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Genetics and Obesity

Genetics and Obesity. Mindi Styn, PhD Obesity Researchers’ Journal Club September 16, 2010. By PresenterMedia.com. Genetics 101. Allele: One of the possible forms of a gene. U.S. Department of Energy Genome Programs : http://genomics.energy.gov. Heritability of Obesity.

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Genetics and Obesity

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  1. Genetics and Obesity Mindi Styn, PhD Obesity Researchers’ Journal Club September 16, 2010 By PresenterMedia.com

  2. Genetics 101 Allele: One of the possible forms of a gene U.S. Department of Energy Genome Programs : http://genomics.energy.gov

  3. Heritability of Obesity • In a study of > 4000 twin pairs heritability for weight was 78%, after 25 yr fup81% • Adopted children have been found to have body sizes more similar to their biological parents than their adoptive parents • In a study of twins reared apart heritability of obesity was reported to be 70% for men and 66% for women • Twin studies have also shown high correlations within twin pairs for weight gain, weight loss and metabolic efficiency Bell C. Nature Reviews Genetics 2005

  4. Heritability of Obesity • May change with age • In a large UK twin study heritability increased from .48 at age 4 to .78 at age 11 Claire M.A. Haworth, Obesity 2008

  5. Monogenic & Syndromic Obesity • Provide possible clues to the genetics of non-syndromic or “common” obesity • Monogenic Obesity • Severe, early-onset obesity related to genetic mutation • Mendelian pattern of inheritance (due to single gene) • Frequently disrupt leptin-melanocortin pathway • Identified mutations in leptin gene, leptin receptor, POMC (results in hyperphagia), melanocortin 4 receptor (MC4R) • Syndromic Obesity • Genetic mutation results in a set of symptoms that includes obesity • Example: Prader-Willi Syndrome I. SadafFarooqi. Monogenic Obesity in Humans. Annual Review of Medicine 2005

  6. Common Obesity • Multiple factors and genes involved • Energy intake • Energy expenditure • Energy storage

  7. Associations with body size • Leptin (LEP) • Associated with decreased weight loss on a reduced calorie diet • G allele more frequent in obese and extremely obese women • Ghrelin (GHRL) • Leu72met minor allele is more common among children with a high BMI • Fat mass and obesity associated gene (FTO) • Strong association with BMI over a 25 year study, associated with increasing BMI • MC4R • 2 recent GWAS supported association

  8. Associations with body size • Dopamine Receptor 2 (DRD2) • PLCO Cancer Screening Trial, obese participants were more likely to carry the DRD2 TaqIA variant allele than were normal weight participants. • DRD4 • Association with BMI among multiple study groups (black, hispanic, former smokers, with bulimia nervosa) • Brain Derived Neurotropic Factor (BDNF) • Associated with BMI and severity of disordered eating

  9. Response to Treatment • Uncoupling protein 2 (UCP2) gene • SNP appears to contribute to variation in response to sibutramine • 131 obese patients from Taiwan • Individuals homozygous for major allele were unresponsive to treatment • Those with a minor allele had significant reductions in weight and fat mass compared to placebo Hsiao TJ. Molecular Diagnosis & Therapy. 2010

  10. Response to Treatment Hsiao TJ. Molecular Diagnosis & Therapy. 2010

  11. Energy Intake • FTO (Fat Mass and Obesity Associated) Gene • High Risk allele (A vs. T) – 1 copy of the high risk allele = 30% more likely to be obese, 2 copies = 70% • Study of 131 children, 4-5 yo, those with a high risk allele ate more highly palatable food after a meal than those without even after controlling for BMI • Study of 289 6-19 year olds, 34.7% of those with a high risk allele reported a loss of control over eating versus 18.2% without • In a subset of 190 participants who participated in a buffet test meal, total energy intake did not differ but fat intake was higher in those with a high risk allele J Wardle.IJO. 2009; M Tanofsky-Kraff. Am J Clin Nutr. 2009

  12. Energy Intake • Dopamine (DRD2, DAT1/SLC6A3) • Reward pathway • Study of 88 smokers with mean BMI of 27, those with a minor allele for DRD2 and a high score on a food reinforcement test consumed more calories • Those who were homozygous for the major allele for DAT1 and a high score consumed more calories • In non-smokers, only DRD2 findings were replicated L Epstein. Behavioral Neuroscience. 2007; L Epstein. Am J ClinNutr. 2004.

  13. Energy Intake • Melanocortin-4 receptor (MC4R) gene • In 221 obese Chilean children one variant was found to be associated with satiety responsiveness and enjoyment of food scores. • In 1016 Hispanic children variation in MC4R was found to be related to energy intake reported on 24-hour dietary recalls Valladares, M. NutritionalNeuroscience. 2010; Cole S. Am J Clin Nutr. 2010.

  14. Energy Expenditure • Heritability for exercise participation: 62% • Heritability for resting metabolic rate: 40% • In the Negative Energy Balance Trial, twins were put on controlled diets and exercised 2X/day Rankinen T. Med Sci Sports Exerc. 2010; Rankinen T. Obesity (Silver Spring). 2008; Bouchard C. Int J Obes. 1990

  15. Discussion • Does the genetic contribution to obesity matter? • Is it worth the cost? • How do we move forward with the information we have?

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