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
Identifieur interne : 009442 ( Main/Exploration ); précédent : 009441; suivant : 009443No 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
Auteurs : Christopher G. Bell [Royaume-Uni, Australie] ; David Meyre [France] ; Enrico Petretto [Royaume-Uni] ; Claire Levy-Marchal [France] ; Serge Hercberg [France] ; Marie Aline Charles [France] ; Cliona Boyle [Royaume-Uni] ; Jacques Weill [France] ; Maïte Tauber [France] ; Charles A. Mein [Royaume-Uni] ; Timothy J. Aitman [Royaume-Uni] ; Philippe Froguel [Royaume-Uni, France] ; Andrew J. Walley [Royaume-Uni]Source :
- European journal of human genetics [ 1018-4813 ] ; 2007.
Descripteurs français
- Pascal (Inist)
- Wicri :
- topic : Analyse quantitative, Homme, Maladie, Génétique.
English descriptors
- KwdEn :
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.
Affiliations:
- Australie, France, Royaume-Uni
- Angleterre, Grand Londres, Hauts-de-France, Midi-Pyrénées, Nord-Pas-de-Calais, Occitanie (région administrative), Île-de-France
- Lille, Londres, Paris, Toulouse
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Bell</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Genomic Medicine, Hammersmith Hospital, Imperial College London</s1><s2>London</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Haematology and Genetics, Prince of Wales Hospital</s1><s2>Sydney, New South Wales</s2><s3>AUS</s3><sZ>1 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Sydney, New South Wales</wicri:noRegion></affiliation></author><author><name sortKey="Meyre, David" sort="Meyre, David" uniqKey="Meyre D" first="David" last="Meyre">David Meyre</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Centre National de la Recherche Scientifique, UMR 8090-Institute of Biology, Pasteur 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Jacques" sort="Weill, Jacques" uniqKey="Weill J" first="Jacques" last="Weill">Jacques Weill</name><affiliation wicri:level="3"><inist:fA14 i1="07"><s1>Pediatric Endocrine Unit, Jeanne de Flandre Hospital</s1><s2>Lille</s2><s3>FRA</s3><sZ>8 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Tauber, Maite" sort="Tauber, Maite" uniqKey="Tauber M" first="Maïte" last="Tauber">Maïte Tauber</name><affiliation wicri:level="3"><inist:fA14 i1="08"><s1>INSERM U563, Children's Hospital</s1><s2>Toulouse</s2><s3>FRA</s3><sZ>9 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author><author><name 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Mein</name><affiliation wicri:level="3"><inist:fA14 i1="09"><s1>Bart's and the London Genome Centre, Queen Mary's School of Medicine</s1><s2>London</s2><s3>GBR</s3><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Aitman, Timothy J" sort="Aitman, Timothy J" uniqKey="Aitman T" first="Timothy J." last="Aitman">Timothy J. Aitman</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Cardiovascular and Metabolic Disorders, MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College London</s1><s2>London</s2><s3>GBR</s3><sZ>3 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Genomic Medicine, Hammersmith Hospital, Imperial College London</s1><s2>London</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Centre National de la Recherche Scientifique, UMR 8090-Institute of Biology, Pasteur Institute</s1><s2>Lille</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Walley, Andrew J" sort="Walley, Andrew J" uniqKey="Walley A" first="Andrew J." last="Walley">Andrew J. 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Bell</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Genomic Medicine, Hammersmith Hospital, Imperial College London</s1><s2>London</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>Haematology and Genetics, Prince of Wales Hospital</s1><s2>Sydney, New South Wales</s2><s3>AUS</s3><sZ>1 aut.