Association between a Single-Nucleotide Polymorphism in the Promoter of the Human Interleukin-3 Gene and Rheumatoid Arthritis in Japanese Patients, and Maximum-Likelihood Estimation of Combinatorial Effect That Two Genetic Loci Have on Susceptibility to the Disease

Genetic variants of interleukin-3 (IL-3), a well-studied cytokine, may have a role in the pathophysiology of rheumatoid arthritis (RA); but reports on this association sometimes conflict. A case-control study was designed to investigate association between RA and a single-nucleotide polymorphism (SNP) in the IL-3 promoter region. Comparison of cases of RA versus control individuals yielded a χ 2 value of 14.28 ( P=.0002), with a genotype odds ratio of 2.24 (95% confidence interval [95%CI] 1.44–3.49). When female cases with earlier onset were compared with female control individuals, the SNP revealed an even more significant correlation, with χ 2=21.75 ( P=.000004) and a genotype odds ratio of 7.27 (95%CI 2.80–18.89). The stronger association that we observed in this clinically distinct subgroup (females with early onset), within a region where linkage disequilibrium was not significantly extended, suggested that the genuine RA locus should locate either within or close to the IL-3 gene. Combined genotype data on SNPs on eight other candidate genes were combined with our IL-3 results, to estimate relationships between pairs of loci and RA, by maximum-likelihood analysis. The utility of combining the genotype data in this way to identify possible contributions of various genes to this disease is discussed.