Journal article
Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes
PLoS genetics, v 7(2), e1001311
01 Feb 2011
PMID: 21379322
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p<5×10
−8
) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4×10
−128
. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8–5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (OR
high-low
= 2.36, p = 9e−9), the immunologic criterion (OR
high-low
= 2.23, p = 3e−7), and age at diagnosis (OR
high-low
= 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (
HLA-DRB1,
OR = 1.37, 95% CI 1.14–1.64) and arthritis (
ITGAM
, OR = 0.72, 95% CI 0.59–0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.
Systemic lupus erythematosus is a chronic disabling autoimmune disease, most commonly striking women in their thirties or forties. It can cause a wide variety of clinical manifestations, including kidney disease, arthritis, and skin disorders. Prognosis varies greatly depending on these clinical features, with kidney disease and related characteristics leading to greater morbidity and mortality. It is also complex genetically; while lupus runs in families, genes increase one's risk for lupus but do not fully determine the outcome. The interactions of multiple genes and/or interactions between genes and environmental factors may cause lupus, but the causes and disease pathways of this very heterogeneous disease are not well understood. By examining relationships between the presence of multiple lupus risk genes, lupus susceptibility, and clinical manifestations, we hope to better understand how lupus is triggered and by what biological pathways it progresses. We show in this work that certain clinical manifestations of lupus are highly associated with cumulative genetic variations, i.e. multiple risk alleles, while others are associated with a single variation or none at all.
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Details
- Title
- Risk Alleles for Systemic Lupus Erythematosus in a Large Case-Control Collection and Associations with Clinical Subphenotypes
- Creators
- Kimberly E. Taylor - University of California, San FranciscoSharon A. Chung - University of California, San FranciscoRobert R. Graham - University of OxfordWard A. Ortmann - University of OxfordAnnette T. Lee - Feinstein Institute for Medical ResearchCarl D. Langefeld - Wake Forest UniversityChaim O. Jacob - University of Southern CaliforniaM. Ilyas Kamboh - University of PittsburghMarta E. Alarcón-Riquelme - Oklahoma Medical Research FoundationBetty P. Tsao - University of California, Los AngelesKathy L. Moser - Oklahoma Medical Research FoundationPatrick M. Gaffney - Oklahoma Medical Research FoundationJohn B. Harley - Cincinnati Children's Hospital Medical CenterMichelle Petri - Johns Hopkins MedicineSusan Manzi - Allegheny-Singer Research InstitutePeter K. Gregersen - Feinstein Institute for Medical ResearchTimothy W. Behrens - University of OxfordLindsey A. Criswell - University of California, San Francisco
- Publication Details
- PLoS genetics, v 7(2), e1001311
- Publisher
- Public Library of Science
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- General Internal Medicine
- Web of Science ID
- WOS:000287697300026
- Scopus ID
- 2-s2.0-79952261842
- Other Identifier
- 991021933906204721
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity