Susceptibility of fat mass and obesity-associated (FTO) gene polymorphisms to obesity has been reported in various populations. Polymorphisms in the melanocortin 4 receptor (MC4R) gene were recently explored as another susceptible locus. However, prognostic significance of these genetic variations has not been fully elucidated. Here, we investigated the involvement of FTO rs9939609 and MC4R rs17782313 polymorphisms in the development of obesity. Association with type 2 diabetes mellitus (T2DM) was also investigated.
We analyzed 2806 community-dwelling middle-aged to elderly subjects (61±14 years). Clinical parameters were obtained from the subjects' personal health records, evaluated at their annual medical check-up.
FTO genotype was significantly associated with current body mass index (BMI; TT 23.2±3.2, TA 23.7±3.2, AA 24.4±3.2 kg m−2, P=2.5 × 10−6) and frequency of obesity (26.6, 32.0, 43.0% respectively, P=2.0 × 10−4). Age- and sex-adjusted odds ratio for obesity was 1.30 (P=0.004) in TA and 2.07 (P=0.002) in AA genotype. During the 9.4 years comprising the follow-up period, 214 new cases of obesity were diagnosed among 1718 subjects whose retrospective data were available. A allele frequency of the FTO genotype was significantly higher in subjects who developed obesity (22.2, 15.8%, P=0.001), Age-, sex- and initial BMI-adjusted odds ratio for the development of obesity was 1.46 (95% confidence interval, 1.04–2.04) (P=0.031). However, association studies and meta-analysis of T2DM did not actively support the involvement of FTO genotype. No significant differences were observed between the MC4R genotype and BMI (P=0.015), and the frequency of obesity (P=0.284).
FTO genotype is an independent risk factor for future development of obesity.
Recent genome-wide association studies on European ancestries have identified the fat mass and obesity-associated (FTO) gene polymorphism, rs9939609, as a variation that induces susceptibility to obesity.1, 2 This association has been replicated in various populations,3, 4 including Japanese, who have a lower mean body mass index (BMI) and lower frequency of obesity.5 A common variant (rs17782313) near the melanocortin-4 receptor (MC4R) gene is another susceptible locus that has been associated with obesity in Caucasians in a number of studies.6, 7 One mechanism thought to explain the relationship between these genetic variants and obesity is the modulation of food intake and food choice, but not energy expenditure.8, 9, 10, 11 In contrast to the accumulated evidence for a cross-sectional association between these genetic variants and adiposity, however, only a few studies have investigated whether variations within the FTO or MC4R loci confer a risk of the future development of obesity.12, 13 Here, to clarify the prognostic significance of these obesity-associated variants, we conducted a longitudinal genetic epidemiological study in a community-dwelling general population. Furthermore, we investigated possible associations with type 2 diabetes mellitus (T2DM).14
Patients and methods
General population sample
Study subjects were selected from residents of a community of 11 000 inhabitants in Ehime Prefecture, a largely rural area located in western Japan.15 Subjects were recruited through a community-based annual medical check-up process in 2002 for self-employees, and included farmers and foresters, employees of small companies, and elderly without fixed employment. The sample population consisted of 2806 middle-aged to elderly residents (Table 1). Overnight fasting plasma samples for the measurement of plasma markers were available for 2043 subjects. Baseline clinical characteristics, including BMI, were obtained from personal health records evaluated during the medical check-up. All study procedures were approved by the ethics committee of Ehime University Graduate School of Medicine, and informed consent was obtained from each participating subject.
Personal health records evaluated at previous medical check-ups were obtained from a clinical database administered by the local government. For each subject, the oldest data available from 1992 to 1996 were obtained. Among 2806 subjects, retrospective data could be obtained for 2273 subjects. Mean duration of follow-up was 9.4±1.0 years. No significant difference in BMI was seen between subjects with (n=2273, 23.4±3.1 kg m−2) and without (n=533, 23.2±3.6 kg m−2, P=0.143) retrospective data.
