rs3807306

This study of 492 SLE patients across three ancestry groups identified genetic variation at the IRF7/PHRF1 locus associated with autoantibody profiles and serum interferonα activity. The rs702966 C allele was associated with anti-dsDNA antibodies (OR=1.83, P=0.0069) in European and Hispanic Americans and with higher IFNα levels in anti-dsDNA-positive patients (P=4.1×10⁻⁵). The rs4963128 T allele was associated with anti-Sm antibodies (OR=1.95, P=0.0017) in African Americans and with increased IFNα levels in anti-Sm-positive African American patients (P=0.0012). These findings demonstrate autoantibody-dependent genetic effects on IFNα production through the endosomal TLR/IRF7 pathway in SLE pathogenesis.

This paper proposes mTDTP (multimarker proportional transmission/disequilibrium test), a new statistical method for genome-wide association filtering in family-based studies that improves locus specificity compared to existing TDT approaches. The method weights haplotypes by their frequency to increase the rate at which associations decay with chromosomal distance from disease susceptibility loci, while maintaining power. Validation using simulations and real data from Multiple Sclerosis (MS) studies demonstrates that mTDTP more precisely identifies MS-associated regions (e.g., KIAA0350/CLEC16A, IRF5 loci) compared to standard mTDT and related tests.

A case-control association study of 281 Japanese systemic sclerosis (SSc) patients and 477 healthy controls examined three IRF5 SNPs (rs2004640, rs10954213, rs2280714) previously associated with systemic lupus erythematosus. rs2280714 showed the strongest association with SSc (OR 1.42, P=0.0012 in all SSc; OR 1.70, P=0.00013 in diffuse cutaneous SSc). The rs2004640 association was replicated in the recessive model, particularly in the anti-topoisomerase I antibody-positive subset.

This study examined IRF5 genetic variants in 199 systemic lupus erythematosus (SLE) patients to determine if the IRF5 SLE risk haplotype associates with elevated serum interferon-α (IFN-α) activity. SLE patients with risk/risk or risk/neutral IRF5 genotypes showed significantly higher serum IFN-α activity compared to protective genotypes (P = 0.025), with the most pronounced effect in patients positive for anti-RBP or anti-dsDNA autoantibodies (P = 0.012). The rs3807306 genotype independently associated with high IFN-α levels in the autoantibody-positive subgroup.