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Prevalence of Loss-Of-Function FTO Mutations in Lean and Obese

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Prevalence of Loss-Of-Function FTO Mutations in Lean and Obese ORIGINAL ARTICLE Prevalence of Loss-of-Function FTO Mutations in Lean and Obese Individuals David Meyre,1 Karine Proulx,2 Hiroko Kawagoe-Takaki,3 Vincent Vatin,1 Ruth Gutie´rrez-Aguilar,1 Debbie Lyon,3 Marcella Ma,2 Helene Choquet,1 Fritz Horber,4 Wim Van Hul,5 Luc Van Gaal,6 Beverley Balkau,7 Sophie Visvikis-Siest,8 François Pattou,9 I. Sadaf Farooqi,2 Vladimir Saudek,2 Stephen O’Rahilly,2 Philippe Froguel,1,10 Barbara Sedgwick,3 and Giles S.H. Yeo2 OBJECTIVE—Single nucleotide polymorphisms (SNPs) in in- tron 1 of fat mass– and obesity-associated gene (FTO) are strongly associated with human adiposity, whereas FtoϪ/Ϫ mice enome-wide association studies have revealed are lean and Ftoϩ/Ϫ mice are resistant to diet-induced obesity. that single nucleotide polymorphisms (SNPs) We aimed to determine whether FTO mutations are dispropor- within the first intron of fat mass– and obesity- tionately represented in lean or obese humans and to use these associated gene (FTO) are strongly associated mutations to understand structure-function relationships within G with adiposity (1–4). These associations have been largely FTO. consistent across multiple different ethnicities including RESEARCH DESIGN AND METHODS—We sequenced all Europeans (5–8), Asians (9–11), Hispanics (12,13), and coding exons of FTO in 1,433 severely obese and 1,433 lean Africans (13,14). At present, it remains unclear whether individuals. We studied the enzymatic activity of selected non- these SNPs influence the expression or splicing of the FTO synonymous variants. gene and/or whether the unequivocal association with RESULTS—We identified 33 heterozygous nonsynonymous vari- obesity is causally related to alterations in expression or ants in lean (2.3%) and 35 in obese (2.4%) individuals, with 8 function of FTO. If the effect of the intron 1 SNPs is mutations unique to the obese and 11 unique to the lean. Two through FTO, it also remains unclear whether the obesity novel mutations replace absolutely conserved residues: R322Q in risk SNPs result in a loss or a gain of FTO function. It the catalytic domain and R96H in the predicted substrate recog- remains possible that the SNPs influence the expression nition lid. R322Q was unable to catalyze the conversion of and/or function of neighboring genes and that such an 2-oxoglutarate to succinate in the presence or absence of 3-meth- effect might underlie the association with adiposity. There ylthymidine. R96H retained some basal activity, which was not are several examples in metabolic disease where common enhanced by 3-methylthymidine. However, both were found in variants close to a particular gene are associated with lean and obese individuals. alterations in risk of common phenotypes such as fat mass CONCLUSIONS—Heterozygous, loss-of-function mutations in or risk of obesity, whereas rare loss- or gain-of-function FTO exist but are found in both lean and obese subjects. mutations in the same gene are associated with a more Although intron 1 SNPs are unequivocally associated with obe- severe version of the same metabolic phenotype (e.g., sity in multiple populations and murine studies strongly suggest MCR4 [5,15–19], POMC [20,21], BDNF [22–24], and PCSK1 that FTO has a role in energy balance, it appears that loss of one [25,26]). When information is available from both types of functional copy of FTO in humans is compatible with being either lean or obese. Functional analyses of FTO mutations have variants, clarity of mechanistic understanding is greatly given novel insights into structure-function relationships in this enhanced. To establish whether nonsynonymous variants enzyme. Diabetes 59:311–318, 2010 of FTO might be enriched in either lean or obese subjects, we sequenced the FTO coding region and intron-exon boundaries in a large group of subjects with severe obesity and a similarly sized group of individuals with lifelong From the 1CNRS 8090-Institute of Biology, Pasteur Institute, Lille, France; the leanness. We have recently established that FTO encodes 2University of Cambridge Metabolic Research Labs, Institute of Metabolic 2ϩ Science, Addenbrooke’s Hospital, Cambridge, U.K.; the 3Cancer Research a 2-oxoglutarate (2-OG) Fe -dependent dioxygenase (27). U.K. London Research Institute, Clare Hall Laboratories, South Mimms, In this study, we have examined the functional enzymatic Hertfordshire, U.K.; the 4Klinik Lindberg, Winterthur, and University of properties of naturally occurring variants to gain further Berne, Berne, Switzerland; the 5Department of Medical Genetics, University insights into structure-function relationships in the human of Antwerp and Antwerp University Hospital, Antwerp, Belgium; the 6Department of Endocrinology, Diabetology and Metabolism, Antwerp enzyme. University Hospital, Edegem, Belgium; 