Localization of a small genomic region associated with elevated ACE

Defining the relationship between multiple polymorphisms in a small genomic region and an underlying quantitative trait locus (QTL) represents a major challenge in human genetics. Pedigree analyses have shown that angiotensin I-converting enzyme (ACE) levels are influenced by a QTL located within or close to the ACE gene and most likely resides in the 3' region of this loc us. We genotyped seven polymorphisms spanning 13 kb in the 3' end of ACE in 159 Afro-Caribbean subjects to evaluate the linkage disequilibrium between these sites and to narrow the genomic region associated with an elevated A CE level using a cladistic analysis. The linkage disequilibrium measurement D' and a haplotype tree revealed three distinct haplotype segments, presum ably because of recombination, The value of the linkage disequilibrium para meter p(excess) was highest for site 22982, which is located in the middle segment. A series of nested, cladistic analyses confirmed that the ether tw o regions are unlikely to be the ACE-linked QTL and that the variant reside s in the middle region. Analyses of the same polymorphisms in 98 unrelated Europeans in the Monitoring Trends and Determinants in Cardiovascular Disea ses (MONICA) study resulted in fewer haplotypes than were observed among th e Afro-Caribbean subjects, suggesting that populations with greater genetic diversity may be especially informative for fine-scale mapping.