Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected given its effect on BMI

Abstract

Objective: Common variation in the FTO gene is associated with BMI and type 2 diabetes. Increased BMI is associated with diabetes risk factors, including raised insulin, glucose, and triglycerides. We aimed to test whether FTO genotype is associated with variation in these metabolic traits.

Research design and methods: We tested the association between FTO genotype and 10 metabolic traits using data from 17,037 white European individuals. We compared the observed effect of FTO genotype on each trait to that expected given the FTO-BMI and BMI-trait associations.

Results: Each copy of the FTO rs9939609 A allele was associated with higher fasting insulin (0.039 SD [95% CI 0.013-0.064]; P = 0.003), glucose (0.024 [0.001-0.048]; P = 0.044), and triglycerides (0.028 [0.003-0.052]; P = 0.025) and lower HDL cholesterol (0.032 [0.008-0.057]; P = 0.009). There was no evidence of these associations when adjusting for BMI. Associations with fasting alanine aminotransferase, gamma-glutamyl-transferase, LDL cholesterol, A1C, and systolic and diastolic blood pressure were in the expected direction but did not reach P < 0.05. For all metabolic traits, effect sizes were consistent with those expected for the per allele change in BMI. FTO genotype was associated with a higher odds of metabolic syndrome (odds ratio 1.17 [95% CI 1.10-1.25]; P = 3 x 10(-6)).

Conclusions: FTO genotype is associated with metabolic traits to an extent entirely consistent with its effect on BMI. Sample sizes of >12,000 individuals were needed to detect associations at P < 0.05. Our findings highlight the importance of using appropriately powered studies to assess the effects of a known diabetes or obesity variant on secondary traits correlated with these conditions.

FIG. 1

Triangulation approach used to estimate the effect size of the FTO–metabolic trait association (c) given the association between FTO and BMI (a) and the observed epidemiological associations between BMI and the traits (b). We hypothesized that associations observed between FTO genotype and metabolic traits would be mediated by BMI (i.e., c = a × b). Effect sizes would therefore be expected to reflect both the FTO-BMI association and the BMI–metabolic trait associations.

FIG. 2

Meta-analysis plots for key quantitative traits associated with insulin resistance and the metabolic syndrome. Effect sizes for A, C, E, and G: SD change in trait (log₁₀scale) per 1 SD higher BMI (log₁₀ scale) (equal to the correlation coefficient between log₁₀[trait] and log₁₀[BMI]). Effect sizes for B, D, F, and H: SD change in trait (log₁₀ scale) per FTO A allele.

FIG. 3

Observed effect size per FTO A allele for each metabolic trait, plotted against expected effect size, given the FTO-BMI per A allele effect size estimate (0.088 SD) and the observed BMI-trait associations. Error bars represent 95% CIs.

FIG. 4

Meta-analysis plot of the association between the NCEP Adult Treatment Panel III definition of metabolic syndrome and FTO genotype in the six studies in which data on all criteria were available. Effect size: OR per FTO A allele.