Abstract
Background: Bariatric surgery (BS) is considered the intervention most effective for patients with severe obesity and to maintain weight loss and glycemic control for the long-term.
Objective: To analyze the effects of genotypes and haplotypes of the FTO and MC4R genes on total body weight loss (TBWL), post-surgery weight, and post- BMI after bariatric surgery.
Methods: We retrospectively selected 101 patients from Bajío High Specialty Regional Hospital, León Guanajuato, México who underwent Roux-en-Y gastric bypass (RYGB) to register their body mass index (BMI), blood pressure, biochemistry characteristics, and comorbidities. Post-surgery, patients were quoted for registered anthropometry and blood pressure. Glucose, lipid and hepatic profiles, insulin, leptin, and ghrelin were measured, and rs9939609, rs9930506, and rs1421085 FTO were genotyped.
Results: After 6 (4 - 8) years post-surgery, TBWL was 34.7 kg, and post-surgery BMI was 33.8 kg/m2. BS induced a remission of T2D in 82% and a remission of hypertension in 78% of patients. Post-surgery weight was higher in carriers of the risk genotypes for the rs9939609 and rs1421085 polymorphisms. TBWL was lower in those with risk genotypes for the rs993056 and rs1421085 polymorphisms. Insulin and HOMA-IR were higher in the risk genotype of three FTO polymorphisms. There were significant interaction effects of rs9930506 and rs1421085 FTO risk genotypes on weight and BMI in response to BS.
Conclusions: Genotypes and haplotypes of FTO influence TBWL, insulin levels, and HOMA-IR. We found an interaction effect of rs9930506 and rs1421085 risk genotypes with response to BS on weight and BMI.
Keywords
Obesity, Bariatric surgery, Interaction of FTO, TBWL, Post-surgery weight
Introduction
Obesity is associated with increased morbidity and mortality and is a risk factor for cardiovascular disease. Therefore, preventing and treating obesity has become a major public health goal [1]. Bariatric surgery is considered the intervention most effective for patients with severe obesity (BMI ≥40 kg/m2 or ≥35 kg/m2) with comorbidities [2] and to maintain weight loss and glycemic control in the long-term [3]. In addition, improvement or long-term remission of comorbidities such as T2D, hypertension, and dyslipidemia after bariatric surgery has been reported [4].
One of the most effective surgical methods for obesity treatment is Roux-en-Y gastric bypass (RYGB), which has been well documented to achieve sustained long-term results [2]. Nevertheless, some studies have reported that 20-30% of patients do not achieve satisfactory weight loss post BC [3,5]. One of the factors involved in the unsuccessful results of BS may be genetic polymorphisms, which remains to be investigated. Given the known associations between the FTO gene and obesity, it is important to examine the role of variants in this gene in bariatric surgery outcomes. In a study performed in 146 patients undergoing Roux-en-Y gastric bypass and genotyped to rs9939609 FTO found that the carriers of one or two risk alleles TA and AA rs9939609 FTO had increased body weight and BMI at 3-, 4-, and 5-years following surgery compared with TT patients [6]. At 36, 48, and 60 months after bariatric surgery, body weight, fat mass, and BMI were higher, while EBWL was lower in carriers of rs9939609 FTO [7]. The study performed in 168 Mexican mestizos and 81 patients with other ancestral origins showed a statistical association of rs9939609 with smaller changes in postoperative %EBWL and BMI [8]. Role of polymorphisms rs1421085 and rs9930506 of FTO on the success of bariatric surgery has been studied little. Therefore, identifying genetic factors related to weight loss in bariatric surgery outcomes may help to guide weight management strategies pre- and post-surgery. The objective of the study was to analyze the effect of rs9939609, rs1421085 and rs9930506 of the FTO gene polymorphisms on changes in weight, BMI, TBWL, and metabolic variables after bariatric surgery.
