Exome Sequencing of Chinese Patients With Anticitrullinated Protein Antibody–Positive Rheumatoid Arthritis in Singapore

Objective More than 130 susceptibility loci for rheumatoid arthritis (RA) have been identified with genome-wide association studies. To investigate the genetic predisposition of Chinese patients to anticitrullinated protein antibody (ACPA)-positive RA, we carried out an exome sequencing study.

Methods Patients were recruited from 3 major public hospitals in Singapore: Tan Tock Seng Hospital (TTSH), Singapore General Hospital, and the National University Hospital. Controls came from an established exome collection and from the TTSH Health Control Biobank. All the participants were of Chinese descent. We performed whole-exome sequencing (WES) in 595 ACPA-positive patients with RA and 1281 controls and validated the candidate variants by genotyping 795 RA cases and 600 controls.

Results The discovery cohort yielded 73 susceptibility single-nucleotide variants (SNVs) that reached statistical significance. In the validation study with an independent cohort, 2 SNVs remained significant: PCNXL4 (P = 1.50 × 10⁻⁵) and DHRS7 (P = 6.02 × 10⁻⁵). The majority of known susceptibility foci were not captured by exome sequencing.

Conclusion In this WES study of ACPA-positive RA in Chinese patients, we discovered 2 new variants in PCNXL4 and DHRS7 associated with risk for RA.