Exome sequencing of Singapore Chinese anti-citrullinated-protein-antibody-positive rheumatoid arthritis patients.

Abstract

Objective: More than 130 susceptibility loci for rheumatoid arthritis (RA) have been identified with genome-wide association studies (GWAS). To investigate the genetic predisposition of Chinese anti-cyclic-citrullinated-peptides-antibody-positive RA, we carried out an exome sequencing study.

Methods: Patients were recruited from three major public hospitals in Singapore, Tan Tock Seng Hospital (TTSH), Singapore General Hospital and National University Health System. 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 RA patients and 1281 controls and validated the candidate variants by genotyping 795 RA cases and 600 controls.

Results: The discovery cohort yielded 73 susceptibility SNVs that reached statistical significance. In the validation study with an independent cohort, two SNVs remained significant: PCNXL4 (p-value 1.50x10^-5) and DHRS7 (p-value 6.02x10 ^-5). The majority of known susceptibility foci are not captured by exome sequencing.

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