Low copy number of the salivary amylase gene predisposes to obesity

被引：173

作者：

Falchi, Mario

El-Sayed Moustafa, Julia Sarah ^{[1
]}

Takousis, Petros ^{[1
]}

Pesce, Francesco ^{[1
,2
]}

Bonnefond, Amelie ^{[3
,4
,5
,6
]}

Andersson-Assarsson, Johanna C. ^{[1
,7
,8
]}

Sudmant, Peter H. ^{[9
]}

Dorajoo, Rajkumar ^{[1
,10
]}

Al-Shafai, Mashael Nedham ^{[1
,11
]}

Bottolo, Leonardo ^{[12
]}

Ozdemir, Erdal ^{[1
]}

So, Hon-Cheong ^{[13
]}

Davies, Robert W. ^{[14
]}

Patrice, Alexandre ^{[1
,6
,15
,16
]}

Dent, Robert ^{[17
]}

Mangino, Massimo ^{[18
]}

Hysi, Pirro G. ^{[18
]}

Dechaume, Aurelie ^{[3
,4
,6
]}

Huyvaert, Marlene ^{[3
,4
,6
]}

Skinner, Jane ^{[19
]}

Pigeyre, Marie ^{[4
,6
,15
,16
]}

Caiazzo, Robert ^{[4
,6
,15
,16
]}

Raverdy, Violeta ^{[6
,15
,16
]}

Vaillant, Emmanuel ^{[3
,4
,6
]}

Field, Sarah ^{[20
]}

Balkau, Beverley ^{[21
,22
]}

Marre, Michel ^{[23
,24
]}

Visvikis-Siest, Sophie ^{[25
]}

Weill, Jacques ^{[26
]}

Poulain-Godefroy, Odile ^{[3
,4
,6
]}

Jacobson, Peter ^{[7
,8
]}

Sjostrom, Lars ^{[7
,8
]}

Hammond, Christopher J. ^{[18
]}

Deloukas, Panos ^{[20
,27
,28
]}

Sham, Pak Chung ^{[13
]}

McPherson, Ruth ^{[29
,30
]}

Lee, Jeannette ^{[31
]}

Tai, E. Shyong ^{[31
,32
,33
]}

Sladek, Robert ^{[34
,35
,36
,37
]}

Carlsson, Lena M. S. ^{[7
,8
]}

Walley, Andrew ^{[1
,38
]}

Eichler, Evan E. ^{[9
,39
]}

Pattou, Francois ^{[4
,6
,15
,16
]}

Spector, Timothy D. ^{[18
]}

Froguel, Philippe ^{[1
,3
,4
,6
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Dept Genom Common Dis, London, England

[2] Univ Bari Aldo Moro, Dept Emergency & Organ Transplantat DETO, Renal Dialysis & Transplant Unit, Bari, Italy

[3] Lille Pasteur Inst, CNRS UMR 8199, Lille, France

[4] Univ Lille 2, Lille, France

[5] QBRI, Doha, Qatar

[6] EGID, Lille, France

[7] Univ Gothenburg, Sahlgrenska Acad, Dept Mol & Clin Med, Gothenburg, Sweden

[8] Univ Gothenburg, Sahlgrenska Acad, Ctr Cardiovasc & Metab Res, Gothenburg, Sweden

[9] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[10] Agcy Sci Technol & Res, Genome Inst Singapore, Singapore, Singapore

[11] Qatar Fdn, Div Res, Doha, Qatar

[12] Univ London Imperial Coll Sci Technol & Med, Dept Math, London, England

[13] Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China

[14] Univ Ottawa, Inst Heart, Cardiovasc Res Methods Ctr, Ottawa, ON, Canada

[15] INSERM UMR 859, Lille, France

[16] CHRU Lille, Lille, France

[17] Ottawa Hosp, Bariatr Program, Ottawa, ON, Canada

[18] Kings Coll London, Dept Twin Res & Genet Epidemiol, London, England

[19] Univ E Anglia, Norwich Med Sch, Norwich NR4 7TJ, Norfolk, England

[20] Wellcome Trust Sanger Inst, Hinxton, England

[21] Ctr Rech Epiderniol Sante Populat, INSERM U1018, Epidemiol Diabet Obes & Chron Kidney Dis Life Cou, Villejuif, France

