Modelling the major histocompatibility complex susceptibility to RA using the MASC method

To explain the association between HLA‐DRB1 gene and rheumatoid arthritis (RA), two main hypotheses have been proposed. The first, the shared epitope hypothesis, assumes a direct role of DRB1 in RA susceptibility. The second hypothesis assumes a recessive disease susceptibility gene in linkage disequilibrium with DRB1. To investigate these two hypotheses, we analysed data on the HLA‐DRB1 and TNF‐LT loci in 49 affected sib‐pairs. We used the Marker Association Segregation Chi‐square (MASC) method in which the genotype distribution of markers among index cases and the haplotype sharing in affected sib‐pairs are jointly taken into account. With DRB1 data alone, both hypotheses were shown to fit but with analysis of TNF data, both hypotheses were strongly rejected. Thus the TNF data provided additional information for a better understanding of genetic susceptibility to RA than was previously possible using only HLA‐DR data. A theoretical standpoint is addressed here on the advisability of using different linked markers in a candidate region for modelling the contribution of this region in disease susceptibility. Genet. Epidemiol. 15:419–430,1998. © 1998 Wiley‐Liss, Inc.