Material and Methods
Subjects
We performed a retrospective analysis of the information contained in the medical files of patients from the surgery service of the Bajío High Specialty Regional Hospital, León Guanajuato, México, who underwent Roux-en-Y gastric bypass (RYGB) only from May 2010 to November 2021, resulting in 169 patients registered. Of them, 101 agreed to participate in the study. We collected personal and clinical data, and the conditions before bariatric surgery, such as weight, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), comorbidities, hypertension, dyslipidemia, and diabetes were registered. All participants were fully informed of the aims of the study and were asked to sign informed consent to participate in the study. The study was carried out according to the ethical standards of the Declaration of Helsinki (1983) and in agreement with the Good Clinical Practice guidelines. The study was approved by the Institutional Ethics Committee of the University of Guanajuato (CIBIUG-P70-2020) and by the Investigation Committee of Bajío High Specialty Regional Hospital (CEI-36-2020), León Guanajuato, México.
Post-surgery procedure
The patients were quoted at 8 AM to record their personal and clinical data, anthropometric measurements were taken, and systolic and diastolic blood pressures were measured in a sitting position after ten minutes of rest. Weight was measured with a Roman-type Tanita BC533 scale, and height was measured using a SECA 406 Stadiometer to calculate BMI (kg/m2). Changes in BMI (DBMI), total body weight loss (TBWL), percent of total body weight loss (%TBWL), and percent excess body weight loss (%EBWL), in which ideal weight is defined by the weight corresponding to a BMI of 25 kg/m2 were calculated according to Brethauer et al. [9]. Venous blood samples were taken after overnight fasting for the measurement of serum glucose and lipid profile, hepatic profile, serum insulin, leptin, and ghrelin levels and for DNA extraction. Serum glucose and lipid and hepatic profiles were measured using enzymatic methods. Insulin, leptin, and ghrelin concentrations were measured using ELISA kits (ALPCO Immunodiagnostic AG, Stubenwald-Allee, Bensheim, USA). Insulin resistance was calculated using the homeostasis model assessment (HOMA-IR) with the formula fasting glucose X fasting insulin/22.5 (U/L) [10].
SNP genotyping
Genomic DNA was isolated from whole blood using a commercial kit. Genotyping of rs9939609, rs9930506, and rs1421085 FTO polymorphisms (SNPs) was carried out with quantitative polymerase chain reaction (qPCR) using validated TaqMan® probes and TaqMan™ Genotyping Master Mix enzyme (Thermo Fisher Scientific, Inc., Waltham, MA, USA) following the supplier specifications.
Statistical analysis
The normality of the distribution of data was assessed by the Kolmogorov-Smirnov test. Hardy-Weinberg equilibrium was evaluated. We used descriptive statistics to present the data as the mean ± standard deviation (SD) or median (25-72 quartiles). To compare groups, we used the T test or Mann-Whitney test or ANOVA according to the distribution of data. Chi-square or Fisher´s exact tests were used to compare categorical variables. To evaluate the interaction effects of FTO polymorphisms with weight and BMI, we designed a variance analysis of repeated measures of one factor. A p value of <0.05 was considered significant. Analyses were carried out using the statistical Statistica 7 package (Statsoft Inc., Tulsa, OK, USA).
Results
We included a total of 101 patients, 78 women and 23 men, with a median of 6 (4–8) years after bariatric surgery. Table 1 shows the anthropometric, clinical, and metabolic characteristics of the patients’ post-surgery. In this cohort, TBWL was 34.7 (22.9–48.9), %TBWL was 23 (16.6–33), %EBWL was 58.5 (40–79), and ideal weight was 64 (58.5–68.9). All polymorphisms were in Hardy Weinberg equilibrium.
