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

Abstract

Candidate gene analyses are often inconclusive owing to genetic or phenotypic heterogeneity, low statistical power, selection of nonfunctional SNPs, and inadequate statistical analysis of the genetic architecture. Angiotensin-converting enzyme (ACE) is involved in adipocyte growth and function and the ACE-processed angiotensin II inhibits adipocyte differentiation. Associations between body mass index (BMI) and ACE polymorphisms have been reported in general populations, but the contribution to severe obesity of this gene, which is located under an obesity genome-scan linkage peak on 17q23, is unknown. ACE is one of the most studied genes and markers responsible for variation in circulating ACE enzyme levels have been extensively characterised. Eight of these variants were genotyped in 1054 severely obese cases and 918 nonobese controls, as well as 116 nuclear families from the genome scan (n ¼ 447), enabling the known clades to be inferred. Qualitative analysis of individual single-nucleotide polymorphisms (SNPs), haplotypes, clades, and diploclades demonstrated no significant associations (Po0.05) after minimal correction for multiple testing. Quantitative analysis of clades and diploclades for BMI, waist-to-hip ratio, or ZBMI in children were also not significant. This rigorous, large-scale study of common, well-defined, severe polygenic obesity provides strong evidence that functionally relevant sequence variation in ACE, whether it is defined at the level of SNPs, haplotypes, or clades, is not associated with severe obesity in French Caucasians. Such a study design exemplifies the strategy needed to clearly define the contribution of the ACE gene to the plethora of complex genetic diseases where weak associations have been previously reported.

Methylene Tetrahydrofolate Reductase and Angiotensin Converting Enzyme Gene Polymorphisms Related to Overweight/Obesity among Saudi Subjects from Qassim Region

“…Likewise, in a rigorous, large-scale Frensh study, authors stated that functionally relevant sequence variation in ACE, whether it is defined at the level of SNPs, haplotypes, or clades, is not associated with obesity [12].…”

“…This enzyme is involved in adipocyte growth and function and the ACE-processed angiotensin II inhibits adipocyte differentiation. Although associations between BMI and ACE polymorphisms have been reported in general populations, the contribution of this gene to severe obesity is generally unknown [12,13].…”

A meta-analysis of the association between angiotensin-converting enzyme insertion/ deletion gene polymorphism and the risk of overweight/obesity

“…Therefore, we included 12 studies 8,[10][11][12][13][14][15][17][18][19][20][21] in the sensitivity analysis.…”

“…However, a number of investigations regarding the association between ACE I/D gene polymorphism and overweight/ obesity risk have generated mixed results in human studies. 5,8,[10][11][12][13][14][15][16][17][18][19][20][21] The contribution of ACE I/D gene polymorphism to the onset of overweight/ obesity is still unclear. Metaanalysis of the association between ACE I/D gene polymorphism and overweight/obesity risk is rare.…”

Power in the phenotypic extremes: a simulation study of power in discovery and replication of rare variants

“…This paper addresses three features related to the design of studies using DNA sequencing to study rare variants: the samples used for variant discovery, selection of specific genes and variants for follow-up, and replication of putative genotype-phenotype relationships in independent samples. We focus on one widely discussed design feature: the ascertainment of samples from the extremes of a population distribution [Ahituv et al, 2007;Bell et al, 2007;Cohen et al, 2004;DeAngelis et al, 2004;Kryukov et al, 2009;Mohammadi et al, 2009;Nebert 2000;PerezGracia et al, 2002;Zhang, 1995, 1996;Romeo et al, 2007] (previously referred to as ''selective genotyping'') [Lander and Botstein, 1989;Van Gestel et al, 2000]. Intuitively, ascertainment of samples from the extremes of phenotype should enrich for the burden of alleles influencing a trait, thus improving power to discover risk variants and to detect their association to phenotype.…”