Human Molecular Genetics Advance Access originally published online on January 6, 2006
Human Molecular Genetics 2006 15(4):519-529; doi:10.1093/hmg/ddi469
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Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context
1Interleukin Genetics, Inc., 135 Beaver Street, Waltham, MA 02452, USA, 2Division of Genomic Medicine, University of Sheffield, Sheffield S10 2RX, UK and 3University of North Carolina, Chapel Hill, NC 27559, USA
* To whom correspondence should be addressed. Tel: +1 7813980705; Fax: +1 7813980720; Email: kkornman{at}ilgenetics.com
Received November 9, 2005; Revised December 22, 2005; Accepted December 30, 2005
We questioned the significance of haplotype structure in gene regulation by testing whether individual single nucleotide polymorphisms (SNPs) within a gene promoter region [interleukin-1-beta (IL1B)] might affect promoter function and, if so, whether function was dependent on haplotype context. We sequenced genomic DNA from 25 individuals of diverse ethnicity, focusing on exons and upstream flanking regions of genes of the cluster. We identified four IL1B promoter region SNPs that were active in transient transfection reporter gene assays. To substantiate allelic differences found in reporter gene assays, we also examined nuclear protein binding to promoter sequence oligonucleotides containing different alleles of the SNPs. The effect of individual SNPs on reporter gene transcription varied according to which alleles of the three other SNPs were present in the promoter construct. The SNP patterns that influenced function reflected common haplotypes that occur in the population, suggesting functionally significant interactions between SNPs according to haplotype context. Of the haplotypes that include the four functional IL1B promoter SNPs (–3737, –1464, –511, –31), the four haplotypes that showed different contextual effects on SNP function accounted for >98% of the estimated haplotypes in Caucasian and African-American populations. This finding underlines the importance of understanding the haplotype structure of populations used for genetic studies and may be especially important in the functional analysis of genetic variation across gene regulatory regions.
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