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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2010

Open Access 01-12-2010 | Research article

Mutation screen and association studies for the fatty acid amide hydrolase (FAAH) gene and early onset and adult obesity

Authors: Timo D Müller, Günter Brönner, Melanie Wandolski, Jophia Carrie, Trang T Nguyen, Brandon H Greene, André Scherag, Harald Grallert, Carla IG Vogel, Susann Scherag, Winfried Rief, Hans-Erich Wichmann, Thomas Illig, Helmut Schäfer, Johannes Hebebrand, Anke Hinney

Published in: BMC Medical Genetics | Issue 1/2010

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Abstract

Background

The orexigenic effects of cannabinoids are limited by activation of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH). The aim of this study was to analyse whether FAAH alleles are associated with early and late onset obesity.

Methods

We initially assessed association of five single nucleotide polymorphisms (SNPs) in FAAH with early onset extreme obesity in up to 521 German obese children and both parents. SNPs with nominal p-values ≤ 0.1 were subsequently analysed in 235 independent German obesity families. SNPs associated with childhood obesity (p-values ≤ 0.05) were further analysed in 8,491 adult individuals of a population-based cohort (KORA) for association with adult obesity. One SNP was further analysed in 985 German obese adults and 588 normal and underweight controls. In parallel, we screened the FAAH coding region for novel sequence variants in 92 extremely obese children using single-stranded-conformation-polymorphism-analysis and denaturing HPLC and assessed the implication of the identified new variants for childhood obesity.

Results

The trio analysis revealed some evidence for an association of three SNPs in FAAH (rs324420 rs324419 and rs873978) with childhood obesity (two-sided p-values between 0.06 and 0.10). Although analyses of these variants in 235 independent obesity families did not result in statistically significant effects (two-sided p-values between 0.14 and 0.75), the combined analysis of all 603 obesity families supported the idea of an association of two SNPs in FAAH (rs324420 and rs2295632) with early onset extreme obesity (p-values between 0.02 and 0.03). No association was, however, found between these variants and adult obesity. The mutation screen revealed four novel variants, which were not associated with early onset obesity (p > 0.05).

