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IL1B gene promoter haplotype pairs predict clinical levels of interleukin-1β and C-reactive protein

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Abstract

Interleukin-1β (IL-1β) activates inflammatory mediator cascades and has been implicated in the pathogenesis of several diseases. Single nucleotide polymorphisms (SNPs) of the IL1B promoter have been associated with various inflammatory diseases. We recently reported that IL1B gene transcription was influenced by four promoter SNPs, and that individual SNP function in vitro was governed by haplotype context. In the present study we tested the in vivo relevance of this observation by comparing IL1B promoter haplotype-pairs with IL-1β protein levels in 900 gingival tissue fluid samples. Three SNPs (−511, −1464, −3737) defined four IL1B promoter haplotypes that occurred in the study population and could be assigned unambiguously to each chromosome. The four haplotypes defined ten haplotype-pairs of which four pairs, representing 57% of the population, were associated with 28–52% higher IL-1β protein levels in vivo. Two of these pairs, characterized by homozygosity for the common allele at −3737, were also associated with raised serum levels of C-reactive protein (p = 0.02). We validated these findings in stimulated peripheral blood mononuclear cells (PBMCs) from a separate population (N = 70). PBMCs with IL1B haplotype-pairs associated with higher in vivo levels of IL-1β produced 86–287% more IL-1β in vitro than the reference group. We believe that this is the first demonstration of a relationship between in vivo levels of an inflammatory mediator and gene promoter haplotypes on both chromosomes. These findings may apply to other inducible genes and could provide a logical framework for exploring disease risk related to genetic variability in pathogenic mediators.

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Acknowledgments

The study was supported in part by Interleukin Genetics. The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022 and Grant. R01-DE11551 from the National Institute of Dental Research. The authors thank the staff and participants of the ARIC Study for their important contributions. MIUR (Ministero dell’Università e Ricerca, Italia) -Programma Triennale di Ricerca, grant D. 1588, supported the in vitro peripheral blood mononuclear cell work by Catholic University in Campobasso, Italy. Drs. Kornman, Rogus, and Huttner are employees of Interleukin Genetics. Dr. Duff is a scientific advisor to Interleukin Genetics, and Dr. Wang is a consulting statistician for Interleukin Genetics.

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Authors and Affiliations

  1. Interleukin Genetics Inc, 135 Beaver Street, Waltham, MA, 02452, USA

    John Rogus, Kenneth Huttner, Hwa-Ying Wang & Kenneth S. Kornman

  2. University of North Carolina, Chapel Hill, NC, 27559, USA

    James D. Beck & Steven Offenbacher

  3. Laboratory of Genetic and Environmental Epidemiology, Research Laboratories, John Paul II Center for High Technology Research and Education in Biomedical Sciences, Catholic University, Campobasso, Italy

    Licia Iacoviello, Maria Carmela Latella & Monica de Gaetano

  4. Division of Genomic Medicine, University of Sheffield, Sheffield, S10 2JF, UK

    Gordon W. Duff

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  1. John Rogus
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  2. James D. Beck
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  3. Steven Offenbacher
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  4. Kenneth Huttner
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  5. Licia Iacoviello
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  9. Kenneth S. Kornman
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Correspondence to Kenneth S. Kornman.

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Rogus, J., Beck, J.D., Offenbacher, S. et al. IL1B gene promoter haplotype pairs predict clinical levels of interleukin-1β and C-reactive protein. Hum Genet 123, 387–398 (2008). https://doi.org/10.1007/s00439-008-0488-6

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  • DOI: https://doi.org/10.1007/s00439-008-0488-6

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