Mindi Styn, PhD Obesity Researchers’ Journal Club September 16, 2010 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 In a study of > 4000 twin pairs heritability for weight was 78%, after 25 yr fup 81% 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 Stunkard study – heritability for weight was .80 Bell C. Nature Reviews Genetics 2005

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 Shared environment decreases with age Claire M.A. Haworth, Obesity 2008

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 Extreme phenotypes I. Sadaf Farooqi. Monogenic Obesity in Humans. Annual Review of Medicine 2005

Common Obesity Multiple factors and genes involved Energy intake Energy expenditure Energy storage

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 Extreme phenotypes

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 Extreme phenotypes

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 Extreme phenotypes Hsiao TJ. Molecular Diagnosis & Therapy. 2010

Response to Treatment Hsiao TJ. Molecular Diagnosis & Therapy. 2010 Extreme phenotypes Hsiao TJ. Molecular Diagnosis & Therapy. 2010

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

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 Extreme phenotypes L Epstein. Behavioral Neuroscience. 2007; L Epstein. Am J Clin Nutr. 2004.

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 Extreme phenotypes Valladares, M. Nutritional Neuroscience. 2010; Cole S. Am J Clin Nutr. 2010.

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

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