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

J. Cui*, K. E. Taylor, Y. C. Lee, H. Källberg, M. E. Weinblatt, J. S. Coblyn, L. Klareskog, L. A. Criswell, P. K. Gregersen, N. A. Shadick, R. M. Plenge, E. W. Karlson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)107-114
Number of pages8
JournalGenes and Immunity
Volume15
Issue number2
DOIs
StatePublished - Mar 2014

Keywords

  • Anti-CCP
  • GWAS
  • Heritability
  • RA

ASJC Scopus subject areas

  • Immunology
  • Genetics
  • Genetics(clinical)

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