[22] Univ Paris 11, UMRS 1018, Villejuif, France

[23] Bichat Claude Bernard Univ Hosp, AP HP, Dept Endocrinol Diabetol & Nutr, Paris, France

[24] Univ Paris 07, INSERM U695, Paris, France

[25] Univ Lorraine, INSERM UMR Interact Gene Environm Physiopathol Ca, Nancy, France

[26] Lille Teaching Hosp, Paediat Endocrine Unit, Lille, France

[27] Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England

[28] King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah 21413, Saudi Arabia

[29] Univ Ottawa, Inst Heart, Atherogen Lab, Ottawa, ON, Canada

[30] Univ Ottawa, Inst Heart, Div Cardiol, Ottawa, ON, Canada

[31] Natl Univ Singapore, Natl Univ Hosp Syst, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore

[32] Natl Univ Singapore, Natl Univ Hosp Syst, Yong Loo Lin Sch Med, Dept Med, Singapore 117548, Singapore

[33] Duke Natl Univ Singapore, Grad Sch Med, Singapore, Singapore

[34] McGill Univ, Fac Med, Dept Human Genet, Montreal, PQ, Canada

[35] McGill Univ, Fac Med, Dept Med, Montreal, PQ, Canada

[36] McGill Univ, Montreal, PQ, Canada

[37] Genome Quebec Innovat Ctr, Montreal, PQ, Canada

[38] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Sect Genom Med, London, England

[39] Howard Hughes Med Inst, Seattle, WA USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 05期

基金：

英国生物技术与生命科学研究理事会; 加拿大健康研究院; 美国国家卫生研究院; 瑞典研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; EARLY-ONSET; SEGMENTAL DUPLICATIONS; HERITABILITY; POLYMORPHISM; MICROBIOTA; DELETIONS; VARIANTS; ACCURACY;

D O I：

10.1038/ng.2939

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Common multi-allelic copy number variants (CNVs) appear enriched for phenotypic associations compared to their biallelic counterparts(1-4). Here we investigated the influence of gene dosage effects on adiposity through a CNV association study of gene expression levels in adipose tissue. We identified significant association of a multi-allelic CNV encompassing the salivary amylase gene (AMY1) with body mass index (BMI) and obesity, and we replicated this finding in 6,200 subjects. Increased AMY1 copy number was positively associated with both amylase gene expression (P = 2.31 x 10(-14)) and serum enzyme levels (P < 2.20 x 10(-16)), whereas reduced AMY1 copy number was associated with increased BMI (change in BMI per estimated copy = -0.15 (0.02) kg/m(2); P = 6.93 x 10(-10)) and obesity risk (odds ratio (OR) per estimated copy = 1.19,95% confidence interval (Cl) = 1.13-1.26; P = 1.46 x 10(-10)). The OR value of 1.19 per copy of AMY1 translates into about an eightfold difference in risk of obesity between subjects in the top (copy number >9) and bottom (copy number < 4) 10% of the copy number distribution. Our study provides a first genetic link between carbohydrate metabolism and BMI and demonstrates the power of integrated genomic approaches beyond genome-wide association studies.

引用

页码：492 / 497

页数：6

共 44 条

[1] Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans [J].

