(c) IgnitePlay 2014 contact: Lisa Andres ThinnerGene.com

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2 Lisa Andres is a Certified Genetic Counselor and founder of IgnitePlay. She has over 20 years of experience in health and health technology including experience counseling people about their genetic risk. Lisa is passionate about making it easier and more fun for people to lose weight and get healthy. I am a board certified genetic counselor. As a genetic counselor I counseled patients about their risks for genetic conditions, recommended and interpreted test results and helped them deal with the impact of testing. I have also worked in biotechnology and clinical trials and with health technology companies. Throughout my career my underlying passion has been to empower people to take control of their health. Which is probably a driving force for many of you as well. And that s why I started IgnitePlay. Our first product was a game called SpaPlay which is currently online. SpaPlay makes it fun for people to lose weight and get healthy. It also connects players to health experts who can help support them in their weight loss journey. While developing our game I talked a lot to our SpaPlay community about their barriers to losing weight. I kept hearing that people were really confused about all of the options and wanted customized weight loss plans. They wanted to know whether they should they do low fat, high protein, low carb etc.? And I am guessing that many of you have faced similar questions. So I started reviewing the latest research on how our genes impact our weight. What got me really interested was research that showed how differences in our genes impact our weight by influencing how our body responds to exercise and to different nutrients like proteins, carbs and fats. This got me excited about the potential of tailoring weight loss programs to each person s DNA. That is why I developed ThinnerGene. So what I would like to do today is share some of this cutting edge research. 2

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4 Typically, all of the cells in our bodies, except for our mature red blood cells, contain 23 pairs of chromosomes. We inherit one of each chromosome from our biological mother and one from our biological father. Our chromosomes contain the instructions for the development and functioning of our cells. Chromosomes are composed of long strands of DNA tightly wrapped around proteins. Each cell in our bodies contains approximately 1.8 meters of DNA in total, although each strand is less than one millionth of a centimeter thick. Our DNA contains around 25,000 genes. A gene is a piece of DNA that contains the instructions to make a specific protein. Proteins are important because they tell each of our cells what to do and when to do it. References Bianconi E et al. An estimation of the number of cells in the human body. Ann Hum Biol Nov-Dec;40(6): University of Leicester. DNA, Genes & Chromosomes. National Human Genome Research Institute. Chromosome Abnormalities. 4

5 DNA Variations Our DNA has two strands. Each of these strands has a sequence made up of a series of four letters, A,T,C,G called bases. The two strands are joined together like a ladder through their bases. A always pairs with T, and C pairs with G. Variations in our DNA sequence are what make each of us unique. We can have different types of variations in our DNA sequence. For example, we can have a rearranged sequence, pieces missing in our sequence, called deletions, or pieces added called insertions. The most common variation occurs when one genetic letter (A, T, C, or G) is replaced by any of the other three letters. This is called a single nucleotide polymorphism or a SNP, pronounced SNIP. In this picture the G in the first sequence (GGC ) has been replaced by the A in the second sequence (CAC). Since the two strands of DNA are complementary you only have to show the sequence of one strand. 5

6 The sequence of DNA that is located in a gene is called the gene sequence. SNPs often occur in a gene sequence. Then this happens it can affect the protein produced by the gene. This can affect how we look or how our body functions. We typically inherit one gene from our mother and one from our father. In the picture to the left, this person has inherited an T SNP variation from their mother and an A variation for their father. Other people could inherit AA, AT or TT. How do our DNA Variations make us Unique? Different variations have different effects. Even SNP variations can have a significant effect on how we look and how our body functions. Some variations don t have any effect. Some variations can influence things like our hair color or the size of our feet. Other variations influence our weight. Other variations can influence things how likely we will be to get a certain disease like diabetes. In many cases it is our genes in combination with our environment that have the greatest effect. 6

7 Our genes affect our weight in many ways as listed in this slide. 7

8 Your genes and the environment each contribute around 50% towards your weight. In fact they work synergistically for or against you! 8

9 What s particularly interesting is how your genes, diet and exercise work together to influence your weight. There are a number of genes that influence how your body responds to exercise and diet. Let me give you some examples. 9

10 FTO gene fat mass and obesity associated associated with increased risk of obesity Function unknown seems to influence appetite 10

