The Influence of Polygenic Risk Scores on Heritability of Anti-CCP Level in RA
Taylor, Kimberly E.
Criswell, Lindsey A.
Gregersen, Peter K.
Plenge, Robert M.
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CitationCui, J., K. E. Taylor, Y. C. Lee, H. Källberg, M. E. Weinblatt, J. S. Coblyn, L. Klareskog, et al. 2014. “The Influence of Polygenic Risk Scores on Heritability of Anti-CCP Level in RA.” Genes and immunity 15 (2): 107-114. doi:10.1038/gene.2013.68. http://dx.doi.org/10.1038/gene.2013.68.
AbstractObjective: To study genetic factors that influence quantitative anti-cyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. Methods: We carried out a genome wide association study (GWAS) meta-analysis using 1,975 anti-CCP+ RA patients from 3 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. Results: 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. Conclusions: Anti-CCP level is a heritable trait. HLA-DR3 and GP2 are associated with lower anti-CCP levels.
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