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The A-allele of the common FTO gene variant rs9939609 complicates weight maintenance in severe obese patients



The A-allele of the fat mass and obesity-associated (FTO) gene variant rs9939609 has been associated with increased body weight, whereas no effect on weight loss during weight reduction programs has been observed. We questioned whether the AA-genotype interferes with weight stabilization after weight loss.


We conducted a monocentric, longitudinal study involving obese individuals. The FTO gene variant rs9939609 was genotyped in participants attending a weight reduction program that was divided into two phases: a weight reduction period with formula diet (12 weeks) and a weight maintenance phase (40 weeks). Body weight, body mass index (BMI), blood pressure and concentrations of blood glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides were determined in week 0 (T0), after 12 weeks (T1) and at the end in week 52 (T2).


A total of 193 obese subjects aged between 18 and 72 years (129 female, 64 male; initial body weight: 122.4±22.3 kg, initial BMI: 41.8±6.7 kg m−2) were included.


Genotyping revealed 32.1% TT-, 39.4% AT- and 28.5% AA-genotype carriers. At T0, carriers of the AA-genotype had significantly higher body weight (P=0.04) and BMI (P=0.005) than carriers of the TT-genotype. Of the 193 participants, 68 discontinued and 125 completed the program. Dropout rate was not influenced by genotype (P=0.33). Completers with AA-genotype showed significantly lower additional weight loss during the weight maintenance phase than TT-genotype carriers (P=0.02). Furthermore, among participants facing weight regain during weight maintenance (n=52), more subjects were carrying the AA-genotype (P=0.006). No influence of genotype on weight reduction under formula diet was observed (P=0.32).


In this program, the AA-genotype of rs9939609 was associated with a higher initial body weight and did influence success of weight stabilization. Thus, emphasizing the maintenance phase during a weight reduction program might result in better success for AA-genotype carriers.


Lifestyle intervention programs can result in considerable weight loss; however, the probability of regaining weight is quite high.1 Thus, weight maintenance has a crucial role for obese people.

Genetic predisposition is one important factor in the pathogenesis of obesity.2 It is estimated that 40–70% of the body mass index (BMI) variance can be explained by direct or indirect genetic factors.3 Recent studies have identified several genes that affect obesity-related traits.4, 5, 6 One of those is the fat mass and obesity-associated (FTO) gene. The FTO gene was first cloned after identification of a fused toe mutant mouse whose phenotype results from a 1.6-Mbp deletion of six genes, including FTO.7 The homozygous fused toe mouse is embryonically lethal, whereas heterozygous mice are characterized by fused toes.8 FTO is a very large gene. In humans it is located on chromosome 16 and consists of nine exons.9 Up to now, the function of the FTO gene remains largely unknown. However, functional studies indicate that FTO is widely expressed in many tissues with the highest expression in the hypothalamus.10 Owing to this expression pattern, it was suggested that FTO might have an important role in appetite regulation and body weight control. Especially the common FTO variant rs9939609 has consistently been associated with increased body weight. This single-nucleotide polymorphism (SNP) is located in the first intron of the FTO gene at a position of 52.38 Mbp, where sequence is strongly conserved across species.11 Several studies demonstrated that A-allele carriers of rs9939609 have a higher body weight than carriers homozygous for the wild-type T-allele.6, 11, 12, 13, 14, 15 Recently it was shown that carriers homozygous for the A-allele of rs9939609 have a higher expression of FTO than carriers of the TT-genotype, indicating that obesity results from an increased expression of the FTO gene.16, 17 Further studies revealed that the FTO risk variant is associated with increased energy18, 19 and fat intake19, 20 and reduced satiety response,21 affirming the assumption that an increased expression of the FTO gene in areas of the brain that are involved in energy homeostasis might be the mechanism of how the FTO risk variant exerts its effect on obesity. Anyway, although much research on the biological function of FTO has been done, its definite function is still unknown.

