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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.

SUBMITTER: Freathy RM

PROVIDER: S-EPMC3073395 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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

Freathy Rachel M RM Timpson Nicholas J NJ Lawlor Debbie A DA Pouta Anneli A Ben-Shlomo Yoav Y Ruokonen Aimo A Ebrahim Shah S Shields Beverley B Zeggini Eleftheria E Weedon Michael N MN Lindgren Cecilia M CM Lango Hana H Melzer David D Ferrucci Luigi L Paolisso Giuseppe G Neville Matthew J MJ Karpe Fredrik F Palmer Colin N A CN Morris Andrew D AD Elliott Paul P Jarvelin Marjo-Riitta MR Smith George Davey GD McCarthy Mark I MI Hattersley Andrew T AT Frayling Timothy M TM

Diabetes 20080317 5

<h4>Objective</h4>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.<h4>Research design and methods</h4>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 genot ...[more]

PMID: 18346983

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Project description:BackgroundObservational studies showed that circulating L-ascorbic acid (vitamin C) is inversely associated with cardiometabolic traits. However, these studies were susceptible to confounding and reverse causation.ObjectivesWe assessed the relation between L-ascorbic acid and 10 cardiometabolic traits by using a single nucleotide polymorphism in the solute carrier family 23 member 1 (SLC23A1) gene (rs33972313) associated with circulating L-ascorbic acid concentrations. The observed association between rs33972313 and cardiometabolic outcomes was compared with that expected given the rs33972313-L-ascorbic acid and L-ascorbic acid-outcome associations.DesignA meta-analysis was performed in the following 5 independent studies: the British Women's Heart and Health Study (n = 1833), the MIDSPAN study (n = 1138), the Ten Towns study (n = 1324), the British Regional Heart Study (n = 2521), and the European Prospective Investigation into Cancer (n = 3737).ResultsWith the use of a meta-analysis of observational estimates, inverse associations were shown between L-ascorbic acid and systolic blood pressure, triglycerides, and the waist-hip ratio [the strongest of which was the waist-hip ratio (-0.13-SD change; 95% CI: -0.20-, -0.07-SD change; P = 0.0001) per SD increase in L-ascorbic acid], and a positive association was shown with high-density lipoprotein (HDL) cholesterol. The variation at rs33972313 was associated with a 0.18-SD (95% CI: 0.10-, 0.25-SD; P = 3.34 × 10⁻⁶) increase in L-ascorbic acid per effect allele. There was no evidence of a relation between the variation at rs33972313 and any cardiometabolic outcome. Although observed estimates were not statistically different from expected associations between rs33972313 and cardiometabolic outcomes, estimates for low-density lipoprotein cholesterol, HDL cholesterol, triglycerides, glucose, and body mass index were in the opposite direction to those expected.ConclusionsThe nature of the genetic association exploited in this study led to limited statistical application, but despite this, when all cardiometabolic traits were assessed, there was no evidence of any trend supporting a protective role of L-ascorbic acid. In the context of existing work, these results add to the suggestion that observational relations between L-ascorbic acid and cardiometabolic health may be attributable to confounding and reverse causation.

Dataset Information

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

Publications

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

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