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.
Gibson
A W
AW
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama, Birmingham, AL 35294, USA.
Edberg
J C
JC
Wu
J
J
Westendorp
R G
RG
Huizinga
T W
TW
Kimberly
R P
RP
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