Recent data indicate that the A-allele exerts no influence on weight loss,15, 22, 23 but it remains still unclear whether it affects weight maintenance, consequently resulting in the observed higher body weight.6, 11, 12, 13, 14, 15 Therefore, the purpose of our study was to analyze whether homozygous A-allele carriers have difficulties to keep their weight during the maintenance phase of a weight reduction program.

Materials and methods

The weight reduction program OPTIFAST52

The present study was a monocentric cross-sectional and longitudinal pilot analysis of data from obese individuals who underwent the defined multidisciplinary non-surgical weight loss program OPTIFAST 52 (franchise holder Nestlé Inc., Vevey, Switzerland).24 The German OPTIFAST 52-program was established in 1999. It is designed to treat obese people of at least 18 years of age and with a BMI of 30 kg m−2. OPTIFAST 52 includes an out-patient-based, comprehensive, interdisciplinary approach combining the expertise of physicians, dietitians/nutritionists, physical therapists and psychologists. The program consists of a four-phase lifestyle modification program designed for 52 weeks based on four modules (psychology, medicine, dietetics and exercise).24 During the program, closed groups of 10–15 people meet weekly for about three and a half hours per session. The four program phases include (i) a 1-week-introduction time; (ii) a 12-week period of low-calorie diet (800 kcal per day) during which participants consume formula diet exclusively (daily consumption of five packets at 160 kcal each of meal replacement products dissolved in 250–300 ml water each; OPTIFAST 800 formula, Nestlé Inc.), accompanied by 12 medical examinations, 12 exercise units, 2 behavior therapy lessons and 2 nutrition counselings; (iii) a 6-week refeeding phase, during which solid food is reintroduced and formula diet is stepwise replaced by normal diet with only a small change of total energy intake, accompanied by six medical examinations, six exercise units, two behavior therapy lessons and six nutrition counselings; (iv) a 33-week stabilization phase in which energy intake is stepwise enhanced to an individual level that allows weight stabilization, and in which nutritional education and behavior modification is intensified to learn coping strategies and to achieve long-term weight control, accompanied by nine medical examinations, 17 exercise units, 26 behavior therapy lessons and eight nutrition counselings.24

For the purpose of our analysis, it was reasonable to divide the program into two phases: a weight reduction phase of 12 weeks and a weight maintenance phase of 40 weeks. In this study, data from the start (T0), from week 12 after the formula-based weight reduction phase (T1) and from week 52 after the weight maintenance period of 40 weeks (T2) is included.

Study population

A population of 193 obese adults taking part in the OPTIFAST 52-program at the university hospital of Heidelberg between 2005 and 2009 was analyzed. The study sample consisted of 129 Caucasian females and 64 Caucasian males aged between 18 and 72 years. At the start of the program, the study population had a mean body weight of 122.4±22.3 kg and a mean BMI of 41.8±6.7 kg m−2. Of the 193 subjects, 68 discontinued and 125 completed the weight reduction program. The study was approved by the ethics committee at the University of Heidelberg, and all participants gave written informed consent.

Anthropometrical and laboratory measurements

Weight and blood pressure were monitored regularly during the 52-week program (at the medical examinations indicated above).24 BMI was computed as weight (calculated in kg) divided by the square of the height (calculated in meters). Waist circumference was only measured at the start of the program. Additionally, blood samples were collected after a fasting time of at least 8 h at six points during the program to control laboratory parameters. Laboratory values were determined in the central laboratory of the university hospital of Heidelberg. In this study, concentrations of blood glucose, total cholesterol, low-density lipoprotein, high-density lipoprotein and triglycerides from the start (T0), from week 12 after the formula-based weight reduction phase (T1) and from week 52 after the weight maintenance period of 40 weeks (T2) were included.


