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

Genes & Immunity volume 15, pages 107–114 (2014)Cite this article

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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 r2 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.

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Authors and Affiliations

  1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

    J Cui, Y C Lee, M E Weinblatt, J S Coblyn, N A Shadick, R M Plenge & E W Karlson

  2. Division of Rheumatology, Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, CA, USA

    K E Taylor & L A Criswell

  3. Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden

    H Källberg & L Klareskog

  4. The Feinstein Institute for Medical Research, North Shore–Long Island Jewish Health System, Manhasset, NY, USA

    P K Gregersen

  5. Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

    R M Plenge

  6. Medical and Population Genetics Program, Chemical Biology Program, Broad Institute, Cambridge, MA, USA

    R M Plenge

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  1. J Cui
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Cui, J., Taylor, K., Lee, Y. et al. The influence of polygenic risk scores on heritability of anti-CCP level in RA. Genes Immun 15, 107–114 (2014). https://doi.org/10.1038/gene.2013.68

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