|
Age (years) |
47 (40–54) |
|
Sex m/f |
23/78 |
|
Weight (kg) |
82 (73–103) |
|
Height (m) |
1.60 (1.53–1.66) |
|
BMI (kg/m2) |
33.8 (29.1–38.8) |
|
SBP (mmHg) |
122 (112–132) |
|
DBP (mmHg) |
74 (60–80) |
|
TBWL (kg) |
34.7 (22.9–48.9) |
|
%TBWL |
23 (16.6–33) |
|
%EBWL |
58.5 (40–79) |
|
Glucose (mmol/L) |
4.88 (4.6–5.2) |
|
Total cholesterol (mmol/L) |
3.95 (3.43–4.49) |
|
HDL-cholesterol (mmol/L)) |
1.39 (1.16–1.6) |
|
LDL-cholesterol (mmol/L) |
2.0 (1.87–2.22) |
|
Triglycerides (mmol/L) |
1.06 (0.88–1.48) |
|
Total protein (g/L) |
7.0 (6.7–7.3) |
|
Serum Albumin (g/L) |
3.9 (3.8–4.1) |
|
AST U/L |
27 (23–33) |
|
ALT U/L |
23 (18–31) |
|
Alkaline Phosphatase UI/L |
87 (73–102) |
|
Total Bilirubin (µmm/L) |
10.2 (8.5–11.9) |
|
Indirect Bilirubin (µmm/L) |
6.8 (5.1–8.5) |
|
Direct Bilirubin (µmm/L) |
3.4 (1.7–5.1) |
|
Insulin µIU/L |
12.6 (9.5–17.5) |
|
HOMA-IR |
2.73 (1.94–4.35) |
|
Serum Leptin (ng/mL) |
25 (14.5–37.9) |
|
Serum Ghrelin (pg/mL) |
322 (270–506) |
|
The values are expressed as the median and interquartile range. SBP: Systolic Blood Pressure; DBP: Diastolic Blood Pressure; BMI: Body Mass Index; HDL: High Density Proteins; HOMA-IR: Homeostasis Model Assessment Insulin Resistance; AST: Aspartate Aminotransferase; ALT: Alanine Aminotransferase |
|
rs9939609, rs9930506, and 1421085 FTO polymorphisms dominant model, after surgery
Under the dominant model, the carriers of one or two risk alleles of the rs9939609 polymorphism showed 8.8 kg more and higher serum insulin, HOMA-IR, and serum leptin levels than the wild type. In the carriers of one or two risk (AG and GG) alleles of rs9930506 polymorphism, the TBWL were lower than in AA carriers. Instead, total cholesterol, insulin, and insulin resistance levels were higher than those of the wild type. Regarding polymorphism rs1421085, in the carriers of the risk genotypes TC and CC, the post-surgery weight, serum insulin, and insulin resistance were significantly higher than those in carriers of the TT genotype, but TBWL was low in the TC and CC groups (Table 2).
|
rs9939609 T>A |
||||
|
|
TT n= 40 |
TA and AA n = 61 |
T ó Z |
p |
|
Post-surgery Weight (Kg) |
84 ± 16.6 |
92.8 ± 24.2 |
t=- 1.98 |
0.049 |
|
Serum Insulin µIU/L |
12.0 ± 4.8 |
16.2 ± 9.2 |
t=-2.66 |
0.008 |
|
Serum Leptin (ng/mL) |
24.5 ±16 |
32.5 ± 21 |
t=-2.01 |
0.049 |
|
HOMA-IR |
2.69 ± 1.2 |
3.8 ± 2.6 |
t=-2.49 |
0.014 |
|
rs9930506 A>G |
||||
|
|
AA n= 41 |
AG and GG n= 59 |
Z |
p |
|
Pre-surgery BMI (kg/m2) |
50.3 (45.7– 55.2) |
45.3 (42.5–54.6) |
Z=1.91 |
0.05 |
|
TBWL Kg |
38.3 (25.2– 59) |
33 (18.6–41.8) |
Z=2.35 |
0.018 |
|
Total Cholesterol (mmol/L) (mg/dl)md/dL(mg/dl) |
3.77 (3.2–4.34) |
4.18 (3.6–4.7) |
Z=-2.09 |
0.036 |
|
Serum Insulin (µIU/L) |
10.5 (7.5–13.4) |
13.7 (10.5–9.4) |
Z=-3.53 |
0.0004 |
|
HOMA-IR |
2.28 (1.7–2.92) |
3 (2.18–4.9) |
Z=-3.47 |
0.0005 |
|
rs1421085 T>C |
||||
|
|
TT n= 44 |
TC and CC n=55 5559 |
T |
p |
|
Post-surgery weight (Kg) |
84 ± 16 |
93.9 ± 25 |
-2.29 |
0.023 |
|
TBWL (Kg) |
42.5 ± 20 |
32.5 ± 20 |
2.49 |
0.014 |
|
Serum insulin (µIU/L) |
12 ± 4.9 |
16.2 ± 9.3 |
-2.67 |
0.008 |
|
HOMA-IR |
2.68 ± 1.3 |
3.82 ± 2.6 |
-2.58 |
0.011 |
|
BMI: Body Mass Index; TBWL: Total Body Weight Loss; *= Z, Mann and Whitney; T: t Student |
||||
Analysis of rs9939609 (T>A) and rs1421085 (T>C) haplotypes
In the carriers of the rs9939609A and rs1421085C risk haplotype of FTO polymorphisms, the TBWL and %EBWL were significantly lower than in the other haplotypes (F=3.42, p=0.020 and F=16.73.47, p=0.018, respectively).
