A 129-kb deletion on chromosome 12 confers substantial protection against rheumatoid arthritis, implicating the gene...

We describe a copy-number variant (CNV) for which deletion alleles confer a protective affect against rheumatoid arthritis (RA). This CNV reflects net unit deletions and expansions to a normal two-unit tandem duplication located on human chr12p13.31, a region with conserved synteny to the rat RA susceptibility quantitative trait loci Oia2. Genotyping, using the paralogue ratio test and SNP intensity data, in Swedish samples (2,403 cases, 1,269 controls) showed that the frequency of deletion variants is significantly lower in cases (P = 0.0012, OR = 0.442 [95%CI 0.258-0.755]). Reduced frequencies of deletion variants were also seen in replication materials comprising 9,201 UK samples (1,846 cases, 7,355 controls) and 2,963 US samples (906 controls, 1,967 cases) (Mantel-Haenszel P = 0.036, OR = 0.559 [95%CI 0.323-0.966]). Combining the three datasets produces a Mantel-Haenszel OR of 0.497 (P < 0.0002). The deletion variant lacks 129-kb of DNA containing SLC2A3, NANOGP1, and SLC2A14. SLC2A3 encodes a high-affinity glucose transporter important in the immune response and chondrocyte metabolism, both key aspects of RA pathogenesis. The large effect size of this association, its potential relevance to other diseases in which SLC2A3 is implicated, and the possibility of targeting drugs to inhibit SLC2A3, argue for further examination of the genetics and the biology of this CNV.