Genomic DNA was extracted from 250 μl EDTA anticoagulated whole blood using peqGOLD Blood DNA Mini Kit (PEQLAB Biotechnologie GmbH, Erlangen, Germany) according to the manufacturer's instructions. The intronic FTO SNP rs9939609 was genotyped by real-time PCR using the LightCycler 2.0 Real-Time PCR System by Roche (Mannheim, Germany). Forward primer (5′-IndexTermGTCATTTTTGACAGCATGGATTCAAT-3′), reverse primer (5′-IndexTermCCACTCCATTTCTGAC TGTTACC-3′) and two sequence-specific oligonucleotide probes—one labeled with a donor dye at the 3′-end (5′-IndexTermCCAAGTGCATCACAAAATTCAC-3′), the other having an acceptor dye (Red 640, Roche) on its 5′-end (5′-IndexTermGCAGTCGCAAGGAACCTAGAATAATAATTC-3′)—were designed by TIB MOLBIOL GmbH (Berlin, Germany). DNA was added to a master mix solution containing the following: distilled water; 10 × buffer, magnesium chloride, deoxynucleotide triphosphates, bovine serum albumin (Fermentas GmbH, St. Leon-Rot, Germany); primers, probes (TIB MOLBIOL); Taq-polymerase (Fermentas). One negative control and one positive control were carried along with every run in the LightCycler. Data was analyzed by means of melting curves with LightCycler 2.0 Software by Roche.

Statistical analysis

The χ2-test was used to determine whether the allele frequencies of the FTO variant rs9939609 were in Hardy-Weinberg equilibrium. Comparisons between genotype groups were tested by Wilcoxon-Mann-Whitney-test (U-test); statistical significance of differences of the distribution of allelic frequencies was determined by the χ2-test. A probability of P<0.05 was considered to indicate statistical significance. All different genotypes were compared with each other. To analyze the influence of the different genotypes of the FTO variant rs9939609 on weight loss, weight maintenance and weight regain during the program, a per-protocol analysis was chosen including only subjects who completed the whole program. Weight regain was defined as any weight gain between week 12 (T1) and week 52 (T2). All data analyses were carried out with the statistical analysis software package SAS version 9.2 (Cary, NC, USA). Variables are expressed as percentages or means±s.d.


Mean subject characteristics of our population divided by genotype are presented in Table 1.

Table 1 Baseline characteristics of the study population (n=193) according to the genotypes of the FTO rs9939609 variant

Genotyping revealed 32.1% individuals carrying the TT-, 39.4% the AT- and 28.5% the AA-genotype. The minor allele frequency of the A-allele was 0.48. No significant deviation of allele frequencies from Hardy-Weinberg equilibrium was observed in this study (P=0.06). At baseline, the A-allele was associated with an increased body weight, BMI and waist circumference (Table 1). Compared to subjects with TT-genotype, homozygous carriers of the A-allele had a significantly higher body weight (AA: 125.7±20.1 kg, TT: 117.1±20.3 kg; P=0.04) and BMI (AA: 42.8±6.1 kg m−2, TT: 39.9±6.1 kg m−2; P=0.005). Considering diabetes and coronary heart disease as comorbidities of obesity, no significant difference of these comorbidities between genotypes was detected (Table 1).

Regarding the adherence to the program, 125 (64.8%) of the 193 subjects completed the program, whereas 68 (35.2%) discontinued. However, no association between the rs9939609 genotypes and dropout rate was found in this study (AA vs TT: P=0.33) (Table 2).

Table 2 Number and percentage of completers and dropouts of each genotype of the FTO rs9939609 variant

By analyzing the weight reduction phase of the program with a predefined formula diet (T0T1), no significant differences in weight loss (AA vs TT: P=0.32) and BMI reduction (AA vs TT: P=0.19) were observed. In addition, no influence of the different genotypes of the rs9939609 variant on changes of arterial hypertension, lipid and glucose metabolism was observed during the program (data not shown).

