Linkage and association analysis of angiotensin I-converting enzyme (ACE)-gene polymorphisms with ACE concentration and blood pressure

Considerable effort has been expended to determine whether the gene for ang iotensin I-converting enzyme (ACE) confers susceptibility to cardiovascular disease. In this study, we genotyped 13 polymorphisms in the ACE gene in 1 ,343 Nigerians from 332 families. To localize the genetic effect, we first performed linkage and association analysis of all the markers with ACE conc entration. In multipoint variance-component analysis, this region was stron gly linked to ACE concentration (maximum LOD score 7.5). Likewise, most of the polymorphisms in the ACE gene were significantly associated with ACE (P < .0013). The two most highly associated polymorphisms, ACE4 and ACE8, acc ounted for 6% and 19% of the variance in ACE, respectively. A two-locus add itive model with an additive x additive interaction of these polymorphisms explained most of the ACE variation associated with this region. We next an alyzed the relationship between these two polymorphisms (ACE4 and ACE8) and blood pressure (BP). Although no evidence of linkage was detected, signifi cant association was found for both systolic and diastolic BP when a two-lo cus additive model developed for ACE concentration was used. Further analys es demonstrated that an epistasis model provided the best fit to the BP var iation. In conclusion, we found that the two polymorphisms explaining the g reatest variation in ACE concentration are significantly associated with BP , through interaction, in this African population sample. Our study also de monstrates that greater statistical power can be anticipated with associati on analysis versus linkage, when markers in strong linkage disequilibrium w ith a trait locus have been identified. Furthermore, allelic interaction ma y play an important role in the dissection of complex traits such as BP.