Type 2 diabetes mellitus patients and control subjects
All T2DM subjects (n=492) were in- or outpatients, who had been evaluated by diabetologists at Ehime University Hospital and Ehime Prefectural Hospital (60±11 years, 24±4 kg m−2, 55% male). Diabetes mellitus was diagnosed based on the 1998 American Diabetes Association (ADA) criteria.16 Non-diabetic control subjects (n=380, 58±8 years, 23±3 kg m−2, 55% male) were chosen based on the absence of a history of diabetes in the subject and among his/her first-degree relatives, and either normal glucose tolerance, confirmed by a 75-g oral glucose tolerance test, or HbA1c levels under 5.6 with fasting plasma glucose levels under 110 mg 100 ml−1. Selection criteria details have been described previously.15, 17
Definition of metabolic syndrome
Metabolic syndrome was defined using the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel III report;18 obesity was defined as a condition with BMI value ⩾25 kg m−2 according to the guidelines of the Japanese Society for the Study of Obesity.19
Genomic DNA was extracted from peripheral blood (QIAamp DNA blood kit, QIAGEN GmbH, Hilden, Germany). All single nucleotide polymorphisms were analyzed by TaqMan probe assay (Applied Biosystems, Foster City, CA, USA) using commercially available primers and probes purchased from the Assay-on-Demand system (FTO rs9939609, C30090620; MC4R rs17782313, C32667060).
Values are expressed as mean±s.d. Frequency differences in each genotype were assessed by the χ2 test. Differences in BMI values among genotypes were assessed by analysis of variance. Adjusted odds ratios were calculated by multiple logistic regression analysis. Pooled odds ratios for allele frequency and for an additive model with those of three other association studies in Japanese populations20, 21, 22 were estimated using the fixed effects model (Mantel–Haenszel method23 and variance-based method,24, 25 respectively). Null hypotheses were rejected at a level of significance of P<0.05.
Table 2 summarizes the associations between the two analyzed single nucleotide polymorphisms and BMI. Significant correlations were observed between FTO genotype and BMI, with A allele carriers showing a higher BMI in both total subject and sex-separated analyses. Although the risk allele frequency (0.175) was slightly lower in the Japanese subjects than the previously reported frequency in Caucasians, the post hoc calculated statistical power (99.7% with a 5% type 1 error rate) was enough to detect the differences in BMI values. Association of the FTO genotype was slightly higher in male subjects. However, a multiple regression analysis identified the FTO genotype as independent determinant for BMI (β=0.095, P=4.4 × 10−7) after adjustment for sex (β=−0.037, P=0.053) and age (β=0.005, P=0.789). The age- and sex-adjusted per-allele difference in BMI was 0.57 kg m−2. Furthermore, the frequency of obese subjects was also significantly higher among the A allele carriers. Multiple logistic regression analysis adjusted for age and sex indicated that the odds ratio for obesity was twice higher in A allele homozygotes than in T allele homozygotes. The age- and sex-adjusted per-allele odds ratio for obesity was 1.35 (95% confidence interval (CI), 1.17–1.57). Frequency of the FTO genotype in non-obese subjects was in agreement with the Hardy–Weinberg disequilibrium (TT/TA/AA=1403/550/49, P=0.571), and not different from that in a previous report on Japanese (P=0.895), which gave an A allele frequency of 0.190 in control subjects.21 In contrast, no significant differences were observed between MC4R genotype, albeit that the study, which reported the involvement of MC4R genotype in obesity and the international HapMap projects reported no apparent differences in allele frequency between Japanese and Caucasians. The post hoc calculated statistical power of our sample was 44.4% with a 5% type 1 error rate.