Next, the influence of the SNP rs9939609 on weight maintenance was evaluated (Table 3). In accordance with a per-protocol analysis, only the completers of the program were included in further calculation. During the maintenance period (T1-T2), AA-genotype carriers displayed a significantly lower additional body weight loss than carriers of the TT-genotype (P=0.02). The same effect was observed for BMI reduction (P=0.02). When patients with weight regain during weight maintenance were analyzed, only 24.3% (n=9) were homozygous for the T-allele, whereas 44.2% (n=23) were carriers of the AT-genotype (P=0.05) and 55.6% (n=20) of the AA-genotype (P=0.006) (Figure 1).

Table 3 Effect of the FTO rs9939609 gene variants on weight loss and BMI reduction in completers during the weight reduction program
Figure 1

Percentage of completers who regained weight after the weight reduction phase (T1) according to the genotypes of the FTO rs9939609 variant. Weight regain is defined as any weight gain between week 12 (T1) and week 52 (T2). Comparisons between genotype groups were tested by a one-sided Wilcoxon-Mann-Whitney-test (U-test). P1 compares the AT- with the AA-genotype, P2 compares the TT- with the AT-genotype and P3 compares the TT- with the AA-genotype.

Regarding weight loss during the weight reduction phase or weight stabilization during the weight maintenance phase, no differences between men and women were seen (data not shown).


In this intervention study, we confirm AA-genotype carriers have a higher body weight than TT-genotype carriers, which is in line with previous reports.6, 11, 12, 13, 14, 15 Moreover, it was shown that AA-genotype carriers were more likely to regain weight during the weight maintenance period of the presented intervention program. Thus, for the first time we describe a negative effect of the AA-genotype on weight maintenance in obese adults. Our findings are supported by an earlier study where healthy newborns with AA-genotype were not different to newborns with TT-genotype, when birth weight was compared but gained significantly more weight in the first two weeks of postnatal life.25 Further, in accordance to previous reports, our study confirmed that AA-genotype carriers are not disadvantaged in losing their weight.22, 23, 24

The effect on weight regain in this intervention study was allele-dose-dependent with TT-genotype carriers having the lowest risk of weight regain, followed by AT- and finally by AA-genotype carriers, who have the highest risk of weight regain. These differences in weight maintenance might be explained by the following factors: first, it has been shown that AA-genotype carriers have a higher energy and fat intake than TT-genotype carriers;18, 19 second, AA-genotype carriers have a larger decrease in resting energy expenditure when they consume a low-fat diet;23 third, they were shown to have a diminished satiety and more frequent loss of control over eating episodes.19, 20 These factors explain why AA-genotype carriers are predisposed to become obese, and might explain why carriers of the A-allele lose less additional weight and are more likely to regain weight when they consume a diet of their own choice and do not follow a given formula diet anymore. In a future study, questionnaires about the quality and amount of food consumed during the weight maintenance phase might clarify this issue. The observed effect is so strong that 193 participants were sufficient to achieve significant results. Anyway, the small sample size might also be a limitation of this study. The sample size proved to be sufficient to disclose an effect of the SNP rs9939609 on weight maintenance, but only a smaller effect on weight loss. A larger number of patients might be more reflective of the association.

In the present study, the minor allele frequency for A-allele of the FTO gene variant rs9939609 was 0.48. The HapMap (haplotype map of the human genome) population frequency of the A-allele is 0.45 in the CEPH (Centre d’Etude du Polymorphisme Humain) Europeans, and therefore a little lower than the minor allele frequency found in our study.26 The higher percentage of A-allele carriers in this study is reflected by the fact that our cohort included subjects with severe obesity (41.8 kg m−2), whereas other studies included subjects with smaller BMI or normal weight subjects as control groups.10, 15, 18, 21 One limitation of our study is that we only analyzed the genetic variant rs9939609, although there is the possibility that our obese subjects may carry several other genetic variants that have been shown to predispose to obesity. Because the FTO SNP rs9939609 showed a strong association to body weight in previous studies and because there are different studies that investigated the effect of this SNP on weight loss, we decided to choose this SNP for our study and concentrate on its effect on weight maintenance, which has not been examined yet.

