A cladistic model of ACE sequence variation with implications for myocardial infarction, Alzheimer disease and obesity

Abstract

Sequence variation in ACE, which encodes angiotensin I converting enzyme, contributes to a large proportion of variability in plasma ACE levels, but the extent to which this impacts upon human disease is unresolved. Most efforts to associate ACE with other heritable traits have involved a single Alu insertion/deletion polymorphism, despite the probable existence of other functional sequence variants with effects that may not be consistently detectable by solely typing the Alu indel. Here, utilizing single nucleotide polymorphisms (SNPs) that differentiate major ACE clades in European populations, we demonstrate a number of significant phenotype associations across more than 4000 Swedish individuals. In a systematic analysis of metabolic phenotypes, effects were detected upon several traits, including fasting plasma glucose levels, insulin levels and measures of obesity (P-values ranging from 0.046 to 8.4 x 10(-6)). Extending cladistic models to the study of myocardial infarction and Alzheimer disease, significant associations were observed with greater effect sizes than those typically obtained in large-scale meta-analyses based on the Alu indel. Population frequencies of ACE genotypes were also found to change with age, congruent with previous data suggesting effects upon longevity. Clade models consistently outperformed those based upon single markers, reinforcing the importance of taking into consideration the possible confounding effects of allelic heterogeneity in this genomic region. Utilizing computational tools, potential functional variants are highlighted that may underlie phenotypic variability, which is discussed along with the broader implications these results may have for studies attempting to link variation in ACE to human disease.

Amyloid β-Protein Is Degraded by Cellular Angiotensin-converting Enzyme (ACE) and Elevated by an ACE Inhibitor

“…Importantly, post-mortem analyses of AD patients determined that those with the I/I genotype had a trend toward increased brain A␤42 load compared with the D/D genotype (25). Single nucleotide polymorphisms in the ACE gene have also been shown to associate with AD, and there is a decrease in the prevalence of the AD-susceptible genotype with increased age, consistent with a modulation of longevity (26).…”

Cuff-induced vascular intima thickening is influenced by titration of the Ace gene in mice

“…Meta-analysis based on a large number of studies has indicated that the D allele that confers increased ACE levels may not be clinically relevant in the general population but may play a role in specific subgroups of individuals (28). Recently, the use of platforms that enable simultaneous test of multiple single nucleotide polymorphisms (SNPs) per locus has provided additional evidence for positive associations between ACE and metabolic or vascular phenotypes, indicating that under certain conditions or genetic backgrounds the ACE locus may play a role (13). Altogether, these data highlight the difficulties in assessing the contribution of single factors to a complex phenotype.…”

No contribution of angiotensin-converting enzyme (ACE) gene variants to severe obesity: a model for comprehensive case/control and quantitative cladistic analysis of ACE in human diseases

“…We found no differences for SNPs rs4343 or rs1800764 for BMI between any case and control grouping, in contrast to the earlier finding reported in a subset of Swedish male patients. 26 In the diploclade analysis, the only significant P-value result was for the AA diplocladotype in male children, which was not significant if any correction for multiple testing was made. This association in children is also opposite to that reported by the Italian I/D study, which found an age effect in the deletion carrying individuals, as the diploclade AA represents homozygosity for the insertion carrying allele.…”

“…Linkage disequilibrium was calculated using HaploXT from the result for all cases and controls and graphically displayed using the programme GOLD. 38 The common clades were inferred using the method of Katzov et al 26 This involved using the genotypes for rs1800764 and rs4343 to assign the possible cladotypes A, B, and C. These are genotypes (for rs1800764 followed by rs4343) of TA, CG, and TG for the respective clades A, B and C. Processing the data from these two SNPs with PHASE v2.1 was used to infer the clades. 37 Diploclades, that is, the clades assigned to the two chromosomes for each individual, were then assigned based on the determined clades.…”

“…25 Secondly, in a Swedish study utilising SNPs and cladistic analysis, an association was found with obesity phenotypes in a cohort ascertained for various risk factors for myocardial infarction. 26 Although both these studies were enriched for subjects with increased weight owing to their selection criteria, they were not specifically gathered for the obesity phenotype. The average body mass index (BMI) of participants in the Italian study was 26.9 kg/m 2 with a comparison made in 21 and 47% of the individuals who were defined as abdominally obese or overweight, respectively and range of BMI was 18.8-37 kg/m 2 , therefore including no individuals who would qualify as morbidly obese.…”