11 RS# - it is an identification number for a SNP. Higher protein: greater weight loss, decrease weight circumference and body fat Data shows at 2 years At the rs location in the FTO gene people can have AA, AT or TT variations. In general, those who are AA or AT are more likely to be overweight than those who are TT. What s interesting is that people with AA or AT who eat a high protein diet are more likely to lose weight than those who eat a lower protein diet.[1] This is true whether they eat a high or low fat diet. Some research has found that AA or AT people tend to normally have a higher appetite and food cravings which is suppressed when they eat higher amounts of protein.[2] Carriers of the risk allele (A allele) of the rs genotype had a greater loss of weight and regional fat in response to a high-protein diet compared with non-carriers, whereas an opposite genetic effect was observed regarding changes in fat distribution in response to a lower-protein diet. High protein 25% protein, low protein 15% This was true on low fat and high fat diets The nutrient goals for the four diet groups were: (LOW PROTEIN) 20% fat, 15% protein, and 65% carbohydrates (low-fat, average-protein, higher carbs); 40% fat, 15% protein, and 45% carbohydrates (high-fat, average-protein, lower carbs) (HIGH PROTEIN) 20% fat, 25% protein, and 55% carbohydrates (low-fat, high protein); higher carbs 40% fat, 25% protein, and 35% carbohydrates (high-fat, high-protein). lower carbs About the research: The POUNDS LOST Trial 2-year randomized intervention trial 645 participants completed 16% AA, 48% AT, 36% TT 61% were women, 80% were white, 15% were black, 3% were Hispanic, and 2% were Asian or other ethnic groups Participants aged years. Major criteria for exclusion were the presence of diabetes or unstable cardiovascular disease, the use of medications that affect body weight effect of four diets varying in proportions of fat, protein, and carbohydrate on weight loss in overweight or obese subjects References Zhang X, Qi Q, Zhang C, et al. FTO genotype and 2-year change in body composition and fat distribution in response to weight-loss diets: The POUNDS LOST trial. Diabetes 2012; 61: A study testing hypothesisdriven gene diet interaction in randomized diet intervention trial. Huang T1, Qi Q, Li Y, Hu FB, Bray GA, Sacks FM, Williamson DA, Qi L. Am. FTO genotype, dietary protein, and change in appetite: the Preventing Overweight Using Novel Dietary Strategies trial. J Clin Nutr Mar 12 N Engl J Med Feb 26;360(9): doi: /NEJMoa Comparison of weight-loss diets with different compositions of fat, protein, and carbohydrates. Sacks FM1, Bray GA, Carey VJ, Smith SR, Ryan DH, Anton SD, McManus K, Champagne CM, Bishop LM, Laranjo N, Leboff MS, Rood JC, de Jonge L, Greenway FL, Loria CM, Obarzanek E, Williamson DA. 11

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13 The 25% Protein is not a precise number. It is likely a good starting point for you client with the rs AA or AT FTO variant You are going to first want to adjust it based on the type of diet that your patient can stick with. This could mean lowering or increasing the protein level You will of course want to work with them to see what type of healthy proteins will work with their lifestyle You may also want to monitor your patient and see how they do on this diet and adjust the levels up or down if required. For those like Sally in the case example who have an aversion to protein. Find out why do they mistakenly think it s unhealthy or haven t found any tasty options 13

14 Variations at location Rs in the FTO gene affect how a person responds to exercise.[3] People who are TT at this location tend to be normal weight whether or not they exercise. People with AA or AT at this location, however, tend to be overweight if they don t exercise. But that changes when they start exercising! AA or AT people who exercise are less likely to be overweight. This seems to be especially true if they are very active and do aerobic exercise. [4],[5] AT people who are very active may have even a lower chance of being overweight than TT people who are very active. Study by Andreasen et al. 17,508 Danes from five different study groups AA: Greater difference in BMI between AA & TT in inactive group. AT: Very active AT individuals had a lower BMI than TT individuals BMI increases do to global increase in fat mass not abdominal fat mass the impact of the FTO rs genotype on BMI levels was highly influenced by insulin sensitivity. We only noticed a modest FTO rs induced increase in BMI levels among participants with a high insulin sensitivity index, whereas low insulin sensitivity index enhanced the genotype effect, particularly among homozygous A-allele carriers. 19% AA 49% AT 32% TT -- genotype frequencies Meta- Study found: (Kilpeläinen & al.) The odds of obesity for the FTO risk allele were 27% smaller (odds ratio [OR]=1.22 versus 1.30, respectively) and the odds of overweight were 26% smaller (OR=1.14 versus 1.19, respectively) in physically active individuals than in inactive individuals inactive when they had a sedentary occupation and if they reported less than 1 h of moderate-to vigorous leisure-time or commuting PA per week. In studies with continuous data on PA, adults were defined as being inactive when their level of PA was in the lowest sex-specific 20% of the study population concerned. All other individuals were defined as physically active. References Kilpeläinen TO et al. (2011). Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children. PLoS Med 8(11):e Andreasen, et al. Rampersaud E1, Mitchell BD, Pollin TI, Fu M, Shen H, O'Connell JR, Ducharme JL, Hines S, Sack P, Naglieri R, Shuldiner AR, Snitker S. Physical activity and the association of common FTO gene variants with body mass index and obesity. Arch Intern Med Sep 8;168(16): ghrelin and FTO exercise and ghrelin 14