In conclusion, it has to be discussed whether practical consequences arise from our observations. A genetic obesity diagnostic prior to participation in weight reduction programs might help to identify subjects having difficulties to maintain their weight. Therefore, genotyping risk genes might provide the opportunity to individualize programs according to participants’ needs by offering personalized exercise regimes and nutritional counseling, or by providing follow-up counseling for patients at a risk for weight regain. However, additional studies in comparable cohorts should confirm our results. Moreover, it would be interesting to examine whether our results can be replicated in cohorts following a surgical approach of weight reduction. Future studies have to show whether weight reduction strategies adapted to the genetic phenotype could promote better long-term success and efficacy.


  1. 1

    Tsai AG, Wadden TA . Systematic review: an evaluation of major commercial weight loss programs in the United States. Ann Intern Med 2005; 142: 56–66.

    Article  Google Scholar 

  2. 2

    Hebebrand J, Sommerlad C, Geller F, Görg T, Hinney A . The genetics of obesity: practical implications. Int J Obes Relat Metab Disord 2001; 25: 10–17.

    Article  Google Scholar 

  3. 3

    Farooqi IS, O’Rahilly S . New advances in the genetics of early onset obesity. Int J Obes 2005; 29: 1149–1152.

    CAS  Article  Google Scholar 

  4. 4

    Loos RJ, Lindgren CM, Li S, Wheeler E, Zhao JH, Prokopenko I et al. Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nature Genet 2008; 40: 768–775.

    CAS  Article  Google Scholar 

  5. 5

    Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T et al. A common genetic variant is associated with adult and childhood obesity. Science 2006; 312: 279–283.

    CAS  Article  Google Scholar 

  6. 6

    Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316: 889–894.

    CAS  Article  Google Scholar 

  7. 7

    Peters T, Ausmeier K, Dildrop R, Rüther U . The mouse Fused toes (Ft) mutation is the result of a 1.6-Mb deletion including the entire Iroquois B gene cluster. Mamm Genome 2002; 13: 186–188.

    CAS  Article  Google Scholar 

  8. 8

    Peters T, Ausmeier K, Rüther U . Cloning of Fatso (Fto), a novel gene deleted by the Fused toe (Ft) mouse mutation. Mamm Genome 1999; 10: 983–986.

    CAS  Article  Google Scholar 

  9. 9

    Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007; 39: 724–726.

    CAS  Article  Google Scholar 

  10. 10

    Gerken T, Girard CA, Tung YCL, Webby CJ, Saudek V, Hewitson KS et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 2007; 318: 1469–1472.

    CAS  Article  Google Scholar 

  11. 11

    Mei H, Chen W, Srinivasan SR, Jiang F, Schork N, Murray S et al. FTO influences on longitudinal BMI over childhood and adulthood and modulation on relationship between birth weight and longitudinal BMI. Hum Genet 2010; 128: 589–596.

    Article  Google Scholar 

  12. 12

    Pausova Z, Syme C, Abrahamowicz M, Xiao Y, Leonard GT, Perron M et al. A common variant of the FTO gene is associated with not only increased adiposity but also elevated blood pressure in French Canadians. Circ Cardiovasc Genet 2009; 2: 260–269.

    CAS  Article  Google Scholar 

  13. 13

    Scuteri A, Sanna S, Chen WM, Uda M, Albai G, Strait J et al. Genome-wide association scan shows genetic variants in the FTO gene are associated with obesity-related traits. PLoS Genetics 2007; 3: 1200–1210.

    CAS  Article  Google Scholar 

  14. 14

    Lappalainen T, Kolehmainen M, Schwab US, Tolppanen AM, Stanèáková A, Lindström J et al. Association of the FTO gene variant (rs9939609) with cardiovascular disease in men with abnormal glucose metabolism – the Finnish Diabetes Prevention Study. Nutr Metab Cardiovasc Dis 2011; 21: 691–698.

