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April 12, 2010

SNPs Genotyping and the diets to lose-weight

Mindy Dopler Nelson and Christopher Gardner from the Stanford Prevention Research Center, and other researchers of Interleukin Genetics Inc. performed a very interesting Clinical Trial entitled:  Genetic Phenotypes Predict Weight Loss Success: The Right Diet Does Matter, presented at the Joint Conference -50th Cardiovascular Disease Epidemiology and Prevention- and -Nutrition, Physical Activity, and Metabolism 2010, scheduled March 3, 2010, San Francisco, California. 

This trial demonstrated that individuals following diets matched to their genotype, its showed statistically significant greater weight loss and other benefits at all time points (2 months, 6 months and 12 months) when compared to individuals on diets not matched to their genotype. They studied overweight/obese premenopausal women, in a one-year weight loss study comparing four weight loss diets: very low carbohydrate, low carbohydrate/high protein, low fat and very low fat.


Beginning in 2008, participants who completed the trial were invited by e-mail and postal mail to provide DNA samples by a simple cheek swab. They genotyped 101 Caucasian participants, who were categorized using a genetic panel with SNPs, into three pre-determined composite genotype patterns of individuals who are more likely to respond to calorie reduction diets that are: low fat (Ornish diet), low carbohydrate (Atkins diet), or balanced in macronutrients (Zone diet). The primary endpoint analysis compared weight loss for women who were on a diet that was consistent with their genotype category to those individuals on diets not suitable for their genetic pattern.

They concluded that individuals on a diet identified as appropriate to their genotype by lost an average of over 2.5 times more weight than individuals on diets that were not appropriate (p less of 0.013), and, they showed a waist size reduction of 2.6 inches or 6.6 cm (p less of 0.01). Those are amazing results. However, I have to say that we need to be cautious with those results mainly by four important considerations:
  1. The sample size is too small (possible bias?) and it comprised only an specific group
  2. The obesity epidemic is an environmental and social problem mostly, even when the genes have shown predisposition
  3. The genotypic and allelic frequencies studied are still unknown in the most ethnic groups
  4. It will be necessary further studies that focus in a strict following, at median and long term.
 The Human Obesity Gene Map reviewed, screened the evidence for all genetic variations that were associated with body weight, body mass index, or body fat and identified those that had been replicated in at least three clinical studies. Five variations in four genes were included in this study, those variants include:
  1. Fatty acid binding protein 2 (FABP2) Ala54Thr
  2. Peroxisome proliferator-activated receptor-gamma (PPARG or γ) Pro12Ala
  3. Beta-2 adrenergic receptor (ADRB2) Arg16Gly and Gln27Glu
  4. Beta-3 adrenergic receptor (ADRB3) Arg64Trp
FABP2 Ala54Thr (A54T) Polymorphism
The FABP2 gene encodes the intestinal form of fatty acid binding protein2 (FABP2). FABP2 protein is found in small intestine epithelial cells where it strongly influences fat absorption. Variations in DNA or polymorphisms in the gene result in greater binding of the fatty acids (released in the intestine from dietary fat consumption) which in turn results in higher absorption of fat. One such polymorphism, Ala54Thr, has been found to be associated with obesity. Multiple clinical research studies have indicated that individuals with the Thr54 form of the protein show increased absorption and/or processing of dietary fatty acids by the intestine. The Thr54 variant has been associated with elevated BMI and body fat, increased abdominal fat, and obesity and higher LEPTIN levels. Homozygotes for 54Thr/Thr variant show increased levels of postprandial triglycerides and increased levels of 14-18-carbon fatty acids compared with the 54Ala/Ala form of the protein. 

PPARG Pro12Ala (P12A) Polymorphism
Peroxisome proliferator-activated receptor-gamma (PPARG) protein is abundantly expressed in fat cells and plays a key role in the formation of fat cells. It is crucial to lipid (fat) metabolism. Polymorphisms in this gene that are responsible for expression of variant forms of the protein have been associated with the development of type 2 diabetes. The variant form of the protein (Ala12) is associated with a decreased binding affinity to its target genes and thus with a reduction in its ability to regulate the expression of these target genes. Pro12Ala polymorphism was the most studied, in individuals with the 12Pro/Pro form of the protein were more affected by the amount of fat in the diet and had a direct association between higher BMI and the amount of fat intake as opposed to the Ala12 carriers. These findings clearly indicated that 12Pro/Ala carrier individuals are more sensitive to the amount of fat in the diet. Clinical studies consistently show that Pro12 allele is the high-risk allele and 12Pro/Pro subjects are more sensitive to the amount of fat in the diet, more resistant to weight loss and at increased risk of diabetes. The evidence of gene-diet interaction is strong.

ADRB2 Arg16Gly (R16E) and Gln27Glu (Q27E) Polymorphisms
The beta-2 adrenergic receptor (ADRB2) gene product ADRB2 protein is expressed in fat cells. This receptor protein is involved in the mobilization of fat from the fat cells for energy in response to hormones called catecholamines. Several polymorphisms of this gene that result in amino acid changes have been identified. The two main well-characterized polymorphisms Arg16Gly and Gln27Glu are the most common in Caucasians. The recent obesity gene map shows association between variants in the ADRB2 gene and obesity, with most of the positive findings involving the Arg16Gly or Gln27Glu polymorphisms. Multiple studies show association between Glu27 and Gly16 allele carriers and abdominal and central obesity. 27Gln/Gln was found to be a risk genetic profile in studies involving overfeeding of identical twins where higher weight gain and subcutaneous fat were observed compared to those with the Glu27 allele. Results from association studies suggest that the Glu27 allele is associated with an increased risk of obesity, abdominal obesity and obesity when adhering to a high carbohydrate diet.

ADRB3 Trp64Arg (R64W) Polymorphism
The beta-3 adrenergic receptor (ADRB3) protein is expressed in visceral adipose tissue and the fat depot where it is involved in the regulation of fat breakdown (lipolysis). Laboratory studies on isolated fat cells (adipocytes) show that the Trp64Arg polymorphism in the gene results in reduced lipolysis in response to a specific agonist in cells carrying the Arg64 allele. Multiple clinical studies showed that Arg64 variant on the ADRB3 gene is strongly associated with increased BMI. Women with the Arg64 variant lost less weight through diet and exercise. ADRB3 Arg64 carriers experienced greater loss of fat mass and trunk fat following of supervised aerobic exercise training compared to non-carriers.

ADRB2 Arg16Gly (R16E) and ADRB3 Trp64Arg (R64W) Polymorphisms and Exercise
A number of studies have investigated the role of ADRB 2 and 3 polymorphisms on the risk of developing obesity and assessed the effect of physical activity on this risk. In a case-control study it was observed that the effect of the ADRB3 variant on obesity changes depending on the recreational physical activity levels. An increased obesity risk among carriers of the mutation (Arg64) was dramatically diminished when subjects had recreational energy expenditure levels higher than the median, the higher risk of obesity among carriers of the ADRB3 variant (Arg64) may be altered by moderate levels of physical activity.

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