Surg Endosc DOI 10.1007/s00464-015-4169-y

and Other Interventional Techniques

The effect of rs9939609 FTO gene polymorphism on weight loss after laparoscopic sleeve gastrectomy ¨ zgu¨r Balasar1 • Tug˘rul C ¨ zgu¨r Erkal3 • Arif Aslaner2 • Bu¨lent C O ¸ akır2 • O ¸ ekic¸4 5 • 2 • 2 Mehmet Uyar Nurullah Bu¨lbu¨ller Mehmet Tahir Oruc¸



Received: 8 November 2014 / Accepted: 14 March 2015 Ó Springer Science+Business Media New York 2015

Abstract Purpose Remarkable differences in weight loss have been observed in obese patients undergoing laparoscopic sleeve gastrectomy (LSG). These high variations might be partly explained by genetic factors. The rs9939609 fat mass and obesity-associated gene (FTO) polymorphism has been implicated in the susceptibility of obesity. We aimed to explore the effects of the rs9939609 FTO gene polymorphism on weight loss among severely obese patients applying for LSG. Materials and methods All individuals were analyzed for the FTO rs9939609 gene polymorphism. A total of 74 morbid obese patients (20 male, 54 female) were operated. Body weight and body mass index (BMI) were measured at before LSG and after surgery at the sixth month. Results Twenty-eight patients (37.8 %) had genotype TT (wild-type allel), 36 patients (48.6 %) had genotype TA, and 10 patients (13.5 %) had genotype AA. In both wildtype group and mutant group, BMI and weight levels decreased at the sixth month after surgery. Percent of excess weight loss (EWL) at 6 months of follow-up was similar in & Tug˘rul C ¸ akır [email protected] 1

Department of Medical Genetics, Dr. Faruk Su¨kan Maternity and Pediatric Hospital, Konya, Turkey

2

General Surgery Department, Antalya Training and Research Hospital, Muratpas¸ a, Antalya 07000, Turkey

3

Department of Medical Genetics, Antalya Training and Research Hospital, Muratpas¸ a, Antalya, Turkey

4

Radiology Department, Antalya Training and Research Hospital, Muratpas¸ a, Antalya, Turkey

5

Department of Public Health, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey

both groups. There were no differences between the mutant and wild-type groups percent of EWL at the sixth month after applying LSG. Conclusion Our data showed that the rs9939609 FTO gene polymorphism is not a useful genetic test prior to LSG to help clinicians predicting the weight loss for severely obese patients in short-term follow-up. Keywords rs9939609 FTO gene polymorphism  Laparoscopic sleeve gastrectomy  Weight loss Obesity is a chronic disease characterized by the weight gain which is derived from an imbalance between energy intake and expenditure [1]. The gain in body weight causes an increase in body mass index (BMI). Individuals with a BMI C 25 kg/m2 are classified as overweight, and those with BMI C 30 kg/m2, BMI C 40 kg/m2 and BMI C 50 kg/m2 are considered as obese, morbid obese and super obese, respectively. Several environmental risk factors such as increased caloric intake, sedentary lifestyle and psychosocial causes lead to obesity [2]. Environmental factors play an important role in the development of obesity; in recent years, extensive researches have also clearly shown genetic contribution [3, 4]. Single nucleotide polymorphisms (SNP) in various genes encoding for proteins involved in the hypothalamic control of nutrition and energy homeostasis have been associated with obesity [5, 6]. A genome-wide association study emphasizes that the importance of fat mass and obesity-associated gene (FTO) as an obesity susceptibility gene [7]. FTO regulates nutrition and energy homeostasis through its action on the leptin–melanocortin pathway in the hypothalamus [8, 9]. The FTO gene, consisting of nine exons, was located on chromosome 16q12.2 [10], that it encodes a 2-oxoglutarate-dependent nucleic acid demethylase and that

