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Observational Study
, 99 (6), e18820

Ancestry Specific Associations of FTO Gene Variant and Metabolic Syndrome: A Longitudinal ARIC Study

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Observational Study

Ancestry Specific Associations of FTO Gene Variant and Metabolic Syndrome: A Longitudinal ARIC Study

Dale S Hardy et al. Medicine (Baltimore).

Abstract

Cross-sectional studies indicate that the fat mass and obesity-associated (FTO) rs9939609 gene variant is associated with metabolic syndrome (MetS) primarily in European ancestry. However, the association is not fully elucidated in African Americans.We hypothesized that rs9939609 (AT = moderate-risk carriers or AA = high-risk carriers compared to TT = low-risk carriers) is associated with MetS and its component risk factors over time; and that its association is ancestry-specific. A secondary hypothesis was that higher levels of physical activity can decrease the deleterious effect of rs9939609 at higher body mass index (BMI).Atherosclerosis Risk in Communities study repeated measures data from 4 visits (1987-1998) were obtained from the database of Genotypes and Phenotypes for 10,358 participants (8170 Whites and 2188 African Americans) aged 45 to 64 years at baseline. Guidelines for elevated blood pressure by the American College of Cardiology and American Heart Association Task Force were updated within the MetS criteria. Risk ratios (RR) and 95% confidence intervals from generalized estimating equations assessed population-average risks.MetS was present among 3479 (42.6%) Whites and 1098 (50.2%) African Americans at baseline, and 50.3% Whites and 57% African Americans over 11-years of follow-up. Among MetS component risk factors, high waist circumference was most prevalent among White AT (RR = 1.07; 1.06-1.09) and AA (RR = 1.12; 1.10-1.14) higher-risk carriers. High triglycerides were elevated among African American AA high-risk carriers (RR = 1.11; 1.02-1.21) compared to TT low-risk carriers. Over time, White AT-and AA higher-risk carriers had 1.07 and 1.08-fold increase (P < .0001) in MetS risk. Physical activity had independent protective effects on MetS among both races (P < .05). White AA high-risk carriers with normal BMI and low vs high physical activity had higher MetS risk (RR = 1.69; 1.25-2.30 and RR = 0.68;0.53-0.87, respectively). In rs9939609 × BMI× physical activity interaction, White A-allele high-risk carriers had lower MetS risk (RR = 0.68; 0.53-0.87). Among Whites, physical activity can lessen the effect of rs9939609 and high BMI on risk for MetS.

Conflict of interest statement

All authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Percent of participants within TT, AT, and AA genotypes at baseline and over time with MetS component risk factors (i.e., high waist circumference, high blood pressure, high fasting blood glucose, low HDL (high density lipoprotein) cholesterol, and high triglycerides) in the ARIC study.
Figure 2
Figure 2
Percentage of participants within TT, AT, and AA genotypes at baseline (visit 1) and through 11 years of follow-up (visit 4) who remained free of metabolic syndrome (≤2 risk factors), those who remained with metabolic syndrome (≥3 risk factors), those who converted from having metabolic syndrome to not having metabolic syndrome (i.e., decreased from ≥3 risk factors to ≤2 risk factors), and those with converted from without metabolic syndrome to having metabolic syndrome (i.e., increased from ≤2 risk factors to ≥3 risk factors) in the ARIC study. X-axis description for time in study: Baseline (visit 1); 5 years (end of visit 2); 8 years (end of visit 3); 11 years (end of visit 4).
Figure 3
Figure 3
Estimated probability by race for those who remained free of metabolic syndrome (≤2 risk factors) at each visit. Log rank test showed no significances differences in survival functions between FTO rs9939609 (TT, AT, and AA carriers) for Whites (P = .686) and African Americans (P = .334). Time in study (Years): 0 = baseline (visit 1), 5 = end of visit 2, 8 = end of visit 3, 11 = end of visit 4.
Figure 4
Figure 4
Associations of FTO rs9930609, BMI, and Physical Activity in Relation to MetS. overwt, overweight. Normal weight, BMI < 25.0 kg/m2; Overweight or obese, BMI ≥ 25.0 kg/m2. Physical activity was determined using the Baecke questionnaire (values range from 1 to 5 Baecke units). Physical activity was dichotomized for Whites as ≤1.6 = low physical activity and >1.6 = high physical activity, and for African Americans as ≤2.1 = low physical activity and >2.1 = high physical activity. Bonferroni correction for multiple comparisons was calculated as P value: .05/2 = .025. Metabolic syndrome was regressed on age, gender, physical activity (Baecke sports domain), education level, duration of study time, and the first 3 genetic principle components to control for population admixture separately for Whites and African Americans using generalized estimating equation analysis. All models were stratified by combinations of high or low BMI or high or low physical activity. The P values for interactions for FTO rs9939609 × BMI × physical activity were as follow, Whites: A-allele P < .001, AT P = .558, AA P = .140, dominant P = .002, and recessive P = .747; African Americans: A-allele P = .028, AT P = .060, AA = .010, dominant P = .039, and recessive P = .013.
Figure 5
Figure 5
A and B. Interactions between FTO rs9939609 × BMI × Physical activity in relation to MetS. Interaction models: Metabolic syndrome was regressed on FTO rs9939609, age, gender, physical activity (Baecke sports domain), body mass index, education level, duration of study time, the first 3 genetic principle components to control for population admixture, and interactions for FTO rs9939609 × BMI × physical activity, for Whites and African Americans separately using generalized estimating equation model. Bonferroni correction for multiple comparisons was calculated as P value: .05/4 = .013.
Figure 5 (Continued)
Figure 5 (Continued)
A and B. Interactions between FTO rs9939609 × BMI × Physical activity in relation to MetS. Interaction models: Metabolic syndrome was regressed on FTO rs9939609, age, gender, physical activity (Baecke sports domain), body mass index, education level, duration of study time, the first 3 genetic principle components to control for population admixture, and interactions for FTO rs9939609 × BMI × physical activity, for Whites and African Americans separately using generalized estimating equation model. Bonferroni correction for multiple comparisons was calculated as P value: .05/4 = .013.

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