Degree Name

Department

Microbiology and Molecular Biology

College

Life Sciences

Defense Date

2019-12-11

Publication Date

2019-12-20

First Faculty Advisor

Brian D. Poole

First Faculty Reader

K. Scott Weber

Honors Coordinator

R. Paul Evans

Keywords

NLRP1, IL-18, IL-1beta, autoimmunity, rs2670660, rs12150220

Abstract

NLRP1 is a protein-coding human gene that plays a crucial role in the NLRP1 inflammasome. Variants to the NLRP1 gene have been associated with autoimmune and autoinflammatory diseases. We examined the effects of polymorphisms at two SNPs on cytokine levels and NLRP1 gene expression in 50 human volunteers without diagnosed autoimmune disease. NLRP1 was genotyped at SNPs rs2670660 and rs12150220 and individuals who were homozygous at one or more SNP were selected for further analysis. Serum IL-18 and IL-1β levels were quantified using ELISA. NLRP1 gene expression was measured using real-time PCR. A strong linkage was found between genotypes of rs2670660 and rs12150220 (p = 2.33 x 10^-13). Participants with an AAAA genotype (written as rs2670660 genotype + rs12150220 genotype) had significantly higher levels of IL-18 than participants with a GGTT genotype (0.439 ng/µL vs 0.152 ng/µL, p = 0.024). A trend towards increased NLRP1 expression was seen in the AAAA genotype (4.392-fold increase, p = 0.101). It is likely that the AAAA genotype represents a combination of two homozygous autoimmunity risk variants. The AAAA genotype showed increased production of IL-18 even in non-autoimmune individuals, with a trend towards higher gene expression, suggesting that the AA variants of rs2670660 and rs12150220 lead to increased NLRP1 activity. Due to the linkage of rs2670660 and rs12150220, it was impossible to differentiate which SNP was responsible for the observed effects. Further studies with a larger sample size would contribute to an increased understanding of the effects of NLRP1 variants on autoimmune disease.