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it is located in the nucleus [11, 12]. Polymorphisms in FTO gene have been determined as genetic risk factors for obesity [13]. Notably SNP rs9939609, located in intron 1, is associated with a 31 % increase in the risk of developing obesity [14]. FTO gene polymorphism rs9939609 may have a place in the control of nutrition and food choice, proposing a possible relation to a hyperphagia or a preference for energydense foods [10]. Individuals with AA genotype for a rs9939609 having a 1.7-fold increased risk of obesity compared with TT individuals [15]. Obese patients profit from any type of weight loss such as diet, lifestyle intervention, oral medication or bariatric surgery [16]. But bariatric surgery is the single method that has been established to result in significant weight loss for severely obese patients [17]. Before laparoscopic sleeve gastrectomy (LSG) was filled as a part of biliopancreatic diversion with duodenal switch (BPD-DS) [18]; at the present day, LSG has been effective and sole method for morbidly obese patients. LSG becomes more popular as a stand-alone process, and long-term outcomes are promising [19]. Data showed various results in terms of weight loss after LSG among obese patients of different ethnic groups [20]. This high difference in responses to LSG might be partially explained by genetic effect. In this study, we purposed to investigate the effects of the rs9939609 FTO gene polymorphism on weight loss after LSG in severely obese patients.

Materials and methods This study was performed at Antalya Education and Research Hospital. The consent of the Ethics Committee at Antalya Education and Research Hospital was achieved (dated May 24, 2013 and numbered 81266704), and the consent of the patients covered by the study was also obtained. A sample of 74 morbid obese patients (20 male, 54 female), aged 19–62 years with a BMI C 40 kg/m2, was operated on from July 2013 to February 2014. Follow-up inspections were carried out at the sixth month. Body weight and BMI were measured before the operation and at the sixth month. gDNA extraction and genotyping Genomic DNA was extracted from buffy coat samples prepared from EDTA-preserved human whole blood (EZ1 DNA Blood 200 ll Kit, Qiagen). Oligonucleotide primers and probes were designed by the PrimerDesign (PrimerDesignÒLtd). Genotyping was performed on rs9939609 (FTO gene) in chromosome 16q12.2 by conducting allelic discrimination using a Taqman Genotyping and Real-Time

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Polymerase Chain Reaction System (Rotorgene, Qiagen). The genotype of each specimen is calculated by comparing the ratio of signals between the two channels (ROX and VIC). Specimens of known genotypes and negative controls were used in every run to provide consistency among runs. Statistical analysis The data were evaluated with the aid of the statistical software SPSS 18.0. The normal distribution of data was analyzed. For comparison of groups, Student’s t test was used. Paired t test was used to test for statistical significance between before and 6 months after LSG. A p value under 0.05 was considered statistically significant. A Chi-square test was used to evaluate the Hardy–Weinberg equilibrium. The statistical analysis was implemented for the combined TA and AA as a group (mutant group) and wild-type TT as the second group, with a dominant model. The genotype distribution obeyed Hardy–Weinberg equilibrium (p [ 0.05).

Results Twenty-eight patients (37.8 %) had genotype TT (wildtype allel), 36 patients (48.6 %) had genotype TA, and 10 patients (13.5 %) had genotype AA. The preoperative clinical characteristics of the groups are shown in Table 1. In the wild-type group, mean age was 38.6 ± 9.7 years and the mean BMI was 48.8 ± 5.6 kg/m2. In the mutant type group, mean age was 38.8 ± 11.3 and the mean BMI was 48.3 ± 6.2 kg/m2. Effect of LSG on BMI and weight Anthropometric data of the groups before LSG and after surgery at the sixth month are shown in Table 2. There were no differences between groups in basal time anthropometric data. In both group, BMI and body weight decreased in a significant way after LSG at the sixth month.

Table 1 Preoperative clinical characteristics of the groups Wild group (TT)

Mutant group (TA and AA)

p

Morbid obese

17

33

0.50

Super obese Male/female

11 4/24

13 16/30

0.50 0.54

Age (years)

38.6 ± 9.7

38.8 ± 11.3

0.93

BMI (kg/m2)

48.8 ± 5.6

48.3 ± 6.2

0.70

Weight (kg)

134.3 ± 16.9

135.6 ± 25.8

0.81

Surg Endosc Table 2 Anthropometric data of the groups before LSG and after surgery at the sixth month

Parameters

Basal time

After LSG at the sixth month

p

Wild group (TT) BMI (kg/m2)

48.8 ± 5.6

35.6 ± 6.2*

\0.001

Weight (kg)

134.3 ± 16.9

98.1 ± 18.7*

\0.001

EWL%



26.9**

[0.054

Mutant group (TA and AA) BMI (kg/m2)

48.3 ± 6.2

35.8 ± 5.1*

\0.001

Weight (kg)

135.6 ± 25.8

100.9 ± 20.6*

\0.001

EWL%



25.5**

[0.054

LSG laparoscopic sleeve gastrectomy, BMI body mass index, EWL% percent of excess weight loss * p \ 0.001 (statistical significance with basal value in each group) ** p [ 0.05 (statistical significance with between groups)

Effect of rs9939609 FTO gene polymorphism on weight loss For comparison of groups, percent of EWL was used to evaluate the effect of rs9939609 FTO gene polymorphism on weight loss. No differences were detected between the mutant and wild-type groups EWL at the sixth month after undergoing LSG (Table 2).

