@article {6127,
	title = {Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.},
	journal = {PLoS Genetics},
	volume = {9},
	year = {2013},
	month = {2013 Feb 18},
	pages = {e1003222},
	abstract = {<p>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 \&nbsp;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) = 5.20{\texttimes}10(-14); odds ratio, 95\% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08{\texttimes}10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16{\texttimes}10(-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.</p>
},
	keywords = {African Americans, Alleles, Antigens, Apoptosis, Autoantibodies, Chromosome Mapping, DEAD-box RNA Helicases, DNA-Binding Proteins, European Continental Ancestry Group, Genetic Predisposition to Disease, Genome, Haplotypes, Human, Humans, Inflammation, Lupus Erythematosus, Nuclear, Polymorphism, Protein Binding, Single Nucleotide, Systemic},
	issn = {1553-7404},
	doi = {10.1371/journal.pgen.1003222},
	author = {Molineros, Julio E and Maiti, Amit K and Sun, Celi and Looger, Loren L and Han, Shizhong and Kim-Howard, Xana and Glenn, Stuart and Adler, Adam and Kelly, Jennifer A and Niewold, Timothy B and Gilkeson, Gary S and Brown, Elizabeth E and Alarc{\'o}n, Graciela S and Edberg, Jeffrey C and Petri, Michelle and Ramsey-Goldman, Rosalind and Reveille, John D and Vil{\'a}, Luis M and Freedman, Barry I and Tsao, Betty P and Criswell, Lindsey A and Jacob, Chaim O and Moore, Jason H and Vyse, Timothy J and Langefeld, Carl L and Guthridge, Joel M and Gaffney, Patrick M and Moser, Kathy L and Scofield, R Hal and Alarc{\'o}n-Riquelme, Marta E and Williams, Scott M and Merrill, Joan T and James, Judith A and Kaufman, Kenneth M and Kimberly, Robert P and Harley, John B and Nath, Swapan K}
}
