The 8.1 ancestral MHC haplotype is strongly associated with colorectal cancer risk

Abstract

Many recent data indicate that some alleles encoded in the central major histocompatibility complex (MHC) region (Class III) of short arm of chromosome 6 may modify the risk of cancer development. Therefore we determined 4 single nucleotide polymorphisms (SNPs) of this region (TNF‐α −308 G > A, RAGE −429 T > C, HSP70‐2 −1267 A > G, LTA 252 A > G) in genomic DNA samples from 183 Hungarian patients with colorectal cancer and 141 age matched control subjects representing the Hungarian population of the same age and gender. No significant differences were found in either SNP tested. When, however, three‐ or four‐locus haplotypes consisting of known constituents of the so‐called 8.1 ancestral haplotype (8.1AH) were considered, marked differences were observed. Frequency of TNF‐α −308A, RAGE −429C, HSP70‐2 −1267G, LTA 252G (8.1AH) haplotype was significantly (p = 0.006) more frequent (19.1%) among patients than in the controls (7.7%). Age‐ and gender‐adjusted ratio of the 8.1AH carriers vs. non‐carriers to have colorectal cancer was 2.514 (1.130–5.594). This risk was higher in ≤67 years old subjects (4.073 (1.317–12.596)) and in females (3.771 (1.302–10.927). These findings—consistent with similar recent results with ovarian cancer—indicate that carriers of the 8.1AH, encoding for an altered immune response and known to be associated with alterations of several immune functions and autoimmune diseases have an increased risk for some cancer types. These findings may contribute to better understanding how the defense mechanisms against tumors could be enhanced/strengthened. © 2007 Wiley‐Liss, Inc.

Tumor necrosis factor–associated susceptibility to type 1 diabetes is caused by linkage disequilibrium with HLA-DR3 haplotypes

“…The fact that TNF Ϫ308A allele is a "high expressor" allele [35,52] explains the immunological basis of its association with the inflammatory stage of pathogenesis of T1D to some extent. Caucasian T1D patients exhibit a strong association of an ancestral haplotype AH8.1 that carries this high expressor allele [53,54]. It is important to note that the population frequency of TNF Ϫ308A in the Caucasian population is around 17-22% [55], higher than that observed in the Asian populations, in which it is very rare, ϳ1-3% [48,56].…”

Ancestral haplotype 8.1 and lung disease severity in European cystic fibrosis patients

“…Moreover, our data are consistent with the current understanding of the roles of 8.1AH in the inflammatory response. 8.1AH has indeed been associated with excessive and uncontrolled inflammation in various inflammatory disorders [18,19]. In CF, inflammation is believed to drive the progressive destruction of the lung and the decline in lung function which is responsible for the major morbidity and mortality [20].…”

Relationship between the polymorphism of tumor necrosis factor-α-308 G>A and susceptibility to inflammatory bowel diseases and colorectal cancer: a meta-analysis

“…Several studies have suggested a positive association between the polymorphisms in cytokines and the risk of CRC. 38,39 In this metaanalysis, we analyzed the relationship between the polymorphism of TNF-a-308 G4A and the susceptibility to CRC. However, no significant association was observed.…”