    CAS  Article  Google Scholar 

  15. 15

    Lappalainen TJ, Tolppanen AM, Kolehmainen M, Schwab U, Lindström J, Tuomilehto J et al. The common variant in the FTO gene did not modify the effect of lifestyle changes on body weight: the Finnish Diabetes Prevention Study. Obesity 2009; 17: 832–836.

    CAS  Article  Google Scholar 

  16. 16

    Church C, Moir L, McMurray F, Girard C, Banks GT, Teboul L et al. Overexpression of Fto leads to increased food intake and results in obesity. Nat Genet 2010; 42: 1086–1092.

    CAS  Article  Google Scholar 

  17. 17

    Berulava T, Horsthemke B . The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels. Eur J Hum Genet 2010; 18: 1054–1056.

    CAS  Article  Google Scholar 

  18. 18

    Speakman JR, Rance KA, Johnstone AM . Polymorphisms of the FTO gene are associated with variation in energy intake, but not energy expenditure. Obesity 2008; 16: 1961–1965.

    CAS  Article  Google Scholar 

  19. 19

    Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CAN . An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med 2008; 359: 2558–2566.

    CAS  Article  Google Scholar 

  20. 20

    Tanofsky-Kraff M, Han JC, Anandalingam K, Shomaker LB, Columbo KM, Wolkoff LE et al. The FTO gene rs9939609 obesity-risk allele and loss of control over eating. Am J Clin Nutr 2009; 90: 1483–1488.

    CAS  Article  Google Scholar 

  21. 21

    Wardle J, Carnell S, Haworth CMA, Farooqi IS, O’Rahilly S, Plomin R . Obesity associated genetic variation in FTO is associated with diminished satiety. J Clin Endocrinol Metab 2008; 93: 3640–3643.

    CAS  Article  Google Scholar 

  22. 22

    Müller TD, Hinney A, Scherag A, Nguyen TT, Schreiner F, Schäfer H et al. Fat mass and obesity associated′ gene (FTO): no significant association of variant rs9939609 with weight loss in a lifestyle intervention and lipid metabolism markers in German obese children and adolescents. BMC Med Genet 2008; 9: 85.

    Article  Google Scholar 

  23. 23

    Grau K, Hansen T, Holst C, Astrup A, Saris WH, Arner P et al. Macronutrient-specific effect of FTO rs9939609 in response to a 10-week randomized hypo-energetic diet among obese Europeans. Int J Obes 2009; 33: 1227–1234.

    CAS  Article  Google Scholar 

  24. 24

    Bischoff SC, Damms-Machado A, Betz C, Herpertz S, Legenbauer T, Löw T et al. Multicenter evaluation of an interdisciplinary 52-week weight loss program for obesity with regard to body weight, comorbidities and quality of life – a prospective study. Int J Obes 2011. e-pub ahead of print 14 June 2011; doi: 10.1038/ijo.2011.107.

    Article  Google Scholar 

  25. 25

    López-Bermejo A, Petry CJ, Díaz M, Sebastiani G, de Zegher F, Dunger DB et al. The association between the FTO gene and fat mass in humans develops by the postnatal age of two weeks. J Clin Endocrinol Metab 2008; 93: 1501–1505.

    Article  Google Scholar 

  26. 26

    International HapMap Project. Internet:

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This work was supported by a Grant of European Foundation of the Study of Diabetes (EFSD) (GR, CW) and of ERC (AdipoDif CW).

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Correspondence to G Rudofsky.

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Woehning, A., Schultz, JH., Roeder, E. et al. The A-allele of the common FTO gene variant rs9939609 complicates weight maintenance in severe obese patients. Int J Obes 37, 135–139 (2013).

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  • weight maintenance
  • weight regain
  • weight loss
  • FTO gene
  • rs9939609

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