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 [Pmeta = 5.20×10−14; odds ratio, 95% confidence interval = 0.82 (0.78–0.87)], and two missense variants, rs1990760 (Ala946Thr) [Pmeta = 3.08×10−7; 0.88 (0.84–0.93)] and rs10930046 (Arg460His) [Pdom = 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.
Highlights
Systemic lupus erythematosus (SLE, [MIM 152700]) is a clinically heterogeneous autoimmune disease with a strong genetic component, characterized by inflammation, dysregulation of type-1 interferon responses and autoantibodies directed towards nuclear components
We identified a genomewide significant association [7] of SLE risk with European ancestry at 2q22–q24 using a weighted prior risk model; the strongest association at the same locus was observed at a fixed prior risk of 1.5, which represents a 1.5-fold increased risk of SLE due to one European ancestral allele at this locus
The risk allele-carrying sequences showed almost a 2-fold reduction (Figure 4D) in luciferase activity compared to those with the ancestral allele. These results suggest that the rs13023380 locus recruits transcriptional activity of IFIH1 through binding of Ku70/80, NCL and HSP90AA1/AB1, and that the risk allele at this base position interferes with this enhancer activity, potentially decreasing IFIH1 transcript levels
Summary
Systemic lupus erythematosus (SLE, [MIM 152700]) is a clinically heterogeneous autoimmune disease with a strong genetic component, characterized by inflammation, dysregulation of type-1 interferon responses and autoantibodies directed towards nuclear components. The recently ‘‘admixed’’ AA population is likely to provide critical information necessary to identify chromosomal regions that harbor variants associated with SLE and provide insights about allele frequency differences among distinct ancestral populations (i.e., European and African). Africans have the smallest haplotype blocks of all human populations: African average population recombination distance is 6 kb, while it is 22 kb in Europeans and Asians [13,14]. This 3-fold smaller haplotype size gives rise to correspondingly tighter genomic associations in admixed populations such as AA, making causal mutations easier to decipher
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