Can Will Power Triumph Over the "Fatso" Gene?

From Medscape Genomic Medicine > Genomics in Practice
Jacquelyn K. Beals, PhD

Summer weather is here again, and with it comes the predictable upsurge in ads for how to look your best in a bikini, tank suit, or Speedo®, depending on your age, figure, or (lack of) self-confidence. Muscles are in, cellulite is frowned on, and fat -- as usual -- is a dirty word. For everyone who dismisses excess weight, saying, "It's in my genes," the bad news is that they're partly right. The good news is that in this realm, as in many others, genes are not destiny.

If ever a gene came by its nickname naturally, it's FTO. Officially designated in humans as the "fat mass and obesity associated" gene, it first gained attention in 1994 as 1 of 6 genes whose deletion caused fused toes in mutant mice. In normal mice, FTO expression was especially high in regions of the hypothalamus involved in energy balance. Its expression levels in these regions were regulated by variations in food intake.[1]

The function of human FTO was demonstrated in 2007.[2] A genome-wide association study involving nearly 39,000 people found that people with 2 copies of an FTO variant weighed an average of 3 kg more than did people with no copies of that variant. Among the study populations, 16% of participants were homozygous for the variant, and the association existed in children as young as age 7 years.

FTO's association with obesity was difficult to ignore: The odds ratio for obesity in homozygotes was 1.67 -- that is, individuals with 2 copies of the variant were 67% more likely to be obese than people without the variant.[2] Although the original genetic designation in mice referenced "fused toes," human FTO clearly deserved its nickname "fatso."

"Fatso" Association With Diabetes Differs Between Ethnic Groups
Considering the association of FTO with obesity, it came as no surprise that FTO variants were also associated with diabetes. Higher body weight, greater likelihood of diabetes mellitus -- it seemed obvious. FTO variants appeared to influence 2 of the 4 major diagnostic criteria for metabolic syndrome. At least that seemed to be the case, until investigators looked beyond their studies on "individuals of European inheritance."

A recent study reported in the May issue of PLoS One [3] assessed 4 single nucleotide polymorphisms (SNPs) of FTO in men and women of European and African American descent enrolled in the Atherosclerosis Risk in Communities (ARIC) study.

In white individuals (1004 with diabetes and 10,038 without), the study showed that the FTO genotypes of each of the 4 single-nucleotide polymorphisms (SNPs) studied (rs9939609, rs17817449, rs8050136, and rs1421085) were significantly associated with body mass index (BMI), waist-hip ratio, and waist circumference (P < .001 in each analysis), but not with height. Among African Americans (670 with diabetes and 2780 without), the rs1421085 genotype was significantly associated with BMI (P = .02); however, waist-hip ratio, waist circumference, and height were not associated with any of the 4 FTO SNP genotypes.

Assessment of FTO risk alleles by race showed that risk alleles of all 4 SNPs were associated with diabetes in white participants (odds ratios, 1.18-1.19; P < .001 for each SNP). But in African American participants, only rs1421085 risk variants were significantly associated with diabetes (odds ratio, 0.79; P = .03). Thus, the same allele that "conferred an elevated risk of being obese for both white and African-American participants" decreased diabetes risk 21% in African Americans. When analyses were adjusted for BMI, all significant associations between genotype and diabetes were retained.

BMI May Mediate FTO Influence on Diabetes
The authors acknowledge that FTO variants have repeatedly been associated with BMI and diabetes in Europeans, but replications in other ethnic groups (including African Americans, Hispanics, Asians, and Oceanics) have been less consistent across numerous studies. Several possibilities may account for the differences between ethnic groups.

The SNPs may be tightly linked in white persons but less strongly linked in people of African heritage. Alternatively, all 4 SNPs may be correlated with the "true causative mutation" in white persons, but only the rs1421085 SNP is correlated with the "true causative mutation" in African Americans. A third possibility -- which the authors present hesitantly -- is that the "genetic architecture of diabetes" differs between ethnic groups. The latter possibility is supported by rs1421085 protecting African Americans against diabetes while contributing significantly to obesity in both whites and African-Americans.

One of the more likely possibilities is that interaction between FTO variants and diabetes is mediated by BMI. The association between FTO genotype and BMI in African Americans was demonstrated only for rs1421085, and at a much lower level of significance (P = .02) than was seen in whites (P < .001). Thus, an association with diabetes might be more difficult to demonstrate in African Americans.

Eat More, Gain More -- For This I Need Genetics?
Although the "correct" possibility is still unknown, there is increasing evidence that FTO affects weight by influencing eating behavior and, specifically, by increasing energy intake and decreasing the satiety response. In several studies,[4,5] SNP rs9939609, which we met above, exerted some of its influence on weight via appetite by reducing the satiety response -- individuals with the rs9939609 variants demonstrated "low postprandial decrease in hunger."

So should individuals with these FTO variants resign themselves to obesity?
In April, a research study published in Archives of Pediatrics and Adolescent Medicine answered this question with a resounding "no."[6] Focusing on FTO SNP rs9939609, the study in European adolescents determined that increased physical activity could "offset the genetic predisposition to obesity associated with the FTO polymorphism."

In this case, at least, genes are not destiny. Even when satiety signals are reduced, willpower and lifestyle changes can prevail. Whether this comes as good news or bad is something that individuals -- and their physicians -- will have to decide for themselves. Meanwhile, summer is upon us and, for the moment, a tall glass of iced tea (no sugar, thanks) sounds pretty good.