Conclusion Obesity is a complex disease that was affected by multiple genetic and environmental factors. Although the mechanism of obesity is unclear, there are strong evidences of that social, cultural, psychological, metabolic and genetic factors play a role in obesity [21]. Many genes involved in obesity interact with environmental factors. The effect of these genes on weight loss that occurred with the treatment of obesity (dietary life changes, medical or surgical) is not clear. Therefore, we investigated whether rs9939609 FTO gene polymorphism in obese patients was associated with weight loss after LSG. There are some cross-sectional studies confirming the relationship between FTO gene polymorphisms and obesity [14, 22]. In a dietary intervention study, mutant group with AA and AT genotype seems to be better at weight loss than wild group with TT genotype [23]. Therefore, some advantages to body weight loss secondary to some type of hypocaloric diets were seen in patients with carrying A allel. Even so, in another study, AA genotype in FTO was significantly associated with the lesser weight loss [22]. Some studies have investigated the effect of the rs9939609 FTO gene polymorphism on weight loss after performing bariatric surgery in severely obese patients [24, 25]. A study has indicated that obese patients with AA genotype (recessive model) had larger decrease in BMI

than patients with TT/AT genotype after laparoscopic minigastric bypass at the sixth month [24]. In an another study, although EWL at 3 months of follow-up was significantly higher in the wild-type (TT) group, the EWL at 9 or 12 months was similar in both groups [25]. In the present study, we observed that there were no differences between mutant and wild-type groups EWL at the sixth month after undergoing LSG. These opposed results may be related to several factors such as preoperative BMI of patients, ratio of sex distribution, ethnicity, duration of follow-up and type of the chosen bariatric surgery [25]. Various types of bariatric surgery may regulate the enteroinsular hormonal axis and might interact with FTO gene polymorphisms. Although FTO expressed in many tissues, the highest expression level has been reported at the hypothalamus, pituitary and adrenal gland [26, 27]. Therefore, it has been proposed that FTO might play a role in the hypothalamic– pituitary–adrenal axis [27]. It was shown that FTO mRNA levels in arcuate nucleus of mice were up-regulated with nutrition and down-regulated by fasting [11, 28]. In humans, the expression levels of FTO vary in cases of hunger or obesity [26]. However, contradictory results on this subject were also obtained in various studies [29]. Since 2000, LSG has become popular among surgeons interested in bariatric surgery because of its positive results on body weight loss and lower comorbidities [30]. A recent study demonstrated that LSG induces stable weight loss and resolution of obesity-associated comorbidities [31]. Our study is the first to assess the association of the rs9939609 FTO gene polymorphism and weight loss after LSG. The major limitation of our study was the less number of patients and the short-term follow-up to infer the whole state of effect of rs9939609 on weight loss after undergoing LSG in obese patients. In conclusion, our study showed that there was no relationship between FTO gene polymorphism and weight

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loss after LSG in short-term follow-up. The effect of rs9939609 FTO gene polymorphism on weight loss after LSG can be more clearly proved along with the results of long-term follow-up. Acknowledgments This work was supported by Antalya Education and Research Hospital (Grant Number: 81266704).

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14.

¨ zgu¨r Balasar, Tug˘rul C¸akır, O ¨ zgu¨r Erkal, Arif Disclosures O Aslaner, Bu¨lent C ¸ ekic¸, Mehmet Uyar, Nurullah Bu¨lbu¨ller and Mehmet Tahir Oruc¸ declare that they have no conflict of interest in relation to this work.

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The effect of rs9939609 FTO gene polymorphism on weight loss after laparoscopic sleeve gastrectomy.

Remarkable differences in weight loss have been observed in obese patients undergoing laparoscopic sleeve gastrectomy (LSG). These high variations mig...
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