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

Abstract

Objective 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.

High-specificity bioinformatics framework for epigenomic profiling of discordant twins reveals specific and shared markers for ACPA and ACPA-positive rheumatoid arthritis

“…Twin, family, and genetic studies have shown that environmental factors make a substantial contribution, besides the genetic factors, to the development of ACPA and ACPA-positive RA [11, 19, 20]. More specifically, the risk for development of ACPA and ACPA-positive RA is associated with smoking and HLA- DRB1 gene alleles [17, 18].…”

The genetics of human autoimmune disease: A perspective on progress in the field and future directions

“…Similarly, some RA studies show stronger associations when the cases are limited to those with anti-cyclic citrullinated peptide antibodies (anti-CCP) [22]. However, in other studies when cases are limited to anti-CCP positive RA there are fewer susceptibility loci associated with disease, probably mostly due to decreased power as a function of a smaller sample size [23]. Similarly, if for example an SLE study was restricted to only those that manifested the same 4 out of 11 American College of Rheumatology criteria it is likely that many of the identified loci would have been missed due to weaker signals from decreased sample sizes.…”

HLA‐DRB1 gene polymorphisms and its associations with rheumatoid arthritis in Chinese Han women of Shaanxi province, northwest of China

“…RF and anti‐cyclic citrullinated peptide (anti‐CCP) antibody is an important biomarker for RA. Higher anti‐CCP levels are also associated with more active disease, more severe joint damage, worse functional disability and reduced quality of life (Ibn Yacoub et al ., ; Cui et al ., ). In this study, HLA‐SE risk alleles were strongly associated with anti‐CCP and RF level, further suggesting that HLA‐SE risk allele might be a valid indicator for predicting RA.…”