15 Ghrelin is a hormone produced by cells in your stomach. High levels of Ghrelin increase your appetite and are associated with feeling hungry. Normally, levels of Ghrelin decrease after you eat a meal, so that you feel full. Remember, that gene variations in the rs location in the FTO gene can affect how a person responds to exercise. People who are TT at this location tend to be normal weight whether or not they exercise. The Ghrelin levels of people who are TT decrease normally after they eat, making them feel full. AA individuals, on the other hand, who do not exercise tend to be overweight and their Ghrelin levels don t decrease as much after they eat. Exercise, may, however decrease their Ghrelin levels, their appetite and ultimately their weight. Aerobic exercise seems to decrease Ghrelin levels more than strength training. There may be other unknown reasons by exercise helps this group References ghrelin and FTO Karra E et al. A link between FTO, ghrelin, and impaired brain food-cue responsivity. J Clin Invest Aug 1;123(8): exercise and ghrelin Broom DR et al. Influence of resistance and aerobic exercise on hunger, circulating levels of acylated ghrelin, and peptide YY in healthy males. Am J Physiol Regul Integr Comp Physiol Jan;296(1):R

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17 Ghrelin is a hormone produced by cells in your stomach. High levels of Ghrelin increase your appetite and are associated with feeling hungry. Normally, levels of Ghrelin decrease after you eat a meal, so that you feel full. Remember, that gene variations in the rs location in the FTO gene can affect how a person responds to exercise. People who are TT at this location tend to be normal weight whether or not they exercise. The Ghrelin levels of people who are TT decrease normally after they eat, making them feel full. AA individuals, on the other hand, who do not exercise tend to be overweight and their Ghrelin levels don t decrease as much after they eat. Exercise, however, can decrease their Ghrelin levels, their appetite and ultimately their weight. Aerobic exercise seems to decrease Ghrelin levels more than strength training. References ghrelin and FTO Karra E et al. A link between FTO, ghrelin, and impaired brain food-cue responsivity. J Clin Invest Aug 1;123(8): exercise and ghrelin Broom DR et al. Influence of resistance and aerobic exercise on hunger, circulating levels of acylated ghrelin, and peptide YY in healthy males. Am J Physiol Regul Integr Comp Physiol Jan;296(1):R

18 Lisa --gene variations in the rs increased appetite --AA subjects rated high calorie food images and much more appealing than TT subjects post their meal -- 17

19 Lisa --gene variations in the rs increased appetite --AA subjects rated high calorie food images and much more appealing --AA & TT subjects underwent Functional MRI (fmri) measures brain activity by detecting associated changes in blood flow. When an area of the brain is in use, blood flow to that region also increases. --AA subjects displayed different brain activity via fmri in response to viewing high calorie images post meal than TT --Normally the brain response for key brain regions encoding food reward and controlling goal-directed behavior is higher for low calorie foods images post a meal and that is the case for TT --For AA individuals you don t see a higher response for low calorie images ----AA individual subjectively seem to prefer high calorie foods References ghrelin and FTO Karra E et al. A link between FTO, ghrelin, and impaired brain food-cue responsivity. J Clin Invest Aug 1;123(8):

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21 Since aerobic exercise seems to be more effective in decreasing Ghrelin it makes sense to focus on making sure that you client gets enough aerobic exercise. Within reason, the more the better but this really needs to be tailored to the client as it is dependent on what type of program they can stick with. As before you need to monitor the results and adjust if necessary You might also want to consider having your client exercise before larger meals and consider exercising on more days but for a shorter time. You might also want to explore whether they are using food as rewards and exploring alternatives to this. 20

