Fat Mass–and Obesity-Associated (FTO) Gene Variant Is Associated With Obesity

Longitudinal Analyses in Two Cohort Studies and Functional Test

  1. Lu Qi12,
  2. Kihwa Kang3,
  3. Cuilin Zhang4,
  4. Rob M. van Dam12,
  5. Peter Kraft25,
  6. David Hunter125,
  7. Chih-Hao Lee3 and
  8. Frank B. Hu125
  1. 1Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
  2. 2Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
  3. 3Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts
  4. 4Epidemiology Branch, Division of Epidemiology, Statistics and Prevention Research, National Institute of Child Health and Human Development, Rockville, Maryland
  5. 5Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
  1. Corresponding author: Lu Qi, nhlqi{at}channing.harvard.edu

Abstract

OBJECTIVE—To examine the longitudinal association of fat mass–and obesity-associated (FTO) variant with obesity, circulating adipokine levels, and FTO expression in various materials from human and mouse.

RESEARCH DESIGN AND METHODS—We genotyped rs9939609 in 2,287 men and 3,520 women from two prospective cohorts. Plasma adiponectin and leptin were measured in a subset of diabetic men (n = 854) and women (n = 987). Expression of FTO was tested in adipocytes from db/db mice and mouse macrophages.

RESULTS—We observed a trend toward decreasing associations between rs9939609 and BMI at older age (≥65 years) in men, whereas the associations were constant across different age groups in women. In addition, the single nucleotide polymorphism (SNP) rs9939609 was associated with lower plasma adiponectin (log[e]− means, 1.82 ± 0.04, 1.73 ± 0.03, and 1.68 ± 0.05 for TT, TA, and AA genotypes, respectively; P for trend = 0.02) and leptin (log[e]− means, 3.56 ± 0.04, 3.63 ± 0.04, and 3.70 ± 0.06; P for trend = 0.06) in diabetic women. Adjustment for BMI attenuated the associations. FTO gene was universally expressed in human and mice tissues, including adipocytes. In an ancillary study of adipocytes from db/db mice, FTO expression was ∼50% lower than in those from wild-type mice.

CONCLUSIONS—The association between FTO SNP rs9939609 and obesity risk may decline at older age. The variant affects circulating adiponectin and leptin levels through the changes in BMI. In addition, the expression of FTO gene was reduced in adipocytes from db/db mice.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 22 July 2008.

  • Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted July 16, 2008.
    • Received January 3, 2008.
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  1. Diabetes vol. 57 no. 11 3145-3151
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