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FTO Gene Variant Is Associated with Obesity: Longitudinal Analyses in Two Cohort Studies and Functional Test

¹ Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
² Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
³ Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
⁴ Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts
⁵ Epidemiology Branch, Division of Epidemiology, Statistics & Prevention Research, National Institute of Child Health and Human Development, Rockville, Maryland

Objective: To examine the longitudinal association of 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 y) in men, whereas the associations were constant across different age groups in women. In addition, 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; 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 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.

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