High-Density SNP genotyping defines 17 distinct haplotypes of the TNF block in the Caucasian population: Implications for haplotype tagging

Abstract

The region spanning the tumor necrosis factor (TNF) cluster in the human major histocompatibility complex (MHC) has been implicated in susceptibility to numerous immunopathological diseases, including type 1 diabetes mellitus and rheumatoid arthritis. However, strong linkage disequilibrium across the MHC has hampered the identification of the precise genes involved. In addition, the observation of "blocks" of DNA in the MHC within which recombination is very rare, limits the resolution that may be obtained by genotyping individual SNPs. Hence a greater understanding of the haplotypes of the block spanning the TNF cluster is necessary. To this end, we genotyped 32 human leukocyte antigen (HLA)-homozygous workshop cell lines and 300 healthy control samples for 19 coding and promoter region SNPs spanning 45 kb in the central MHC near the TNF genes. The workshop cell lines defined 11 SNP haplotypes that account for approximately 80% of the haplotypes observed in the 300 control individuals. Using the control individuals, we defined a further six haplotypes that account for an additional 10% of donors. We show that the 17 haplotypes of the "TNF block" can be identified using 15 SNPs.

Does a central MHC gene in linkage disequilibrium with HLA-DRB1*0401 affect susceptibility to type 1 diabetes?

“…13 Here carriage of IKBL þ 446*T was similar in patients and controls (17.7% of COD, 14.3% of AOD vs 14.1% of controls). This suggests that many controls carry IKBL þ 446 without the HLA class II alleles of the 62.1 AH, possibly with HLA-B35 and/or DR1, which were negatively associated with T1DM in most comparisons (eg Table 2).…”

“…We have used 19 SNP spanning the TNF cluster (including IKBL þ 446) to define 17 haplotypes describing 90% of the control population. 13 Haplotypes containing HLA-DRB1*0401 and -DRB1*0404 were distinguished by several alleles including IKBL þ 446.…”

“…IKBL þ 446 is a suitable marker for this purpose. 12,13 Additional markers may be required to map the telomeric end, as HLA-A2 is common to several haplotypes, but this analysis can include donors carrying C4B3.…”

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

“…MALDI-MS yielded median (range) success rates of 72(15-97)% for BAT1-223 (rs41293919) and 58(49-69)% for NFKBIL1 þ 1372 (rs45457097) with no deviation from HWE (P40.05). 3 A preliminary screen suggested that the minor allele of BAT1-223 was a unique marker of the FV1 haplotype in the European, Australian Aboriginal and North Indian populations. On the other hand, NFKBIL1 þ 1372 split the common FV18 haplotype and created novel haplotypes.…”

“…Subsequently, we investigated 19 SNPs spanning 45 kb around TNF and found only 17 distinct haplotypes (occurring at frequencies 41%) in a mixed European population from Western Australia. 3 This work is extended here to characterise haplotypes defined by 38 SNPs spanning seven genes, which we defined as the 'TNF block', MCCD1, BAT1 (UAP56), ATP6V1G2, NFKBIL1 (IKBL), LTA (TNFB), TNF (TNFSF2, TNFA) and LST1 (B144) (see Figure 1; Table 1), in European (Western Australian), Asian (Bidayuh, Chinese, Indian, Jehai, Malay, Temuan) and Australian Aboriginal populations. The data provides a framework for disease-association and ethnographic studies.…”