Gene Polymorphisms of NLRP3 Associated With Plasma Levels of 4-Hydroxycholesterol, an Endogenous Marker of CYP3A Activity, in Patients With Asthma

Inflammation decreases the activity of cytochrome P450 3A (CYP3A). Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) is responsible for regulating the inflammatory response, and its genetic polymorphisms have been linked to inflammatory diseases such as asthma. However, there have been few studies on the effect of NLRP3 on CYP3A activity. We aimed to investigate the association between polymorphisms in the NLRP3 gene and plasma 4 beta-hydroxycholesterol (4 beta OHC), an endogenous marker of CYP3A activity, in patients with asthma. In this observational study including 152 adult asthma patients, we analyzed 10 NLRP3 gene single-nucleotide polymorphisms (SNPs). Plasma 4 beta OHC levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that five SNPs were associated with significantly lower plasma 4 beta OHC concentrations. Among these SNPs, rs3806265, rs4612666, rs1539019, and rs10733112 contributed to a significant increase in plasma IL-6 concentrations. Moreover, a multivariate regression model showed that the rs3806265 TT, rs4612666 CC, rs1539019 AA, and rs10733112 TT genotypes were significant factors for decreased plasma 4 beta OHC, even after including patient background factors and CYP3A5*3 (rs776746) gene polymorphisms as covariates. These results were also observed when plasma 4 beta OHC concentrations were corrected for cholesterol levels. We conclude that NLRP3 gene polymorphisms are involved in increasing plasma IL-6 concentrations and decreasing plasma 4 beta OHC concentrations in patients with asthma. Therefore, NLRP3 gene polymorphisms may be a predictive marker of CYP3A activity in inflammatory diseases such as asthma.