Vitamin D Receptor Gene Polymorphisms Are Associated with Obesity and Inflammosome Activity

<div><p>To explore the mechanisms underlying the suggested role of the vitamin D/vitamin D receptor (VDR) complex in the pathogenesis of obesity we performed genetic and immunologic analyses in obese and non-obese Saudi individuals without other concomitant chronic diseases. Genomic DNA was genotyped for gene single nucleotide polymorphisms (SNPs) of VDR by allelic discrimination in 402 obese (body mass index –BMI≥30 kg/m2) and 489 non-obese (BMI<30 kg/m2) Saudis. Q-PCR analyses were performed using an ABI Prism 7000 Sequence Detection System. The inflammosome pathway was analysed by PCR, cytokines and plasma lipopolysaccaride (LPS) concentrations with ELISA assays. Results showed that the VDR SNPs rs731236 (G) (TaqI) and rs1544410 (T) (Bsm-I) minor allele polymorphisms are significantly more frequent in obese individuals (p = 0.009, β = 0.086 and p = 0.028, β = 0.072, respectively). VDR haplotypes identified are positively (GTA) (p = 0.008, β = 1.560); or negatively (ACC) (p = 0.044, β = 0.766) associated with obesity and higher BMI scores. The GTA "risk" haplotype was characterized by an up-regulation of inflammosome components, a higher production of proinflammatory cytokines (p<0.05) and a lower VDR expression. Plasma LPS concentration was also increased in GTA obese individuals (p<0.05), suggesting an alteration of gut permeability leading to microbial translocation. Data herein indicate that polymorphisms affecting the vitamin D/VDR axis play a role in obesity that is associated with an ongoing degree of inflammation, possibly resulting from alterations of gut permeability and microbial translocation. These results could help the definition of VDR fingerprints that predict an increased risk of developing obesity and might contribute to the identification of novel therapeutic strategies for this metabolic condition.</p></div

Association study and meta-analysis for rs30187 in RRMS and CD.

a<p>P value from Pearson's Chi-squared test with Yates' continuity correction.</p>b<p>P value from Cochran Q heterogeneity test.</p>c<p>Heterogeneity index.</p>d<p>Random-effects meta-analysis p value.</p

Plasma LPS concentration in obese subjects carrying the VDR “at-risk” (GTA) (black bars) or the “protective” (ACC) (white bars) haplotype.

<p>Mean values ± standard error is shown.</p

VDR polymorphisms association with BMI scores.

<p>Linear regression analyses were used to compare the VDR genotypes adjusted for the co-variants age and gender. Significance was set at p<0.05. Responsible variable: BMI scores, covariates: age and gender (female vs male). Model 1: VDR rs731236(G):AG/GG <i>vs.</i> AA; Model 2: VDR rs1544410(T): CT/TT <i>vs.</i> CC; Model 3: VDR rs7975232(A):AC/AA <i>vs</i>. CC.</p

IL1β, IL6 (panel A) IL18 and TNFα (panel B) production assessed by multiplex ELISA in supernatant of LPS stimulated PBMC isolated from obese individuals carrying the VDR “at-risk” (GTA)(black bars) or the “protective” (ACC)(white bars) haplotype.

<p>Results are shown as mean values fold-change expression from the unstimulated sample ± standard error.</p

Expression of 96 genes involved in the inflammosome pathway assessed by real-time quantitative RT-PCR in obese and non-obese subjects carrying the VDR “at-risk” (GTA) or the “protective” (ACC) haplotype.

<p>Following LPS stimulation the expression of genes within the inflammosome pathway is significantly more increased in obese individuals with the GTA “risk” haplotype. Results are shown as fold-change expression compared to the ACC non obese controls assumed as baseline expression level. Only the targets showing different expression levels in the different groups are shown.</p