7INSERM U780, Villejuif, France, and University Paris-Sud, Orsay, France; 8INSERM “Cardiovascular Genet- ics” team, Nancy, France; 9INSERM U859, CHRU Lille, Lille North of France RESEARCH DESIGN AND METHODS 10 University, Lille, France; and the Section of Genomic Medicine, Hammer- FTO was sequenced in 1,433 severely obese subjects. All adults had BMI Ͼ40 smith Hospital, Imperial College London, London, U.K. kg/m2, and all obese children had a BMI Ͼ97th percentile for sex and age Corresponding author: Giles Yeo, [email protected]. Received 11 May 2009 and accepted 24 September 2009. Published ahead of (Table 1). Three hundred forty-five French morbidly obese adults were print at http://diabetes.diabetesjournals.org on 15 October 2009. DOI: recruited by the CNRS UMR8090 at Lille and the Department of Nutrition of 10.2337/db09-0703. Paris Hotel Dieu Hospital. Thirty-three French morbidly obese adults were D.M., K.P., and H.K.-T. contributed equally to this work. patients of the CHRU Lille hospital. We also sequenced 287 Swiss morbidly © 2010 by the American Diabetes Association. Readers may use this article as obese adults, all of them recruited after gastric surgery in Zurich, Switzerland. long as the work is properly cited, the use is educational and not for profit, Eighty-eight morbidly obese adult patients were recruited at the Antwerp and the work is not altered. See http://creativecommons.org/licenses/by University Hospital. Three hundred ninety-nine French obese children were -nc-nd/3.0/ for details. recruited in CNRS UMR8090, and 281 obese children were recruited as part of The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance the Genetics of Obesity Study (GOOS) cohort (28). A total of 1,221 lean adult with 18 U.S.C. Section 1734 solely to indicate this fact. subjects were part of the French DESIR (Data from an Epidemiological Study diabetes.diabetesjournals.org DIABETES, VOL. 59, JANUARY 2010 311 FTO MUTATIONS IN LEAN AND OBESE INDIVIDUALS TABLE 1 Clinical characteristics for obese and lean subjects n (male/female) Age (years) BMI (kg/m²) zBMI Obese (adults: BMI Ͼ40 kg/m²; children: BMI Ͼ97th percentile) French adults 378 (79/299) 43.15 Ϯ 11.52 51.63 Ϯ 9.17 — Swiss adults 287 (79/208) 41.56 Ϯ 11.21 52.32 Ϯ 5.80 — Belgian adults 88 (36/52) 45.45 Ϯ 11.21 54.79 Ϯ 5.20 — French children 399 (188/211) 10.56 Ϯ 3.23 — 5.01 Ϯ 1.04 English children 281 (135/146) 11.5 Ϯ 2.40 — 4.6 Ϯ 1.80 Lean (adults: BMI Ͻ23 kg/m²; children: BMI Ͻ90th percentile) French adults 1,221 (378/843) 43.26 Ϯ 9.37 20.42 Ϯ 1.28 — French children 212 (96/116) 11.77 Ϯ 2.42 — 0.10 Ϯ 0.98 Data are means Ϯ SD unless otherwise indicated. on the Insulin Resistance syndrome) general prospective study (29). Selection buffer (20 mmol/l HEPES, pH 8, 5% glycerol, 50 mmol/l NaCl) was added to the criteria were BMI Ͻ23 kg/m2 at inclusion. We included 212 lean French concentrated fraction, which was concentrated again down to 100 ␮lby children selected from the Stanislas study (30). Inclusion criteria was BMI z centrifugation at 2500g. FTO preparations were aliquoted and then stored at score (zBMI) Ͻ90th percentile for sex and age according to the Eastern Ϫ80°C. FTO proteins were visualized by SDS–10% PAGE and stained with Cooperative Oncology Group (ECOG) (31). All patients were of European Coomassie blue. ancestry. The study protocol was approved by all local ethics committees, and Assays of FTO activity. Conversion of 14C-2-oxoglutarate to 14C-succinate by informed consent was obtained from each subject before participating in the 2-OG Fe2ϩ-dependent DNA dioxygenases has been assayed previously (33). study. This method was modified and optimized to assay FTO as previously Genotyping of the FTO rs9939609 SNP. Genotyping of the FTO rs9939609 described (32). To measure the uncoupled reaction (no prime substrate SNP was performed using a Taqman SNP Genotyping Assay (Applied Biosys- present), 1.5 ␮mol/l FTO was assayed in 10 ␮l reaction mixture containing tems) on an ABI 7900HT Fast Real-Time PCR System (Applied Biosystems) 50 mmol/l HEPES-KOH, pH 7, 50 ␮g/ml BSA, 4 mmol/l ascorbate, 75 ␮mol/l ␮ 14 according to the manufacturer’s instructions. Fe(NH4)2(SO4)2, and 20 mol/l [5- C]-2-oxoglutarate (30 mCi/mmol from Sequencing. We screened the nine exons of the FTO by direct nucleotide Moravek Biochemicals) and incubated at 37°C for various times. To sequencing. We amplified overlapping PCR fragments according to primers measure stimulation of this activity by 3-methylthymidine, 1 mmol/l and PCR-optimized conditions (available from the authors upon request). PCR 3-methylthymidine (Moravek Biochemicals) was included in the assay mix. amplifications were inspected for single bands of expected sizes on agarose The reaction was stopped by adding 5 ␮l stop solution containing 20 gels before purification with Agencourt AMPure on Biomek NX (Beckman mmol/l succinate, 20 mmol/l 2-OG, followed by 5 ␮l 160 mmol/l dinitro- Coulter).
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