Evidence for disease phenotype associated haplotypes (DR.TNF) in sarcoidosis

In a previous study, gene polymorphisms of the MHC locus (-308 TNFalpha promotor, HLA-DR) in patients with pulmonary sarcoidosis had been investigated and significant correlations with the presentation of the disease as defined by the presence of Löfgren syndrome had been found. Since genotyping of both loci was necessary to reveal a significant difference on the genetic level between the two patient groups Löfgren and non-Löfgren, a working hypothesis was derived in which a disease course associated haplotype, rather than single specific genes, was considered to play a role in the pathogenesis of sarcoidosis.

A first step to test this hypothesis was taken by calculating virtual haplotypes from these previous data. Statistical analysis of disease phenotype association and relative risk of these virtual haplotypes was performed to assess correlations with sarcoidosis and the two disease phenotypes.

The results not only substantiated the previous findings, but also showed that the virtual haplotype DR3.TNFalpha2 was significantly associated with Löfgren syndrome and that the virtual haplotype DR2.TNFalpha1 was noticeably although not significantly associated with the non-Löfgren patients.

Using theoretical calculations based on actual data, haplotypes, rather than single genes interacting with each other, were found to be a highly likely explanation for the previously published observations. In addition, the results allow the conclusion to be drawn that disease course associated haplotypes in sarcoidosis are highly probable and that further investigation of polymorphisms in the MHC gene region holds the potential of defining prognostic markers.