Background Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a strong genetic component. Dozens of SLE-associated loci have been identified by genome-wide associated studies (GWAS) and included in the ImmunoChip for fine-mapping.
Materials and methods Using ImmunoChip, we assessed case-control subjects including Chinese, European Americans (EA) and African Americans (AA) for association with SLE. Subsequently, we carried out trans-ancestral mapping and resequenced the complex GTF2IRD1-GTF2I-NCF1 region on 7q11.23 to identity underlying causal variant.
Results The strongest association signal in Chinese was unexpectedly detected at rs73366469 (OR = 2.88, P = 3.6×10–29) within the GTF2IRD1-GTF2I intergenic region on 7q11.23 rather than SLE-associated GWAS loci. This association was confirmed in EA (OR = 1.37, P = 2.5×10–3) but not in AA. By trans-ancestral mapping and sequencing, we identified R90H of NCF1, a neighbouring gene of GTF2I encoding the p47phox subunit of NADPH oxidase, as a highly plausible causal variant. R90H was associated with SLE in East Asians (OR = 3.47, P meta = 3.0×10–105), EA (OR = 2.11, P meta = 7.0×10–8) and AA (OR = 1.91, P = 7.2×10–3), and in conditional test R90H eliminated SLE-associated signals within the GTF2IRD1-GTF2I region including rs73366469. Furthermore, R90H was dose-dependently associated with early age of onset in Korean (P = 0.011) and EA (P = 0.012) patients with SLE. In addition to SLE, R90H was associated with seropositive rheumatoid arthritis (RA) in Koreans (OR = 1.66, P = 1.2×10–8) and primary Sjögren’s syndrome (SS) in EA (OR = 1.72, P = 5.8×10–3). The conserved arginine 90 to histidine substitution located in the PX-?binding domain of p47phox is predicted deleterious, which is supported by a report showing R90H results in reduced reactive oxygen species (ROS) production.
Conclusions We identified R90H of NCF1 as a novel risk variant for multiple autoimmune diseases, highlighting the pathogenic role of reduced ROS production in developing autoimmune diseases.
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