To clarify the prognostic significance of FTO genotype in the development of obesity, we retrospectively analyzed the association between single nucleotide polymorphism rs9939609 and the development of obesity with a 9.4-year follow-up (Table 3). Among the 1718 subjects who were not obese at baseline (BMI less than 25 kg m−2; TT (n=1191), 21.8±2.0; TA (n=485), 22.1±1.8; AA (n=42) 22.6±1.6 kg m−2, P=2.1 × 10−4), 214 cases of obesity were newly diagnosed during the follow-up period. Risk allele frequency in these subjects was significantly higher than that in the 1504 subjects who remained non-obese (additive model (TT/TA/AA), 128/77/9 vs 1063/408/33, P=0.003; allelic model (A allele frequency), 0.222 vs 0.158, P=0.001). Although the initial mean BMI was also significantly higher in those subjects who developed obesity in both TT (n=1,191, 23.8±1.2, 21.5±1.9, P=1.4 × 10−35) and TA+AA genotype (n=527, 24.0±0.9, 21.8±1.7, P=3.1 × 10−28), FTO polymorphism remained an independent determinant of the development of obesity after adjustment for possible confounding factors (Table 3). In a separate analysis using median age (57 years), prognostic significance was observed in the younger group only (46±8 years, 121 cases, odds ratio 1.58 (95% CI 1.00–2.450), P=0.050) and not in older subjects (64±5 years, 93 cases, odds ratio 1.28 (95% CI 0.76–2.12), P=0.355).
The prevalence of metabolic disorders and metabolic syndrome among the FTO genotype is shown in Table 4. The frequency of subjects with each metabolic disorder did not differ between FTO genotype, except for obesity. The frequency difference in metabolic syndrome was marginally significant. Further, the accumulated number of five metabolic disorders was slightly different among genotypes (TT, 1.43±1.09; TA, 1.47±1.10; AA, 1.74±1.19; P=0.074), but this association disappeared if obesity was not included (TT, 1.16±0.90; TA, 1.14±0.90; AA, 1.29±0.96; P=0.430). Quantitative trait analysis also indicated a lack of associations between the FTO genotype and systolic blood pressure (P=0.465); plasma levels of glucose (P=0.171); triglyceride (P=0.191); and high-density lipoprotein cholesterol (P=0.682).
The association of the FTO rs9939609 genotype with T2DM is summarized in Table 5. In this study, A allele frequency was slightly higher in T2DM patients than in control subjects, albeit without statistical significance. This lack of association has also been reported in three other studies conducted on Japanese subjects.20, 21, 22 Furthermore, meta-analysis of these four association studies did not actively support the involvement of FTO genotype in T2DM.
In this study, we replicated the cross-sectional association of the FTO rs9939609, but not MC4R rs17782313, genotype with obesity in a general Japanese population. Furthermore, we clarified the prognostic significance of the FTO genotype in the development of obesity in a longitudinal genetic retrospective study. Recent genome-wide association studies using cross-sectional analysis to explore disease-associated variants have identified new susceptible loci for various diseases, including obesity. The application of these findings to identify at-risk populations requires the accumulation of sufficient longitudinal data to ensure prognostic significance. Although this study is retrospective setting, our findings provide valuable evidence supporting the application of genetic information about FTO in the field of public health genomics.
In our cross-sectional analysis, the per-allele difference in BMI (0.57 kg m−2) was slightly higher than those in previously reported population-based studies in Caucasians.1 The per-allele odds ratio for obesity (1.35; 95% CI 1.17–1.57) was also higher than that in Caucasian populations, which were 1.18 (95% CI 1.13–1.24) for being overweight (⩾25 kg m−2), and 1.31 (95% CI 1.23–1.39) for obesity (⩾30 kg m−2),1 whereas the risk allele frequency was reported to be lower in Japanese subjects (HapMap database: 16.7% for Japanese origins, 45.0% for European origins). Several ethnic differences may interact with the genetic influence on the obese phenotype. As the FTO genotype confers a risk for obesity by modulating food habits, a plausible reason for the ethnic differences is thought to be a difference in nutrient intake and consequently lower basal BMI in Japanese subjects.26 The effects of physical activity on genetic susceptibility, if any, remain to be clarified.27, 28
In contrast, no significant differences were observed in the MC4R genotype, albeit risk allele frequency not differing markedly between Japanese and European origins (HapMap database: 22.2% for Japanese origins, 28.3% for European origins). One suggested physiological function of the MC4R variant is the modulation of energy intake as similar to the FTO variants;10 however, the size of this effect on BMI was reported to be modest compared with that of the FTO variants.29 Although further epidemiological data are needed, the susceptibility to obesity conferred by the MC4R genotype may not be conserved in Japanese subjects.
