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Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes

Taylor, KE and Chung, SA and Graham, RR and Ortmann, WA and Lee, AT and Langefeld, CD and Jacob, CO and Kamboh, MI and Alarcón-Riquelme, ME and Tsao, BP and Moser, KL and Gaffney, PM and Harley, JB and Petri, M and Manzi, S and Gregersen, PK and Behrens, TW and Criswell, LA (2011) Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes. PLoS Genetics, 7 (2). ISSN 1553-7390

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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 (ORhigh-low = 2.36, p = 9e-9), the immunologic criterion (ORhigh-low = 2.23, p = 3e-7), and age at diagnosis (ORhigh-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.


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Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Taylor, KE
Chung, SA
Graham, RR
Ortmann, WA
Lee, AT
Langefeld, CD
Jacob, CO
Kamboh, MIkamboh@pitt.eduKAMBOH
Alarcón-Riquelme, ME
Tsao, BP
Moser, KL
Gaffney, PM
Harley, JB
Petri, M
Manzi, S
Gregersen, PK
Behrens, TW
Criswell, LA
Date: 1 February 2011
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 7
Number: 2
DOI or Unique Handle: 10.1371/journal.pgen.1001311
Schools and Programs: Graduate School of Public Health > Human Genetics
Refereed: Yes
ISSN: 1553-7390
MeSH Headings: Alleles; Antibodies, Antinuclear--immunology; Area Under Curve; Case-Control Studies; Female; Genetic Predisposition to Disease; Humans; Logistic Models; Lupus Erythematosus, Systemic--genetics; Lupus Erythematosus, Systemic--immunology; Lupus Erythematosus, Systemic--pathology; Male; Models, Genetic; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide--genetics; Principal Component Analysis; ROC Curve; Reproducibility of Results
Other ID: NLM PMC3040652
PubMed Central ID: PMC3040652
PubMed ID: 21379322
Date Deposited: 07 Aug 2012 15:52
Last Modified: 30 Mar 2019 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/13419

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