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Genes Immun DOI:10.1038/gene.2013.68

The influence of polygenic risk scores on heritability of anti-CCP level in RA.

Publication TypeJournal Article
Year of Publication2014
AuthorsCui, J, Taylor, KE, Lee, YC, Källberg, H, Weinblatt, ME, Coblyn, JS, Klareskog, L, Criswell, LA, Gregersen, PK, Shadick, NA, Plenge, RM, Karlson, EW
JournalGenes Immun
Volume15
Issue2
Pages107-14
Date Published2014 Mar
ISSN1476-5470
KeywordsArthritis, Rheumatoid, Autoantibodies, Case-Control Studies, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, GPI-Linked Proteins, HLA-DR3 Antigen, HLA-DRB1 Chains, Humans, Linkage Disequilibrium, Male, Middle Aged, Models, Genetic, Peptides, Cyclic, Polymorphism, Single Nucleotide, Prospective Studies
Abstract

The objective of this study was to study genetic factors that influence quantitative anticyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. We carried out a genome-wide association study (GWAS) meta-analysis using 1975 anti-CCP+ RA patients from three large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC) and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. GWAS-meta-analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a P-value of 2 × 10(-11) for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5 × 10(-8), and all were in linkage disequilibrium (LD) with the HLA- DRB1*03 allele with LD r(2) in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a P-value of 3 × 10(-7). None of the known RA risk alleles (∼52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. In summary, anti-CCP level is a heritable trait, and HLA-DR3 and GP2 are associated with lower anti-CCP levels.

URLhttp://dx.doi.org/10.1038/gene.2013.68
DOI10.1038/gene.2013.68
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24385024?dopt=Abstract

Alternate JournalGenes Immun.
PubMed ID24385024
PubMed Central IDPMC3948067
Grant List250167 / / European Research Council / International
U01 GM092691 / GM / NIGMS NIH HHS / United States