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 that as much as 75% of the differences in quantitative IL-10 production in man derive from heritable genetic factors. Studies of single nucleotide polymorphisms (SNP) in the proximal 1.0 kb of the IL-10 promoter have yielded inconsistent association with IL-10 production and variable results in promoter-reporter studies. However, in normal donors, an association of quantitative production with certain alleles of the IL-10.R short tandem repeat polymorphism 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 sequence 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 phenotype. We have also identified eight SNP haplotypes in the distal promoter that segregate with significant differences in quantitative IL-10 production in normal donors. These SNPs are significantly associated with systemic lupus erythematosus in African-Americans and may define one component of the genetic susceptibility to systemic lupus erythematosus in this group.
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, AL 35294, USA.
A W
AW
Gibson
J C
JC
Edberg
J
J
Wu
R G
RG
Westendorp
T W
TW
Huizinga
R P
RP
Kimberly
D020121:5' Untranslated Regions / Q000276:immunology; D000483:Alleles; D044383:Black People / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008969:Molecular Sequence Data; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012307:Risk Factors; D014158:Transcription, Genetic / Q000276:immunology; D044465:White People / Q000235:genetics; D001741:Black or African American
D020121:5' Untranslated Regions; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016753:Interleukin-10