Journal
PLOS GENETICS
Volume 9, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1003222
Keywords
-
Categories
Funding
- National Institutes of Health [AR060366, AR049084, AI094377, AR053483, AR33062, RR020143, RR0155577, AI082714, AR058554, AI083194, AI024717, GM103510, AR057172]
- U.S. Department of Defense [AI082714, AI024717, PR094002, AR002138, AR30692, RR025741, AR042460, AI031584, AI101934, AR062277, AR048940, AR043814, DE018209, AI062629, DE015223, RR027190, P60 AR053308, R01 AR44804, M01 RR-00079, UL1 TR000165]
- U.S. Department of Veterans Affairs [IMMA 9]
- Alliance for Lupus Research
- Swedish Research Council
- Kirkland Scholar Award
- Instituto de Salud Carlos III (European Union Fonds Europeen de Developpement Regional (FEDER)) [PS09/00129]
- European Science Foundation (BIOLUPUS)
Ask authors/readers for more resources
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD = 6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio similar to 1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [P-meta = 5.20x10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P-meta = 3.08x10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P-dom = 1.16x10(-8); 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available