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Two Genetic Effects At The Irf5/ Tnpo3 Locus Are Independently Associated With The Development Of Specific Lupus Symptoms, Samantha Hawtrey

Mahurin Honors College Capstone Experience/Thesis Projects

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that can affect every tissue in the body. Single nucleotide polymorphisms (SNPs) in the IRF5 and TNPO3 genes are statistically associated with the development of SLE. My research identified correlations between IRF5/TNPO3 SNPs and specific lupus symptoms. Logistic regression analyses were conducted using 101 genetic variants in the IRF5/TNPO3 region that were genotyped in over 6,000 lupus patients of different ethnicities, with admixture covariates applied. Three clinical phenotypes displayed significant correlation (p < 1.6x10-5) in subjects of European ancestry. For each of these phenotypes, a step-wise conditional analysis was conducted using two lupus associated single nucleotide polymorphisms (SNPs) at this genetic loci. In Europeans, lupus disease onset (p-valueEU=2.44x10-16, OR=0.67*) and the presence of anti-Ro (p-valueEU=2.09x10-7, OR=0.67) and anti-dsDNA (p-valueEU=4.15x10-7, OR=0.75) antibodies were associated with SNPs in the IRF5/TNPO3 genes. SNPs in the IRF5 promoter and those spanning IRF5 and TNPO3 were both associated with disease onset. The presence of anti-Ro and anti-dsDNA antibodies is only associated with SNPs in the IRF5 promoter. Genetic variants at the IRF5/TNPO3 locus are associated with lupus disease onset and production of anti-dsDNA and anti-Ro antibodies in lupus patients. SNPs in the promoter region of iii IRF5 (associated with rs4728142) and SNPs spanning the IRF5 and TNPO3 genes (associated with rs12534421) contribute independently to these symptoms.