Conclusions

As we observed some evidence for an association of the FAAH variants rs2295632 rs324420 with early onset but not adult obesity, we conclude that the FAAH variants analyzed here at least do not seem to play a major role in the etiology of obesity within our samples.
Literature
1.
Di Marzo V, Bifulco M, De Petrocellis L: The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004, 3: 771-784. 10.1038/nrd1495.CrossRefPubMed
2.
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R: Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992, 258: 1946-1949. 10.1126/science.1470919.CrossRefPubMed
3.
Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, Yamashita A, Waku K: 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995, 215: 89-97. 10.1006/bbrc.1995.2437.CrossRefPubMed
4.
Williams CM, Kirkham TC: Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psychopharmacology (Berl). 1999, 143: 315-317. 10.1007/s002130050953.CrossRef
5.
Williams CM, Kirkham TC: Observational analysis of feeding induced by Delta9-THC and anandamide. Physiol Behav. 2002, 76: 241-250. 10.1016/S0031-9384(02)00725-4.CrossRefPubMed
6.
Kirkham TC, Williams CM, Fezza F, Di Marzo V: Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002, 136: 550-557. 10.1038/sj.bjp.0704767.CrossRefPubMedPubMedCentral
7.
Di Marzo V, Goparaju SK, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura GI, Palmiter RD, Sugiura T, Kunos G: Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001, 410: 822-825. 10.1038/35071088.CrossRefPubMed
8.
Di Marzo V, De Petrocellis L, Bisogno T, Melck D: Metabolism of anandamide and 2-arachidonoylglycerol: an historical overview and some recent developments. Lipids. 1999, 34 (Suppl): S319-325. 10.1007/BF02562332.CrossRefPubMed
9.
Dinh TP, Carpenter D, Leslie FM, Freund TF, Katona I, Sensi SL, Kathuria S, Piomelli D: Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA. 2002, 99: 10819-10824. 10.1073/pnas.152334899.CrossRefPubMedPubMedCentral
10.
Puffenbarger RA: Molecular biology of the enzymes that degrade endocannabinoids. Curr Drug Targets CNS Neurol Disord. 2005, 4: 625-631. 10.2174/156800705774933050.CrossRefPubMed
11.
Hillard CJ, Wilkison DM, Edgemond WS, Campbell WB: Characterization of the kinetics and distribution of N-arachidonylethanolamine (anandamide) hydrolysis by rat brain. Biochim Biophys Acta. 1995, 257: 249-256.CrossRef
12.
Engeli S, Böhnke J, Feldpausch M, Gorzelniak K, Janke J, Bátkai S, Pacher P, Harvey-White J, Luft FC, Sharma AM, Jordan J: Activation of the peripheral endocannabinoid system in human obesity. Diabetes. 2005, 54: 2838-2843. 10.2337/diabetes.54.10.2838.CrossRefPubMedPubMedCentral
13.
Maccarrone M, Di Rienzo M, Finazzi-Agrò A, Rossi A: Leptin activates the anandamide hydrolase promoter in human T lymphocytes through STAT3. J Biol Chem. 2003, 278: 13318-13324. 10.1074/jbc.M211248200.CrossRefPubMed
14.
Lambert DM, Muccioli GG: Endocannabinoids and related N-acylethanolamines in the control of appetite and energy metabolism: emergence of new molecular players. Curr Opin Clin Nutr Metab Care. 2007, 10: 735-744. 10.1097/MCO.0b013e3282f00061.CrossRefPubMed
15.
Sipe JC, Waalen J, Gerber A, Beutler E: Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obes (Lond). 2005, 29: 755-759. 10.1038/sj.ijo.0802954.CrossRef
16.
Chiang KP, Gerber AL, Sipe JC, Cravatt BF: Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet. 2004, 13: 2113-2119. 10.1093/hmg/ddh216.CrossRefPubMed
17.
Jensen DP, Andreasen CH, Andersen MK, Hansen L, Eiberg H, Borch-Johnsen K, Jørgensen T, Hansen T, Pedersen O: The functional Pro129Thr variant of the FAAH gene is not associated with various fat accumulation phenotypes in a population-based cohort of 5,801 whites. J Mol Med. 2007, 85: 445-449. 10.1007/s00109-006-0139-0.CrossRefPubMed
18.
Papazoglou D, Panagopoulos I, Papanas N, Gioka T, Papadopoulos T, Papathanasiou P, Kaitozis O, Papatheodorou K, Maltezos E: The Fatty Acid Amide Hydrolase (FAAH) Pro129Thr Polymorphism is not Associated with Severe Obesity in Greek Subjects. Horm Metab Res. 2008, 40: 907-910. 10.1055/s-0028-1087169.CrossRefPubMed
19.
Lieb W, Manning AK, Florez JC, Dupuis J, Cupples LA, McAteer JB, Vasan RS, Hoffmann U, O'Donnell CJ, Meigs JB, Fox CS: Variants in the CNR1 and the FAAH Genes and Adiposity Traits in the Community. Obesity (Silver Spring). 2009, 17: 755-760. 10.1038/oby.2008.608.CrossRef
20.
