MODELING THE MAJOR HISTOCOMPATIBILITY COMPLEX SUSCEPTIBILITY TO RA USING THE MASC METHOD

To explain the association between HLA-DRB1 gene and rheumatoid arthri tis (RA), two main hypotheses have been proposed. The first, the share d epitope hypothesis, assumes a direct role of DRB1 in RA susceptibili ty. The second hypothesis assumes a recessive disease susceptibility g ene in linkage disequilibrium with DRB1. To investigate these two hypo theses, we analysed data on the HLA-DRB1 and TNF-LT loci in 49 affecte d sib-pairs. We used the Marker Association Segregation Chi-square (MA SC) method in which the genotype distribution of markers among index c ases 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 under standing 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 regi on for modelling the contribution of this region in disease susceptibi lity. Genet. Epidemiol. 15:419-430, 1998. (C) 1998 Wiley-Liss,Inc.