Analysis of rs9939609 (T>A) and rs9930506 (A>G) haplotypes
The carriers of the rs9939609A and rs9930506G risk haplotype lost less total weight (TBWL) (p=0.008), and serum insulin and HOMA-IR (p=0.003, and p=0.009) were significantly higher than in the other haplotypes.
Interaction effects of FTO polymorphisms in bariatric surgery
Significant interaction effects of both rs9930506 and rs1421085 FTO risk genotypes on weight and BMI in response to bariatric surgery were found. No interaction effects of rs9939609 risk genotypes by bariatric surgery were observed (Table 3).
|
rs9930506 A>G |
|||||
|
|
AA (n=41) |
AG and GG (n=59) |
p |
||
|
|
Before surgery |
After surgery |
Before surgery |
After surgery |
Genotype |
|
Weight (Kg) |
128.5 ± 25.5 121 (117–140) |
85 ± 16* 81.7 (76–93.9) |
125.4 ± 26.3 121 (106–140) |
92.8 ± 24.6* 89 (73–110) |
0.007 |
|
BMI (kg/m2) |
51.7 ± 10.8 50.3 (45.7–55.2) |
34 ± 6.2* 33.8 (29–38.5) |
47.9 ± 8 45.3 (42.5–54.6) |
35.3 ± 7.8* 34 (29.3–39.4) |
0.002 |
|
rs1421085 T>C |
|||||
|
|
TT (n=44) |
TC and CC (n=55) |
p |
||
|
|
Before surgery |
After surgery |
Before surgery |
After surgery |
Genotype |
|
Weight (Kg) |
126.4 ± 23.7 12 1(116–138) |
84 ± 16* 80.4 (73–94.5) |
126.4 ± 28 121 (106–142) |
93.9 ± 25* 91.7(73.3–111) |
0.014 |
|
BMI (kg/m2) |
50.6 ± 10 50 (44.5–54.3) |
33.3 ± 6* 33.2 (29–38.2) |
48.4 ± 9 46 (41.3–54.8) |
35.8 ± 8* 35.5 (29.6–40.7) |
0.005 |
|
Data presented as median ± ED, and median 25–75 quartile. BMI: Body Mass Index. p value = genotype interaction, variance analysis of repeated measure of one factor. *p<0.00001 difference within-subject before and after surgery. |
|||||
Discussion
After a median of 6 (4–8) years from bariatric surgery, we analyzed the effects of FTO gene polymorphisms on pre-surgery weight, post-surgery weight, pre-BMI, post-BMI, TBWL, % EBWL, and metabolic condition. Successful bariatric surgery in terms of weight outcomes has been described as >50% excess weight loss (%EWL), 20-30% loss of initial weight or achieving a BMI <35 kg/m2 [11]. Our cohort maintained a %TBWL of 58.5 (40-79) and a BMI of 33.8 (29-38.8) 6 years after bariatric surgery. In addition, metabolic parameters corresponded to individuals without metabolic problems and had important remission of T2DM and hypertension. Nevertheless, the patients had moderately satisfactory results in weight loss, TBWL, and %EBWL. Our data still shows clinical variability in outcomes of patients after RYGB.
