Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus

Family studies of first-degree relatives and analysis of twins indicate tha t as much as 75% of the differences in quantitative IL-10 production in man derive from heritable genetic factors. Studies of single nucleotide polymo rphisms (SNP) in the proximal 1.0 kb of the IL-IO promoter have yielded inc onsistent association with IL-10 production and variable results in promote r-reporter studies. However, in normal donors, an association of quantitati ve production with certain alleles of the IL-10.R short tandem repeat polym orphism at -4.0 kb suggested that SNPs in the more distal promoter might be informative. We have identified seven novel SNP sites in the genomic seque nce of the first 4 kb of the IL-10 promoter region 5' to the ATG start site from Caucasian individuals with either a high or a low IL-10 production ph enotype. We have also identified eight SNP haplotypes in the distal promote r that segregate with significant differences in quantitative IL-10 product ion in normal donors. These SNPs are significantly associated with systemic lupus erythematosus in African-Americans and may define one component of t he genetic susceptibility to systemic lupus erythematosus in this group.