ArticlePLoS genetics2013
Admixture mapping in lupus identifies multiple functional variants within IFIH1 associated with apoptosis, inflammation, and autoantibody production.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers, 1 of them a synthesis that pooled it.
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Who cites it
79 citing papers in PubMed, 1 synthesis or guideline pooled it, 120 citations in OpenAlex.
- Association of the rs1990760, rs3747517, and rs10930046 polymorphisms in theFrontiers in immunology · 2023Pooled it
- Trial
- Genomic Landscape of Systemic Lupus Erythematosus and Lupus Nephritis Globally and the Gaps in Africa.International journal of molecular sciences · 2026Review
- Genetic risk factors and clinical manifestations of systemic lupus erythematosus: Large-scale analysis of genetic predisposition and disease subtypes.Journal of internal medicine · 2026Article
- In Silico Analysis of Post-COVID-19 Condition (PCC) Associated SNP rs9367106 Predicts the Molecular Basis of Abnormalities in the Lungs and Brain Functions.International journal of molecular sciences · 2025Article
- Machine learning combined multi-omics analysis to explore key oxidative stress features in systemic lupus erythematosus.Frontiers in immunology · 2025Article
- Changes in DNA methylation are associated with systemic lupus erythematosus flare remission and clinical subtypes.Clinical epigenetics · 2024Article
- MDA5 Is a Major Determinant of Developing Symptoms in Critically Ill COVID-19 Patients.Clinical reviews in allergy & immunology · 2024Review
- Bioinformatic analysis predicts the regulatory function of noncoding SNPs associated with Long COVID-19 syndrome.Immunogenetics · 2024Article
- Article
- A Multilayered Post-Genome-Wide Association Study Analysis Pipeline Defines Functional Variants and Target Genes for Systemic Lupus Erythematosus.Arthritis & rheumatology (Hoboken, N.J.) · 2024Article
- Local Ancestry at the Major Histocompatibility Complex Region is Not a Major Contributor to Disease Heterogeneity in a Multiethnic Lupus Cohort.Arthritis & rheumatology (Hoboken, N.J.) · 2024Article
- The 330 risk loci known for systemic lupus erythematosus (SLE): a review.Frontiers in lupus · 2024Article
- Polymorphisms inGenes · 2022Article
- RIG-I-like Receptor Regulation of Immune Cell Function and Therapeutic Implications.Journal of immunology (Baltimore, Md. : 1950) · 2022Review
- A loosened gating mechanism of RIG-I leads to autoimmune disorders.Nucleic acids research · 2022Article
- Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19.Translational research : the journal of laboratory and clinical medicine · 2022Article
- Cellular origins of dsRNA, their recognition and consequences.Nature reviews. Molecular cell biology · 2022Review
- Systemic lupus erythematosus as a genetic disease.Clinical immunology (Orlando, Fla.) · 2022Article
- Lupus Susceptibility Region Containing CDKN1B rs34330 Mechanistically Influences Expression and Function of Multiple Target Genes, Also Linked to Proliferation and Apoptosis.Arthritis & rheumatology (Hoboken, N.J.) · 2021Article
19 more citing papers are in PubMed but not listed here.
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Authors and funding
38 authors at 16 institutions in 4 countries.
Funding
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.
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Registered trials
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