title: Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.
abstract: 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 ~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) = 5.20×10(-14); odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [P(meta) = 3.08×10(-7); 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [P(dom) = 1.16×10(-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.
authors: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States of America.
authors: Julio E
authors: JE
authors: Molineros
authors: Amit K
authors: AK
authors: Maiti
authors: Celi
authors: C
authors: Sun
authors: Loren L
authors: LL
authors: Looger
authors: Shizhong
authors: S
authors: Han
authors: Xana
authors: X
authors: Kim-Howard
authors: Stuart
authors: S
authors: Glenn
authors: Adam
authors: A
authors: Adler
authors: Jennifer A
authors: JA
authors: Kelly
authors: Timothy B
authors: TB
authors: Niewold
authors: Gary S
authors: GS
authors: Gilkeson
authors: Elizabeth E
authors: EE
authors: Brown
authors: Graciela S
authors: GS
authors: Alarcón
authors: Jeffrey C
authors: JC
authors: Edberg
authors: Michelle
authors: M
authors: Petri
authors: Rosalind
authors: R
authors: Ramsey-Goldman
authors: John D
authors: JD
authors: Reveille
authors: Luis M
authors: LM
authors: Vilá
authors: Barry I
authors: BI
authors: Freedman
authors: Betty P
authors: BP
authors: Tsao
authors: Lindsey A
authors: LA
authors: Criswell
authors: Chaim O
authors: CO
authors: Jacob
authors: Jason H
authors: JH
authors: Moore
authors: Timothy J
authors: TJ
authors: Vyse
authors: Carl L
authors: CL
authors: Langefeld
authors: Joel M
authors: JM
authors: Guthridge
authors: Patrick M
authors: PM
authors: Gaffney
authors: Kathy L
authors: KL
authors: Moser
authors: R Hal
authors: RH
authors: Scofield
authors: Marta E
authors: ME
authors: Alarcón-Riquelme
authors: Scott M
authors: SM
authors: Williams
authors: Joan T
authors: JT
authors: Merrill
authors: Judith A
authors: JA
authors: James
authors: Kenneth M
authors: KM
authors: Kaufman
authors: Robert P
authors: RP
authors: Kimberly
authors: John B
authors: JB
authors: Harley
authors: Swapan K
authors: SK
authors: Nath
mesh_terms: D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D034961:Antigens, Nuclear / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000235:genetics; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology; D002874:Chromosome Mapping; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D007249:Inflammation / Q000235:genetics; D000072640:Interferon-Induced Helicase, IFIH1; D000072200:Ku Autoantigen; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D044465:White People / Q000235:genetics
chemical_list: D034961:Antigens, Nuclear; D001323:Autoantibodies; D004268:DNA-Binding Proteins; C452815:IFIH1 protein, human; C000606509:Xrcc6 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D000072200:Ku Autoantigen