Dk. Moczulski et al., MAJOR SUSCEPTIBILITY LOCUS FOR NEPHROPATHY IN TYPE-1 DIABETES ON CHROMOSOME 3Q - RESULTS OF NOVEL DISCORDANT SIB-PAIR ANALYSIS, Diabetes, 47(7), 1998, pp. 1164-1169
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.