THE EUROPEAN CONSORTIUM ON MEN1 - LINKAGE DISEQUILIBRIUM STUDIES IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-1 (MEN1)

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant di sorder characterised by tumours of the parathyroids, pancreas and ante rior pituitary. The MEN1 gene has been localised to a 2-Mb region of c hromosome 11q13 by meiotic mapping studies in MEN1 families. Such stud ies may have a limited resolution of approximately 1 cM (i.e. 1 Mb) an d we have therefore investigated 96 MEN1 families (40 British, 17 Fren ch, 12 Finnish, 7 Swedish, 7 Dutch, 7 North American, 2 Australian, 1 New Zealand, 1 German, 1 Spanish and 1 Danish) for linkage disequilibr ium, in order to facilitate a finer mapping resolution. We have utilis ed five microsatellite DNA sequence polymorphisms from the candidate r egion and have accurately determined their allele sizes, which ranged from 161 bp to 272 bp. The heterozygosity and number of alleles (given in brackets), respectively, at the loci were: D11S1883 (76%, 11), D11 S457 (55%, 5), PYGM (94%, 18), D11S1783 (10%, 4) and D11S449 (87%, 16) . Allelic association was assessed by Chi-square 2 x n contingency tab les, by Fisher exact 2 x n contingency tables and by a likelihood-base d approach. The results of haplotype analysis revealed 91 different af fected haplotypes in the 96 families, an identical affected haplotype being observed in no more than two families. These results indicate th e absence of an ancestral affected haplotype. Significant linkage dise quilibrium (P < 0.005) could be established amongst the microsatellite loci but not between the loci and MEN1 in either the total population or in any of the geographical sub-populations, The absence of linkage disequilibrium between MEN1 and the polymorphic loci is probably the result of the occurrence of multiple different disease-causing mutatio ns in MEN1.