TNFA promoter alleles--frequencies and linkage with classical HLA genes in a South German Caucasian population.

The tumor necrosis factor alpha (TNFA) promoter region exhibits several polymorphisms, which have been hypothesized to influence gene expression, thereby associating positively or negatively with inflammatory conditions. Many studies have focused on single nucleotide polymorphisms (SNPs) taking not into account additive or inverse effects between different SNPs. We typed 1,021 healthy Caucasian volunteer stem cell donors for their TNFA promoter as well as their HLA-A,-C,-B,-DRB1 loci. Using statistical methods, we reconstructed TNFA promoter alleles and analyzed their frequency and linkage with HLA genes. We show that the number of TNFA promoter alleles frequent enough to be analyzed in clinical studies is limited and that a strong linkage with classical HLA genes is present, especially for the extended HLA-haplotype HLA-A01:01/HLA-C07:01/HLA-B08:01/TNFA promoter allele 3/HLADRB1*03:01. Taking into account SNP frequency information, it is possible to quite accurately deduce TNFA promoter alleles by generic Sanger sequencing, obviating the need for elaborating allele-specific sequencing. This information may enable investigators to consider the complete TNFA regulatory region in a phase-separated manner in contrast to previous approaches examining only one or few isolated SNPs.