An association of the risk rs9939609 genotype with smaller changes in postoperative BMI and %EBWL in patients with obesity after RYGB has been reported [7,8]. In our work, post-surgery weight, insulin, leptin, and insulin resistance levels were significantly higher in carriers of one or two risk alleles. In a recent study, carriers of the AT genotype had less weight loss than carriers of the TT genotype and lower resting-state activity in posterior cingulate cortex at 12-60 months after laparoscopic sleeve gastrectomy [12], which suggests that the FTO gene may play an important role in the long-term outcomes of bariatric surgery. The effect of the rs9930506 FTO polymorphism on the outcomes after bariatric surgery has been briefly explored. In our previous work in patients with severe obesity, we found at baseline that carriers of one or two risk alleles rs9930506 FTO weighed 34 kg more than wild-type carriers. After sleeve gastrectomy (SG), we found a higher weight loss in carriers of one or two risk alleles (37 kg) in comparison with wild-type carriers (13.7 kg), similar results were observed in BMI 11.5 vs 5.2 kg/m2, total cholesterol, insulin, and insulin resistance at 6 months of SG [13]. Several studies have confirmed the association of rs1421085 FTO with the risk of development obesity [14]. We found that carriers of the risk TC and CC genotypes had higher post-surgery weight and insulin and HOMA-IR levels and minor TBWL than carriers of the TT genotype. Interestingly, in the three polymorphisms of the FTO gene, higher insulin and HOMA-IR levels in risk genotypes. In a previous report, subjects with the rs9939609A risk allele were significantly associated with higher plasma insulin levels (P=0.05) and higher HOMA-IR (P=0.02) [15]. The variance analysis of repeated measures of one factor showed interaction effects between of rs9930506 and rs1421085 FTO polymorphisms with bariatric surgery on weight and BMI. This is the first report of interaction effects of these FTO polymorphisms with anthropometric changes for BS. In the literature, we found only one study by Harbron et al. that showed an association of the FTO rs1421085 and 17817449 haplotypes with dietary intake, eating behavior, and psychological health [16].
Limitations
The first limitation is that we carried out only two evaluations of the patients, pre-surgery and post-surgery 6 (4–8 years), and therefore, we do not have data on the changes in BS outcomes at a short-time (6 or 12 months, per example). Another limitation is the small sample size, which could not influence the lack of association of rs9939609 with bariatric surgery on weight and BMI
Conclusions
In this cohort, we showed the effect of rs9939609 and rs1421085 risk genotypes on post-surgery weight, and also the effect of the rs9930506 and rs1421085 risk genotypes on TBWL. Insulin and insulin resistance levels were higher in risk genotypes of three FTO polymorphisms. In the carriers of the rs9939609 and rs1421085 risk haplotype, as well as, in the rs9939609 and rs9930506 risk haplotype, TBWL were lower than those of the other haplotypes. Analysis additionally confirmed the interaction effects of rs9930506 and rs1421085 risk genotypes with response to bariatric surgery on weight and BMI. These results may be considered as a screening tool prior to bariatric surgery to help clinicians predict weight loss for patients with severe obesity and could be used prior to surgery to prognosticate their success.
Conflict of Interest
All authors of this paper state that they do not have any direct or indirect financial or other relationship that might lead to conflicts of interest.
Funding Source Declaration
This work was supported by the grant CIIC 2020 (120/2020) from University of Guanajuato to Elva Perez-Luque, and Bajío High Specialty Regional Hospital, León Guanajuato, México (HRAEB/DPEI/SEI/2020) to Claudia Martinez-Cordero.
Elva Perez-Luque and Claudia Martinez-Cordero developed the study design and wrote the manuscript. Edgar S. Daza-Hernández and Norberto Muñoz-Montes selected of the patients and data collection. Nicté Figueroa-Vega and Edgar S. Daza-Hernández developed and carried out the experiments. Elva Perez-Luque and Mónica I. Cardona-Alvarado carried out data interpretation and statistical analysis. All authors reviewed and approved the manuscript and approved the submission of the article.