</sZ></inist:fA14><country>Australie</country><wicri:noRegion>Sydney, New South Wales</wicri:noRegion></affiliation></author><author><name sortKey="Meyre, David" sort="Meyre, David" uniqKey="Meyre D" first="David" last="Meyre">David Meyre</name><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Centre National de la Recherche Scientifique, UMR 8090-Institute of Biology, Pasteur Institute</s1><s2>Lille</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Petretto, Enrico" sort="Petretto, Enrico" uniqKey="Petretto E" first="Enrico" last="Petretto">Enrico Petretto</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Cardiovascular and Metabolic Disorders, MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College London</s1><s2>London</s2><s3>GBR</s3><sZ>3 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Levy Marchal, Claire" sort="Levy Marchal, Claire" uniqKey="Levy Marchal C" first="Claire" last="Levy-Marchal">Claire Levy-Marchal</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>INSERM U457, Robert Debre Hospital</s1><s2>Paris</s2><s3>FRA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Hercberg, Serge" sort="Hercberg, Serge" uniqKey="Hercberg S" first="Serge" last="Hercberg">Serge Hercberg</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>INSERM U457, Robert Debre Hospital</s1><s2>Paris</s2><s3>FRA</s3><sZ>4 aut.</sZ><sZ>5 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Charles, Marie Aline" sort="Charles, Marie Aline" uniqKey="Charles M" first="Marie Aline" last="Charles">Marie Aline Charles</name><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>INSERM U258-IFR69</s1><s2>Villejuif</s2><s3>FRA</s3><sZ>6 aut.</sZ></inist:fA14><country>France</country><wicri:noRegion>Villejuif</wicri:noRegion><wicri:noRegion>INSERM U258-IFR69</wicri:noRegion><wicri:noRegion>INSERM U258-IFR69</wicri:noRegion></affiliation></author><author><name sortKey="Boyle, Cliona" sort="Boyle, Cliona" uniqKey="Boyle C" first="Cliona" last="Boyle">Cliona Boyle</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Genomic Medicine, Hammersmith Hospital, Imperial College London</s1><s2>London</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Weill, Jacques" sort="Weill, Jacques" uniqKey="Weill J" first="Jacques" last="Weill">Jacques Weill</name><affiliation wicri:level="3"><inist:fA14 i1="07"><s1>Pediatric Endocrine Unit, Jeanne de Flandre Hospital</s1><s2>Lille</s2><s3>FRA</s3><sZ>8 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Tauber, Maite" sort="Tauber, Maite" uniqKey="Tauber M" first="Maïte" last="Tauber">Maïte Tauber</name><affiliation wicri:level="3"><inist:fA14 i1="08"><s1>INSERM U563, Children's Hospital</s1><s2>Toulouse</s2><s3>FRA</s3><sZ>9 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Occitanie (région administrative)</region><region type="old region">Midi-Pyrénées</region><settlement type="city">Toulouse</settlement></placeName></affiliation></author><author><name sortKey="Mein, Charles A" sort="Mein, Charles A" uniqKey="Mein C" first="Charles A." last="Mein">Charles A. Mein</name><affiliation wicri:level="3"><inist:fA14 i1="09"><s1>Bart's and the London Genome Centre, Queen Mary's School of Medicine</s1><s2>London</s2><s3>GBR</s3><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Aitman, Timothy J" sort="Aitman, Timothy J" uniqKey="Aitman T" first="Timothy J." last="Aitman">Timothy J. Aitman</name><affiliation wicri:level="3"><inist:fA14 i1="04"><s1>Cardiovascular and Metabolic Disorders, MRC Clinical Sciences Centre, Hammersmith Hospital, Imperial College London</s1><s2>London</s2><s3>GBR</s3><sZ>3 aut.</sZ><sZ>11 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Genomic Medicine, Hammersmith Hospital, Imperial College London</s1><s2>London</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Centre National de la Recherche Scientifique, UMR 8090-Institute of Biology, Pasteur Institute</s1><s2>Lille</s2><s3>FRA</s3><sZ>2 aut.</sZ><sZ>12 aut.</sZ></inist:fA14><country>France</country><placeName><region type="region">Hauts-de-France</region><region type="old region">Nord-Pas-de-Calais</region><settlement type="city">Lille</settlement></placeName></affiliation></author><author><name sortKey="Walley, Andrew J" sort="Walley, Andrew J" uniqKey="Walley A" first="Andrew J." last="Walley">Andrew J. Walley</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Genomic Medicine, Hammersmith Hospital, Imperial College London</s1><s2>London</s2><s3>GBR</s3><sZ>1 aut.</sZ><sZ>7 aut.</sZ><sZ>12 aut.