to frequencies in a Swedish population, 14 and to frequencies in other European populations. 13,15,16 Furthermore, 4 common ancestry informative 17 SNPs in, respectively, APOE (22/32/42/33/43/44; rs429358 and rs7412), CETP (Taq1b, rs708272), and APOB (XbaI, rs693) were equally distributed between the 3 LXR␣ Ϫ115GϾA genotypes in our studies (Supplemental Table I). …”

“…the general population. Other studies have reported associations with obesity, 14 life span, 18 and plasma lipid levels 13,15,19,20 for common genetic variants in LXR␣. LXR␣ and LXR␤ have similar functions in lipid metabolism and inflammation, but whereas LXR␣ is expressed in the liver, adipose tissue, kidney, adrenals, and macrophages, LXR␤ is expressed ubiquitously.…”

Role of Nuclear Receptors Peroxisome Proliferator-Activated Receptors (PPARs) and Liver X Receptors (LXRs) in the Human Placental Pathophysiology

“…The human endoglin gene promoter contains six putative LXRE sequences and at least one of them binds the LXR/RXR heterodimer to stimulate transcription in response to 22(R)-hydroxycholesterol, T0901317 or synthetic RXR agonists (Henry-Berger et al, 2008). Interestingly, circulating endoglin level is increased in preeclampsia and may contribute to endothelial dysfunction associated with this disorder (Legry et al, 2008). Apart from stimulating endoglin, LXR agonists may reduce trophoblast invasiveness by downregulating MMP9, as has been demonstrated in macrophages (Castrillo et al, 2003).…”