The evolution and diversity of TNF block haplotypes in European, Asian and Australian Aboriginal populations

Abstract

The region spanning the tumour necrosis factor (TNF) cluster in the human major histocompatibility complex is implicated in susceptibility to immunopathological disease, but ethnic differences and linkage disequilibrium have hampered identification of critical polymorphisms. Here, we investigate Europeans, Asians (Bidayuh, Chinese, Indian, Jehai, Malay, Temuan) and Australian Aborigines to provide a framework for disease-association studies. DNA from 999 unrelated healthy donors was genotyped at 38 loci, primarily in coding and promoter regions over a 60-kb region spanning seven genes near TNF. The PHASE algorithm was used to statistically infer TNF block haplotypes and estimate their frequencies in each population. The TNF block is carried as 31 haplotypes in all populations combined, with o19 in any single population. Only six haplotypes have a unique tag single nucleotide polymorphism (SNP) valid for all populations, but seven haplotypes could be tagged with individual SNPs in selected populations. Four to eight TNF block haplotypes exist across all ethnicities, and hence must predate the divergence of these populations from a common ancestor 4160 000 years ago. Some haplotypes are unique to isolated populations, but they do not contain unique SNP. Hence, they reflect restricted migration and/or extinction of some families rather than de novo mutation.

The Search for a Genetic Factor Associating with Immune Restoration Disease in HIV Patients Co-Infected withMycobacterium tuberculosis

“…Alleles are recorded as "gene-nucleotide position*allele 1/allele 2", with allele 1 being the most frequent allele in Caucasians (previously defined as wildtype). In accordance with our earlier publications [15,16], TNF polymorphisms are described by their "traditional" names, TNF-308 and TNF-1031. We note that they lie 307 and 1030 bases (resp.)…”

“…Carriage of the variant allele in TNFA-1031 (rs1799964) in TB-IRD patients associated with a 4-fold greater risk in Cambodians, but this was not evident in the Indian cohort. TNFA-1031*2 affects neuropathy in Malay and Chinese HIV-infected patients [3] and haplotype blocks carrying TNF-1031 differ in frequency between Indian, Chinese and Cau-casian donors [16]. TNFA-308*2 and TNFA-1031*2 lie in distinct "TNF block haplotypes".…”

Role of TNF block genetic variants in HIV-associated sensory neuropathy in black Southern Africans

“…As expected, we also observed a unique LD pattern across the TNF block in this Southern African population, as compared with other non-African groups. 22 While it would be premature to assign a particular biological phenotype to carriage of a particular haplotype, the associations with HIV-SN demonstrate an inflammatory etiology and in time will help to elucidate pathogenic pathways. Importantly, improving our understanding of SN pathogenesis may lead to effective preventative strategies, or even pathogenesis-based treatments for a condition that currently lacks effective analgesic options.…”

“…* = SNPs that are significant following correction for covariates (age and height) ** = SNPs that are significant following correction for covariates (age and height) and multiple comparisons Figure 2 Original FV haplotypes 15,22 and FV sub-haplotypes (generated with population-specific tagSNPs) in this Southern African population. SNPs found to be associated with HIV-SN are shown in bold.…”

“…21 These have been defined with a consistent nomenclature (FV haplotypes). 22 As African populations have greater genetic diversity compared with non-African populations, 23 we included 30 additional population-appropriate tagSNPs. Each of the 61 SNPs individually, the 31-SNP FV haplotypes and novel 61-SNP haplotypes (FV ext haplotypes) were used to assess associations with HIV-SN in black Southern Africans.…”