</sZ><sZ>13 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author></analytic><series><title level="j" type="main">European journal of human genetics</title><title level="j" type="abbreviated">Eur. j. hum. genet.</title><idno type="ISSN">1018-4813</idno><imprint><date when="2007">2007</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">European journal of human genetics</title><title level="j" type="abbreviated">Eur. j. hum. genet.</title><idno type="ISSN">1018-4813</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Body mass index</term><term>Case study</term><term>Disease</term><term>Gene</term><term>Genetic determinism</term><term>Genetics</term><term>Human</term><term>Models</term><term>Nitric oxide</term><term>Nutritional status</term><term>Obesity</term><term>Peptidyl-dipeptidase A</term><term>Quantitative analysis</term><term>Severe</term><term>Single nucleotide polymorphism</term><term>Variant</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Obésité</term><term>Azote monoxyde</term><term>Peptidyl-dipeptidase A</term><term>Gène</term><term>Variant</term><term>Grave</term><term>Modèle</term><term>Etude cas</term><term>Analyse quantitative</term><term>Homme</term><term>Maladie</term><term>Polymorphisme mononucléotide</term><term>Indice masse corporelle</term><term>Déterminisme génétique</term><term>Génétique</term><term>Etat nutritionnel</term><term>Linkage</term><term>Association génétique</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Analyse quantitative</term><term>Homme</term><term>Maladie</term><term>Génétique</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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 <sup>17</sup>q23, 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.</div></front></TEI><affiliations><list><country><li>Australie</li><li>France</li><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Londres</li><li>Hauts-de-France</li><li>Midi-Pyrénées</li><li>Nord-Pas-de-Calais</li><li>Occitanie (région administrative)</li><li>Île-de-France</li></region><settlement><li>Lille</li><li>Londres</li><li>Paris</li><li>Toulouse</li></settlement></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Bell, Christopher G" sort="Bell, Christopher G" uniqKey="Bell C" first="Christopher G." last="Bell">Christopher G. Bell</name></region><name sortKey="Aitman, Timothy J" sort="Aitman, Timothy J" uniqKey="Aitman T" first="Timothy J." last="Aitman">Timothy J. Aitman</name><name sortKey="Boyle, Cliona" sort="Boyle, Cliona" uniqKey="Boyle C" first="Cliona" last="Boyle">Cliona Boyle</name><name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name><name sortKey="Mein, Charles A" sort="Mein, Charles A" uniqKey="Mein C" first="Charles A." last="Mein">Charles A. Mein</name><name sortKey="Petretto, Enrico" sort="Petretto, Enrico" uniqKey="Petretto E" first="Enrico" last="Petretto">Enrico Petretto</name><name sortKey="Walley, Andrew J" sort="Walley, Andrew J" uniqKey="Walley A" first="Andrew J." last="Walley">Andrew J. Walley</name></country><country name="Australie"><noRegion><name sortKey="Bell, Christopher G" sort="Bell, Christopher G" uniqKey="Bell C" first="Christopher G." last="Bell">Christopher G. Bell</name></noRegion></country><country name="France"><region name="Hauts-de-France"><name sortKey="Meyre, David" sort="Meyre, David" uniqKey="Meyre D" first="David" last="Meyre">David Meyre</name></region><name sortKey="Charles, Marie Aline" sort="Charles, Marie Aline" uniqKey="Charles M" first="Marie Aline" last="Charles">Marie Aline Charles</name><name sortKey="Froguel, Philippe" sort="Froguel, Philippe" uniqKey="Froguel P" first="Philippe" last="Froguel">Philippe Froguel</name><name sortKey="Hercberg, Serge" sort="Hercberg, Serge" uniqKey="Hercberg S" first="Serge" last="Hercberg">Serge Hercberg</name><name sortKey="Levy Marchal, Claire" sort="Levy Marchal, Claire" uniqKey="Levy Marchal C" first="Claire" last="Levy-Marchal">Claire Levy-Marchal</name><name sortKey="Tauber, Maite" sort="Tauber, Maite" uniqKey="Tauber M" first="Maïte" last="Tauber">Maïte Tauber</name><name sortKey="Weill, Jacques" sort="Weill, Jacques" uniqKey="Weill J" first="Jacques" last="Weill">Jacques Weill</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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