NLRP3 Susceptible Gene Polymorphisms in Patients with Primary Gouty Arthritis and Hyperuricemia

Abstract

Polymorphisms have been identified to predispose to primary gouty arthritis (GA) and hyperuricemia (HUA). Here, we accessed the five polymorphisms of rs10754558, rs35829419, rs3738448, rs3806268, and rs7525979 in NLRP3 on GA and HUA susceptibility. We collected 1198 samples (314 GA, 377 HUA, and 507 controls) for this case-control study. Our data detected that the rs3806268 (GA vs. AA: OR = 0.65, p = 0.012) was significantly associated with the susceptibility to GA. The rs3738448 (TT vs. GG: OR = 2.05, p = 0.024) and rs7525979 (TT vs. CC: OR = 1.96, p = 0.037) were significantly associated with the susceptibility to HUA. The rs3806268 AG genotype presented decreased risk of GA among the hypertension (OR = 0.54, p = 0.0093), smoking (OR = 0.59, p = 0.018), and no obesity (OR = 0.60, p = 0.0097) subjects compared to the GG genotype group. The rs3738448 TT genotype demonstrated increased risk of HUA among the hypertension (OR = 4.10, p = 0.0056) and no drinking population (OR = 3.56, p = 0.016) compared to the GG genotype group. The rs7525979 TT genotype demonstrated increased risk of HUA among the hypertension (OR = 4.01, p = 0.0064) and no drinking population (OR = 3.24, p = 0.034) compared to the CC genotype group. Furthermore, a significant haplotype effect of rs10754558/C-rs35829419/C-rs3738448/G-rs3806268/A-rs7525979/C was found (OR = 1.60, p = 0.0046) compared with GCGAC haplotype. Bioinformatics analyses indicated that rs3738448, rs3806268, and rs7525979 might influence the gene regulation, while the T-allele of rs3738448 increased the stability of NLRP3-mRNA. Collectively, our case-control study confirms NLRP3 polymorphisms might participate in regulating immune and inflammation responses in GA and HUA.

Figure 1

Analysis of rs3738448 G/T, rs3806268 G/A, and rs7525979 C/T, variant effects on local mRNA structure of NLRP3 using RNAfold server. (a, b) G and T allele of rs3738448, (c, d) G and A allele of rs3806268, (e, f) C and T allele of rs7525979. The most important structural change is related to rs2466294 C/G.

Figure 2

Multitissue expression quantitative trait loci (eQTL) comparison of rs3806268. NES: the slope of the linear regression of normalized expression data versus the three genotype categories using single-tissue eQTL analysis, representing eQTL effect size. m value: the posterior probability that an eQTL effect exists in each tissue tested in the cross-tissue meta-analysis; large m value (m value > 0.9): the tissue is predicted to have an eQTL effect.