title: Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context.
abstract: 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.
authors.affiliation: Interleukin Genetics Inc., 135 Beaver Street, Waltham, MA 02452, USA.
authors.forename: Hongmin
authors.initials: H
authors.lastname: Chen
authors.forename: Leon M
authors.initials: LM
authors.lastname: Wilkins
authors.forename: Nazneen
authors.initials: N
authors.lastname: Aziz
authors.forename: Christopher
authors.initials: C
authors.lastname: Cannings
authors.forename: David H
authors.initials: DH
authors.lastname: Wyllie
authors.forename: Colin
authors.initials: C
authors.lastname: Bingle
authors.forename: John
authors.initials: J
authors.lastname: Rogus
authors.forename: James D
authors.initials: JD
authors.lastname: Beck
authors.forename: Steven
authors.initials: S
authors.lastname: Offenbacher
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cork
authors.forename: Maryam
authors.initials: M
authors.lastname: Rafie-Kolpin
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Hsieh
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Kornman
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Duff
mesh_terms: D001741:Black or African American; D002460:Cell Line; D005091:Exons / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics*; D044465:White People
chemical_list: D007375:Interleukin-1