References
2. Puzziferri N, Roshek TB 3rd, Mayo HG, Gallagher R, Belle SH, Livingston EH. Long-term follow-up after bariatric surgery: a systematic review. JAMA. 2014 Sep 3;312(9):934-42.
3. Chikunguwo SM, Wolfe LG, Dodson P, Meador JG, Baugh N, Clore JN, et al. Analysis of factors associated with durable remission of diabetes after Roux-en-Y gastric bypass. Surg Obes Relat Dis. 2010 May-Jun;6(3):254-9.
4. Sjöström L, Peltonen M, Jacobson P, Ahlin S, Andersson-Assarsson J, Anveden Å, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA. 2014 Jun 11;311(22):2297-304.
5. Brethauer SA, Kothari S, Sudan R, Williams B, English WJ, Brengman M, et al. Systematic review on reoperative bariatric surgery: American Society for Metabolic and Bariatric Surgery Revision Task Force. Surg Obes Relat Dis. 2014 Sep-Oct;10(5):952-72.
6. Ehrlich AC, Friedenberg FK. Genetic Associations of Obesity: The Fat-Mass and Obesity-Associated (FTO) Gene. Clin Transl Gastroenterol. 2016 Jan 28;7(1):e140.
7. Rodrigues GK, Resende CM, Durso DF, Rodrigues LA, Silva JL, Reis RC, et al. A single FTO gene variant rs9939609 is associated with body weight evolution in a multiethnic extremely obese population that underwent bariatric surgery. Nutrition. 2015 Nov-Dec;31(11-12):1344-50.
8. Velázquez-Fernández D, Mercado-Celis G, Flores-Morales J, Clavellina-Gaytán D, Vidrio R, Vidrio E, et al. Analysis of Gene Candidate SNP and Ancestral Origin Associated to Obesity and Postoperative Weight Loss in a Cohort of Obese Patients Undergoing RYGB. Obes Surg. 2017 Jun;27(6):1481-92.
9. Brethauer SA, Kim J, el Chaar M, Papasavas P, Eisenberg D, Rogers A, et al. Standardized outcomes reporting in metabolic and bariatric surgery. Surg Obes Relat Dis. 2015 May-Jun;11(3):489-506.
10. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985 Jul;28(7):412-9.
11. Johnson Stoklossa C, Atwal S. Nutrition care for patients with weight regain after bariatric surgery. Gastroenterol Res Pract. 2013;2013:256145.
12. Li G, Hu Y, Zhang W, Wang J, Sun L, Yu J, et al. FTO variant is associated with changes in BMI, ghrelin, and brain function following bariatric surgery. JCI Insight. 2024 Aug 1;9(17):e175967.
13. Figueroa-Vega N, Jordán B, Pérez-Luque EL, Parra-Laporte L, Garnelo S, Malacara JM. Effects of sleeve gastrectomy and rs9930506 FTO variants on angiopoietin/Tie-2 system in fat expansion and M1 macrophages recruitment in morbidly obese subjects. Endocrine. 2016 Dec;54(3):700-13.
14. Najd-Hassan-Bonab L, Safarpour M, Moazzam-Jazi M, Azizi F, Daneshpour MS. The role of FTO variant rs1421085 in the relationship with obesity: a systematic review and meta-analysis. Eat Weight Disord. 2022 Dec;27(8):3053-62.
15. Legry V, Cottel D, Ferrières J, Arveiler D, Andrieux N, Bingham A, et al. Effect of an FTO polymorphism on fat mass, obesity, and type 2 diabetes mellitus in the French MONICA Study. Metabolism. 2009 Jul;58(7):971-5.
16. Harbron J, van der Merwe L, Zaahl MG, Kotze MJ, Senekal M. Fat mass and obesity-associated (FTO) gene polymorphisms are associated with physical activity, food intake, eating behaviors, psychological health, and modeled change in body mass index in overweight/obese Caucasian adults. Nutrients. 2014 Aug 6;6(8):3130-52.