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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.

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.
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.
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=447), enabling the known clades to be inferred. Qualitative analysis of individual single-nucleotide polymorphisms (SNPs), haplotypes, clades, and diploclades demonstrated no significant associations (P<0.05) 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.
1018-4813
320-327
Bell, Christopher G.
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Meyre, David
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Petretto, Enrico
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Levy-Marchal, Claire
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Hercberg, Serge
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Charles, Marie Aline
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Boyle, Cliona
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Weill, Jacques
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Tauber, Maïte
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Mein, Charles A.
c1cc43af-6c34-47a4-a959-5105593bcbde
Aitman, Timothy J.
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Froguel, Philippe
563ee961-98a3-4aed-98a5-d70e8350ef8c
Walley, Andrew J.
354e9819-2ef2-44ac-81dc-8068aa354c74
Bell, Christopher G.
44982df7-0746-4cdb-bed1-0bdfe68f1a64
Meyre, David
023f567d-798c-41f0-a096-2028569a3976
Petretto, Enrico
a8a7d254-ea06-4ab3-ba7e-b653349a29f4
Levy-Marchal, Claire
2f09decb-6c29-4901-bf09-135c5691af34
Hercberg, Serge
9de31452-a0ff-4918-ae84-666b71056a41
Charles, Marie Aline
de6a8f2e-075c-48d6-af11-ca6431616f56
Boyle, Cliona
b99cd2c8-3e00-4700-834a-6948c76b11d5
Weill, Jacques
88b8cfe1-f76d-435f-a7a3-72cdb7d93c01
Tauber, Maïte
d8ed1a1e-c7ff-45c8-a5eb-7d7907b07a96
Mein, Charles A.
c1cc43af-6c34-47a4-a959-5105593bcbde
Aitman, Timothy J.
f43e8bea-6d43-44f0-9d63-601d7bf366d1
Froguel, Philippe
563ee961-98a3-4aed-98a5-d70e8350ef8c
Walley, Andrew J.
354e9819-2ef2-44ac-81dc-8068aa354c74

Bell, Christopher G., Meyre, David, Petretto, Enrico, Levy-Marchal, Claire, Hercberg, Serge, Charles, Marie Aline, Boyle, Cliona, Weill, Jacques, Tauber, Maïte, Mein, Charles A., Aitman, Timothy J., Froguel, Philippe and Walley, Andrew J. (2007) 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. European Journal of Human Genetics, 15 (3), 320-327. (doi:10.1038/sj.ejhg.5201754). (PMID:17164796)

Record type: Article

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=447), enabling the known clades to be inferred. Qualitative analysis of individual single-nucleotide polymorphisms (SNPs), haplotypes, clades, and diploclades demonstrated no significant associations (P<0.05) 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.

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Accepted/In Press date: 26 October 2006
e-pub ahead of print date: 13 December 2006
Published date: March 2007
Organisations: Human Development & Health, Centre for Biological Sciences, MRC Life-Course Epidemiology Unit

Identifiers

Local EPrints ID: 400996
URI: https://eprints.soton.ac.uk/id/eprint/400996
ISSN: 1018-4813
PURE UUID: 1ed214f9-fad2-4e60-936f-faec025a09f8
ORCID for Christopher G. Bell: ORCID iD orcid.org/0000-0003-4601-1242

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Date deposited: 03 Oct 2016 13:42
Last modified: 20 Jul 2019 00:34

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