IDENTIFICATION OF NEW POLYMORPHISMS OF THE ANGIOTENSIN-I-CONVERTING ENZYME (ACE) GENE, AND STUDY OF THEIR RELATIONSHIP TO PLASMA ACE LEVELSBY 2-QTL SEGREGATION-LINKAGE ANALYSIS

Plasma angiotensin I-converting enzyme (ACE) levels are highly genetic ally determined. A previous segregation-linkage analysis suggested the existence of a functional mutation located within or close to the ACE locus, in almost complete linkage desequilibrium (LD) with the ACE in sertion/deletion (I/D) polymorphism and accounting for half the ACE va riance. In order to identify the functional variant at the molecular l evel, we compared ACE gene sequences between four subjects selected fo r having contrasted ACE levels and I/D genotypes. We identified 10 new polymorphisms, among which 8 were genotyped in 95 healthy nuclear fam ilies, in addition to the VD polymorphism. These polymorphisms could b e divided into two groups: five polymorphisms in the 5' region and thr ee in the coding sequence and the 3' UTR. Within each group, polymorph isms were in nearly complete association, whereas polymorphisms from t he two groups were in strong negative LD. After adjustment for the I/D polymorphism, all polymorphisms of the 5' group remained significantl y associated with ACE levels, which suggests the existence of two quan titative trait loci (QTL) acting additively on ACE levels. Segregation -linkage analyses including one or two ACE-Linked QTLs in LD with two ACE markers were performed to test this hypothesis. The two QTLs and t he two markers were assumed to be in complete LD. Results supported th e existence of two ACE-linked QTLs, which would explain 38% and 49% of the ACE variance in parents and offspring, respectively. One of these QTLs might be the I/D polymorphism itself or the newly characterized 4656(CT)(2/3) polymorphism. The second QTL, would have a frequency of similar to.20, which is incompatible with any of the yet-identified po lymorphisms. More extensive sequencing and extended analyses in larger samples and in other populations will be necessary to characterize de finitely the functional variants.