Substantial departure from multiplicativity was observed between smoking and SNPs in genes CTLA4, PADI4, MIF, and SNPs on chromosome 5 and one haplotype of PTPN22. The strongest evidence of association was identified between the PTPN22 gene and RA status, which was consistently detected in single SNP association, gene × gene interaction and gene × smoking interaction analyses. The gene discussed is PTPN22; the disease is rheumatoid arthritis.