Finding causative genes underlying rheumatic disease: could NCF1 pave the way?

ABSTRACT The identification of genetic risk factors could facilitate our understanding of the cause and pathogenesis of rheumatic diseases. Maps of susceptibility loci have been established for most complex diseases, including all major rheumatic diseases, but definitive causal variants have been identified only very infrequently. Here, we highlight the need to both position and confirm the role of causative polymorphisms in humans using experimental animals. The approach is best exemplified by the positional cloning of a causative single-nucleotide polymorphism (SNP) (rs201802280), which results in the substitution of arginine with histidine at position 90 in the NCF1 gene (neutrophil cytosolic factor 1, a component of the phagocyte NOX2 (Nicotinamide adenine dinucleotide phosphate oxidase 2) complex. This variant was independently identified and validated using 2 distinct approaches: by positioning the gene in animal models, followed by exon sequencing and validation of the identified SNPs, and by targeted resequencing and linkage disequilibrium mapping in multiethnic case-control studies. This causal SNP, located in a region with copy number variation, has emerged as a major susceptibility variant for multiple rheumatic diseases, including systemic lupus erythematosus, rheumatoid arthritis, primary Sjögren's disease, and systemic sclerosis. It represents the first major causal polymorphism conclusively linked to both increased susceptibility and disease severity across multiple rheumatic conditions, in both patients and animal models. The functional impact of the NCF1 variant has been explored mechanistically, and a viral infection has been identified as an interacting environmental factor contributing to lupus disease in animal studies. Importantly, the significance of the NCF1 polymorphism extends beyond rheumatic diseases—it has also been implicated in cancer, cardiovascular syndromes, infections, and physiological traits.