Hinney A, Hinney A, Bettecken T, Tarnow P, Brumm H, Reichwald K, Lichtner P, Scherag A, Nguyen TT, Schlumberger P, Rief W, Vollmert C, Illig T, Wichmann HE, Schäfer H, Platzer M, Biebermann H, Meitinger T, Hebebrand J: Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. Clin Endocrinol Metab. 2006, 91: 1761-1769. 10.1210/jc.2005-2056.CrossRef
21.
Holle R, Happich M, Lowel H, Wichmann HE, MONICA/KORA Study Group: KORA: a research platform for population based health research. Gesundheitswesen. 2005, 67 (Suppl 1): S19-S25. 10.1055/s-2005-858235.CrossRefPubMed
22.
Hinney A, Nguyen TT, Scherag A, Friedel S, Brönner G, Müller TD, Grallert H, Illig T, Wichmann HE, Rief W, Schäfer H, Hebebrand J: Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS ONE. 2007, 2: e1361-10.1371/journal.pone.0001361.CrossRefPubMedPubMedCentral
23.
Hinney A, Hohmann S, Geller F, Vogel C, Hess C, Wermter AK, Brokamp B, Goldschmidt H, Siegfried W, Remschmidt H, Schäfer H, Gudermann T, Hebebrand J: Melanocortin-4 receptor gene: case-control study and transmission disequilibrium test confirm that functionally relevant mutations are compatible with a major gene effect for extreme obesity. J Clin Endocrinol Metab. 2003, 88: 4258-4267. 10.1210/jc.2003-030233.CrossRefPubMed
24.
Spielman RS, McGinnis RE, Ewens WJ: Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet. 1993, 52: 506-516.PubMedPubMedCentral
25.
26.
Martin ER, Monks SA, Warren LL, Kaplan NL: A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet. 2000, 67: 146-154. 10.1086/302957.CrossRefPubMedPubMedCentral
27.
Cordell HJ, Clayton DG: A unified stepwise regression procedure for evaluating the relative effects of polymorphisms within a gene using case/control or family data: application to HLA in type 1 diabetes. Am J Hum Genet. 2002, 70: 124-141. 10.1086/338007.CrossRefPubMed
28.
Sipe JC, Chiang K, Gerber AL, Beutler E, Cravatt BF: A missense mutation in human fatty acid amide hydrolase associated with problem drug use. Proc Natl Acad Sci USA. 2002, 99: 8394-8399. 10.1073/pnas.082235799.CrossRefPubMedPubMedCentral
29.
Lasky-Su J, Lyon HN, Emilsson V, Heid IM, Molony C, Raby BA, Lazarus R, Klanderman B, Soto-Quiros ME, Avila L, Silverman EK, Thorleifsson G, Thorsteinsdottir U, Kronenberg F, Vollmert C, Illig T, Fox CS, Levy D, Laird N, Ding X, McQueen MB, Butler J, Ardlie K, Papoutsakis C, Dedoussis G, O'Donnell CJ, Wichmann HE, Celedón JC, Schadt E, Hirschhorn J, Weiss ST, Stefansson K, Lange C: On the replication of genetic associations: timing can be everything!. Am J Hum Genet. 2008, 82: 849-858. 10.1016/j.ajhg.2008.01.018.CrossRefPubMedPubMedCentral
30.
Heid IM, Huth C, Loos RJ, Kronenberg F, Adamkova V, Anand SS, Ardlie K, Biebermann H, Bjerregaard P, Boeing H, Bouchard C, Ciullo M, Cooper JA, Corella D, Dina C, Engert JC, Fisher E, Francès F, Froguel P, Hebebrand J, Hegele RA, Hinney A, Hoehe MR, Hu FB, Hubacek JA, Humphries SE, Hunt SC, Illig T, Järvelin MR, Kaakinen M, Kollerits B, Krude H, Kumar J, Lange LA, Langer B, Li S, Luchner A, Lyon HN, Meyre D, Mohlke KL, Mooser V, Nebel A, Nguyen TT, Paulweber B, Perusse L, Qi L, Rankinen T, Rosskopf D, Schreiber S, Sengupta S, Sorice R, Suk A, Thorleifsson G, Thorsteinsdottir U, Völzke H, Vimaleswaran KS, Wareham NJ, Waterworth D, Yusuf S, Lindgren C, McCarthy MI, Lange C, Hirschhorn JN, Laird N, Wichmann HE: Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?. PLoS Genet. 2009, 5: e1000694-10.1371/journal.pgen.1000694.CrossRefPubMedPubMedCentral
31.
Walley AJ, Asher JE, Froguel P: The genetic contribution to non-syndromic human obesity. Nat Rev Genet. 2009, 10: 431-442. 10.1038/nrg2594.CrossRefPubMed
32.
33.
Den Dunnen JT, Antonarakis SE: Nomenclature for the description of human sequence variations. Hum Genet. 2001, 109: 121-124. 10.1007/s004390100505.CrossRefPubMed
34.
Knapp M, Becker T: Family-based association analysis with tightly linked markers. Hum Hered. 2003, 56: 2-9. 10.1159/000073727.CrossRefPubMed
Metadata
Title
Mutation screen and association studies for the fatty acid amide hydrolase (FAAH) gene and early onset and adult obesity
Authors
Timo D Müller
Günter Brönner
Melanie Wandolski
Jophia Carrie
Trang T Nguyen
Brandon H Greene
André Scherag
Harald Grallert
Carla IG Vogel
Susann Scherag
Winfried Rief
Hans-Erich Wichmann
Thomas Illig
Helmut Schäfer
Johannes Hebebrand
Anke Hinney
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2010
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-11-2

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