Haplotype structure of inflammatory cytokines genes (IL1B, IL6 and TNF/LTA) in US Caucasians and African Americans

Abstract

The major inflammatory cytokines interleukin(IL)1b, IL6 and tumor necrosis factor a (TNFa) play a crucial role in infection, inflammation and stress responses. Previously, three coding genes were resequenced, identifying promoter polymorphisms that were used in association studies of neurodegenerative diseases, metabolic disorders and cancer. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: IL1B-511 C4T, IL6-174 G4C and TNF-308 G4A provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for IL1B, IL6 and TNF/LTA that included the known functional marker but also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 26 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations, a single block with little evidence of historical recombination was observed in IL1B, IL6 and TNF/LTA. For each gene, haplotypes captured the information content of each functional locus, even if that locus was not genotyped, and presumably haplotypes would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using gene haplotype maps and marker panels as tools for linkage studies on related phenotypes.

Common Genetic Variants in Proinflammatory and Other Immunoregulatory Genes and Risk for Non-Hodgkin Lymphoma

“…Because the analysis of single common polymorphisms does not necessarily capture the extent of genetic variation across a locus or gene function (32,35), our haplotype findings are instrumental in showing that this locus could be associated with non-Hodgkin lymphoma and that an untested SNP in linkage disequilibrium could be the causal variant(s) (28). We show the importance of this locus in all nonHodgkin lymphoma and specifically for DLBCL and T-cell lymphomas.…”

“…27) and (b) TNF/LTA (rs909253, rs2239704, rs1800629, rs361525, and rs1799724; ref. 28). Although haplotype blocks were constructed for IL-1, IL-4, and IL-6, their high correlation (r 2 z 0.91) in our population provided low frequencies of haplotypic variants for further analysis.…”

Tumour necrosis factor and lymphotoxin A polymorphisms and lung function in smokers

“…LTA is clustered with TNF within a 6.1-kb region on chromosome 6p21.3, and polymorphisms of LTA and TNF have been reported to be in strong linkage disequilibrium (LD) in many populations [11]. LTA is involved in the normal development of lymphoid tissue and also acts as an inducer of the inflammatory response [12].…”

Allele-specific induction of IL1B −31 T/C promoter polymorphism by lung carcinogens

“…The second most common haplotype, G/ACTC, was evenly distributed between cases and controls. Data on larger IL1B haplotype blocks exist for control groups in Taiwan Chinese, US Caucasians and African-American populations [186,187]. This suggests that there are differences between ethnic groups that should be investigated in future studies.…”