MAJOR SUSCEPTIBILITY LOCUS FOR NEPHROPATHY IN TYPE-1 DIABETES ON CHROMOSOME 3Q - RESULTS OF NOVEL DISCORDANT SIB-PAIR ANALYSIS

Diabetic nephropathy (DN) clusters in families with type 1 diabetes an d the degree of clustering suggests that a major gene having a common disease allele may be responsible. To investigate the chromosomal regi ons containing genes for the renin-angiotensin system, we performed a linkage study using pairs of siblings with type 1 diabetes who were di scordant for DN. Theoretical considerations supported by simulation st udies indicated that such discordant pairs, rather than the usual conc ordant pairs, mould be more effective in detecting a major susceptibil ity gene for DN. me applied this novel strategy to test for linkage be tween DN and chromosomal regions containing genes for the ACE, angiote nsinogen (AGT), and angiotensin II type 1 receptor (AT1). Two polymorp hic markers mere genotyped in the vicinity of each of the three loci i n 66 discordant sib pairs and were analyzed with multipoint methods. T he regions containing ACE and AGT loci were not linked with DN, while the region containing the AT1 locus showed linkage with DN. As a resul t of these positive findings, eight additional polymorphic markers spa nning a 63-cM region around AT1 locus mere genotyped. Linkage was demo nstrated between DN and a 20-cM region that includes AT1 (P = 7.7 x 10 (-5)), an obvious candidate gene for DN. To investigate whether AT1 co uld account for the observed Linkage, we sequenced all exons, splicing junctions, and the promoter region and examined the identified polymo rphisms/mutations for association with DN using the transmission diseq uilibrium test. Four nem polymorphisms in the gene mere found, but nei ther these nor previously described polymorphisms were associated with DN. Thus, while our study does not implicate AT1 itself in the etiolo gy of DN, it provides very strong evidence that a 20-cM region around AT1 contains a major locus for susceptibility to DN.