Variation in FTO contributes to childhood obesity and severe adult obesity

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Abstract

We identified a set of SNPs in the first intron of the FTO (fat mass and obesity associated) gene on chromosome 16q12.2 that is consistently strongly associated with early-onset and severe obesity in both adults and children of European ancestry with an experiment-wise P value of 1.67 x 10(-26) in 2,900 affected individuals and 5,100 controls. The at-risk haplotype yields a proportion of attributable risk of 22% for common obesity. We conclude that FTO contributes to human obesity and hence may be a target for subsequent functional analyses.

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The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals.

Serge Hercberg, Pilar Galan, Paul Preziosi … (2004)

It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer. To date, however, the published results of randomized, placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect. We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population. The Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study is a randomized, double-blind, placebo-controlled primary prevention trial. A total of 13 017 French adults (7876 women aged 35-60 years and 5141 men aged 45-60 years) were included. All participants took a single daily capsule of a combination of 120 mg of ascorbic acid, 30 mg of vitamin E, 6 mg of beta carotene, 100 mug of selenium, and 20 mg of zinc, or a placebo. Median follow-up time was 7.5 years. No major differences were detected between the groups in total cancer incidence (267 [4.1%] for the study group vs 295 [4.5%] for the placebo group), ischemic cardiovascular disease incidence (134 [2.1%] vs 137[2.1%]), or all-cause mortality (76 [1.2%] vs 98 [1.5%]). However, a significant interaction between sex and group effects on cancer incidence was found (P = .004). Sex-stratified analysis showed a protective effect of antioxidants in men (relative risk, 0.69 [95% confidence interval [CI], 0.53-0.91]) but not in women (relative risk, 1.04 [95% CI, 0.85-1.29]). A similar trend was observed for all-cause mortality (relative risk, 0.63 [95% CI, 0.42-0.93] in men vs 1.03 [95% CI, 0.64-1.63] in women; P = .11 for interaction). After 7.5 years, low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women. Supplementation may be effective in men only because of their lower baseline status of certain antioxidants, especially of beta carotene.

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Evaluation of regulatory potential and conservation scores for detecting cis-regulatory modules in aligned mammalian genome sequences.

Charles King, Francesca Chiaromonte, Webb Miller … (2005)

Techniques of comparative genomics are being used to identify candidate functional DNA sequences, and objective evaluations are needed to assess their effectiveness. Different analytical methods score distinctive features of whole-genome alignments among human, mouse, and rat to predict functional regions. We evaluated three of these methods for their ability to identify the positions of known regulatory regions in the well-studied HBB gene complex. Two methods, multispecies conserved sequences and phastCons, quantify levels of conservation to estimate a likelihood that aligned DNA sequences are under purifying selection. A third function, regulatory potential (RP), measures the similarity of patterns in the alignments to those in known regulatory regions. The methods can correctly identify 50%-60% of noncoding positions in the HBB gene complex as regulatory or nonregulatory, with RP performing better than do other methods. When evaluated by the ability to discriminate genomic intervals, RP reaches a sensitivity of 0.78 and a true discovery rate of approximately 0.6. The performance is better on other reference sets; both phastCons and RP scores can capture almost all regulatory elements in those sets along with approximately 7% of the human genome.

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Comment on "A common genetic variant is associated with adult and childhood obesity".

Andrea Samson, David Meyre, Christian Dina … (2007)

Herbert et al. (Reports, 14 April 2006, p. 279) reported an association between the INSIG2 gene variant rs7566605 and obesity in four sample populations, under a recessive model. We attempted to replicate this result in 10,265 Caucasian individuals, combining family-based, case-control, and general population studies, but found no support for a major role of this variant in obesity.