Aitman, TJ ;

Dong, R ;

Vyse, TJ ;

Norsworthy, PJ ;

Johnson, MD ;

Smith, J ;

Mangion, J ;

Roberton-Lowe, C ;

Marshall, AJ ;

Petretto, E ;

Hodges, MD ;

Bhangal, G ;

Patel, SG ;

Sheehan-Rooney, K ;

Duda, M ;

Cook, PR ;

Evans, DJ ;

Domin, J ;

Flint, J ;

Boyle, JJ ;

Pusey, CD ;

Cook, HT .

NATURE, 2006, 439 (7078) :851-855

[2] Measurement methods and accuracy in copy number variation: failure to replicate associations of beta-defensin copy number with Crohn's disease [J].

Aldhous, Marian C. ;

Abu Bakar, Suhaili ;

Prescott, Natalie J. ;

Palla, Raquel ;

Soo, Kimberley ;

Mansfield, John C. ;

Mathew, Christopher G. ;

Satsangi, Jack ;

Armour, John A. L. .

HUMAN MOLECULAR GENETICS, 2010, 19 (24) :4930-4938

[3]

Balkau B, 1997, DIABETES METAB, V23, P428

[4] A robust statistical method for case-control association testing with copy number variation [J].

Barnes, Chris ;

Plagnol, Vincent ;

Fitzgerald, Tomas ;

Redon, Richard ;

Marchini, Jonathan ;

Clayton, David ;

Hurles, Matthew E. .

NATURE GENETICS, 2008, 40 (10) :1245-1252

[5] Nutritional methods in the European prospective investigation of cancer in Norfolk [J].

Bingham, SA ;

Welch, AA ;

McTaggart, A ;

Mulligan, AA ;

Runswick, SA ;

Luben, R ;

Oakes, S ;

Khaw, KT ;

Wareham, N ;

Day, NE .

PUBLIC HEALTH NUTRITION, 2001, 4 (03) :847-858

[6] Large, rare chromosomal deletions associated with severe early-onset obesity [J].

Bochukova, Elena G. ;

Huang, Ni ;

Keogh, Julia ;

Henning, Elana ;

Purmann, Carolin ;

Blaszczyk, Kasia ;

Saeed, Sadia ;

Hamilton-Shield, Julian ;

Clayton-Smith, Jill ;

O'Rahilly, Stephen ;

Hurles, Matthew E. ;

Farooqi, I. Sadaf .

NATURE, 2010, 463 (7281) :666-670

[7] Accuracy and differential bias in copy number measurement of CCL3L1 in association studies with three auto-immune disorders [J].

Carpenter, Danielle ;

Walker, Susan ;

Prescott, Natalie ;

Schalkwijk, Joost ;

Armour, John A. L. .

BMC GENOMICS, 2011, 12

[8] Salivary alpha-amylase as a measure of endogenous adrenergic activity [J].

Chatterton, RT ;

Vogelsong, KM ;

Lu, YC ;

Ellman, AB ;

Hudgens, GA .

CLINICAL PHYSIOLOGY, 1996, 16 (04) :433-448

[9] famCNV: copy number variant association for quantitative traits in families [J].

Eleftherohorinou, Hariklia ;

Andersson-Assarsson, Johanna C. ;

Walters, Robin G. ;

Moustafa, Julia S. El-Sayed ;

Coin, Lachlan ;

Jacobson, Peter ;

Carlsson, Lena M. S. ;

Blakemore, Alexandra I. F. ;

Froguel, Philippe ;

Walley, Andrew J. ;

Falchi, Mario .

BIOINFORMATICS, 2011, 27 (13) :1873-1875

[10] A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon [J].

Fellermann, Klaus ;

Stange, Daniel E. ;

Schaeffeler, Elke ;

Schmalzl, Hartmut ;

Wehkamp, Jan ;

Bevins, Charles L. ;

Reinisch, Walter ;

Teml, Alexander ;

Schwab, Matthias ;

Lichter, Peter ;

Radlwimmer, Bernhard ;

Stange, Eduard F. .

AMERICAN JOURNAL OF HUMAN GENETICS, 2006, 79 (03) :439-448

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