In our longitudinal retrospective analysis with non-obese subjects, BMI was the most significant determinant for the future development of obesity (Table 3). Several literatures have been reported that childhood BMI is predictive of adulthood obesity.30, 31 Siervogel et al.32 also reported that the serial increases in body composition during 18–72 years were higher in overweight subjects than in lean persons. Reasons why body composition could associate with future obesity are uncertain. Lower physical activity or unbalanced eating habits are thought to be plausible reasons. In addition to this anthropometric parameter, FTO variant was also identified as an independent risk factor, particularly in younger subjects. Qi et al.13 reported that cross-sectional associations between FTO variant and obesity were found to be decreased in older age, especially in men. One plausible explanation for this diminished involvement of genetic factors in the elderly is thought to be the loss of adiposity. Other reasons may be changes in life-style factors or the age-related accumulation of environmental influences. From a clinical point of view, however, this observed association with FTO variant further clarifies the target population requiring preventive intervention.
The association of FTO variant with T2DM has been reported in several studies.1, 33 Furthermore, a meta-analysis of seven association studies in Caucasians reported positive correlations with metabolic traits, including plasma insulin and glucose levels.34 However, these associations disappeared on adjustment for BMI, suggesting that the genetic susceptibility for T2DM and metabolic traits was largely due to the effect on BMI. In this regard, another genome-wide association study recently reported the adiposity-related heterogeneity of the T2DM-susceptible genotype,35 with the finding that an association between FTO variants and T2DM was detectable only in T2DM subjects with obesity. In these data, although the FTO genotype was modestly associated with metabolic syndrome (Table 4), this association was largely dependent on the increased frequency of obese subjects, and the prevalence of other metabolic disorders did not differ among genotypes. Furthermore, an association study with T2DM, which included a meta-analysis of three other studies reporting a negative association in Japanese population, also failed to support an independent association with T2DM. On these bases, we suggest that the association of common FTO variants with metabolic traits, if any, is probably mediated through the effect of the variant on adiposity.
One limitation of this study warrants mention. As our study subjects consisted of middle-aged and elderly persons, our findings cannot be simply extrapolated to adolescents. Extension of these findings to estimate the size of the genetic effect will require further studies with younger subjects.
In summary, we have attempted to clarify the prognostic significance of the FTO genotype in the development of obesity in a longitudinal genetic retrospective study. In addition to the initial BMI, the FTO genotype was found to be an independent determinant for the development of obesity, and this prognostic significance was more prominent in younger persons. As body weight is a trait that is modifiable by dietary and exercise interventions, early detection of at-risk populations using genetic information may be useful in preventing future obesity-related diseases.
The authors declare no conflict of interest.
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This study was supported by a Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Ministry of Health, Labour and Welfare of Japan; the Japan Arteriosclerosis Prevention Fund; and a Research Promotion Award from Ehime University.
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Tabara, Y., Osawa, H., Guo, H. et al. Prognostic significance of FTO genotype in the development of obesity in Japanese: the J-SHIPP study. Int J Obes 33, 1243–1248 (2009). https://doi.org/10.1038/ijo.2009.161
- longitudinal study
- retrospective analysis
- gene polymorphism
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