22 Rs SNP also called Pro12ala C allele ---- proline, more common, Pro12 G allele ---- alanine, Ala12 PRO/PRO (CC) GC or GG (Ala12) appear to maintain a more stable body weight than CC (Pro12 carriers) with a greater resistance to weight gain (obesity) but also to weight loss. The PPARG gene appears to influence our weight and is sensitive to the type of diet that we eat. PPARG affects how our body stores and breaks down the fats that we eat. People who are GC or GG at a particular location in the PPARG gene are less likely to be overweight if they eat a Mediterranean style diet. Mediterranean style diets are high in a particular type of fat (MUFA) which is found in foods like olive oil and nuts. CC people, on the other hand, do better on a diet that is low in all fats. Individuals with any of the three variants tend to be lower weight if they follow a diet that is low in saturated fats. Ala12 (G allele) protective against insulin resistance. Study Memisoglu et al study women USA study participants All genotypes (CC, GG, GC) Intake of saturated fat was directly associated with increased BMI among individuals of both genotype classes CC high total fat higher BMI MUFA not associated with BMI homozygous wild-type Pro/Pro (CC) individuals, those in the highest quintile of total fat intake, had significantly higher mean body mass index (BMI) compared with those in the lowest quintile (27.3 versus 25.4 kg/m2, respectively; Ptrend<0.0001) intake of monounsaturated fat was not associated with BMI among homozygous wild-type women (CC) CG or GG High total fat not associated with BMI Higher MUFA lower BMI intake of monounsaturated fat inversely associated with BMI among 12Ala (CG or GG) variant allele-carriers (mean in lowest quintile¼27.6 versus mean in highest quintile¼25.5 kg/m2; P-trend¼0.006; P-interaction¼0.003). whereas among 12Ala variant allele-carriers (GC or CC) there was no significant trend observed between dietary fat intake and BMI (P-trend¼0.99; P-interaction¼0.003). Study (Garaulet et al.) 1465 subjects years from Southern Spain 600 kcal/day less than burn rate per day eaten 1200 to 1800 kcal/day for women and 1500 to 2000 for men GG or GC less obese than CC if follow a >MUFA diet, no significant difference between people with different genotypes on a low MUFA diet weight loss rate (g/wk) was significantly lower in Ala12 carriers as compared to Pro12 Diet: 35% fat (<10% saturated and 20% monounsaturated), 50% carbohydrates and 15 20% protein. Unrestricted amounts of vegetables (a minimum of 200 g/ day), at least g of fruits and to use olive oil as the only cooking fat. They were also encouraged to consume the following foods for lunch: at least 100 g of legumes three times/ wk, 100 g rice once/wk, 100 g wheat and pasta once/wk, and at least 1 day of fish. Recommendations for daily intake of cholesterol and fiber were <300mg and >15 g, References Marta Garaulet, Caren E Smith, Teresa Hernández-González,1 Yu-Chi Lee, and Jose M. Ordovás. PPARγ Pro12Ala interacts with fat intake for obesity and weight loss in a behavioural treatment based on the Mediterranean diet. Mol Nutr Food Res. Dec 2011; 55(12): Memisoglu A et al. (2003). Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass. Hum Mol Genet 12(22): Razquin C et al. (2009). The Mediterranean diet protects against waist circumference enlargement in 12Ala carriers for the PPARgamma gene: 2 years' follow-up of 774 subjects at high cardiovascular risk. Br J Nutr 102(5):672-9 Memisoglu A et al, Interaction between a peroxisome proliferator-activated receptor gamma gene polymorphism and dietary fat intake in relation to body mass. Hum Mol Genet Nov 15;12(22): Epub 2003 Sep

23 People with AA or AG variations in the Plin1 gene are more likely to be resistant to losing weight even when they are on a low calorie diet. What s interesting is, that if they eat a diet high in complex carbs, like fruit, vegetables and whole grains then they are less resistant to losing weight and are, therefore, less likely to be overweight., The opposite is true if they eat a diet low in carbs. Eating lots of simple carbs, on the other hand like donuts and white bread doesn t seem to help these individuals lose weight. Heating a lot of fiber doesn t help either Caren et al study Caribbean origin Hispanics (n = 920, aged y) in Boston. When complex carbohydrate intake was <144 g/d, waist circumference was larger in AA or AG (PLIN 11482G > A carriers (P = 0.024). When complex carbohydrate intake was 144 g/d, waist and hip circumferences were less in AA or AG (PLIN 11482G > Acarriers (P < 0.05). each additional variant allele was associated with an incremental decrease or increase in waist circumference depending on whether complex carbohydrate was high or low, respectively. These interactions were not found for simple sugars or total carbohydrates or fiber 7% AA 39% AG 53% GG Corella D et al study 4,107 subjects (1,909 men and 2,198 women) 64% Chinese, 21% Malays, and 15% Asian Indians AA Women in the highest SFA tertile ( %) had higher HOMA-IR (48% increase; P trend _ 0.006) than women in the lowest ( %) only ;AG or GG noe effect AA Or AG HOMA-IR decreased (_24%; P trend _ 0.046) as carbohydrate intake increased. These effects were stronger when SFAs and carbohydrate were combined as an SFA-to-carbohydrate ratio. This gene-diet interaction was homogeneously found across the three ethnic groups. AA women in the lowest carbohydrate tertile had a 24% higher HOMA-IR score than women in the highest carbohydrate tertile. Perilipin: protein found in adipocytes fat cells, store energy as fat plays a central role in lipid storage and breakdown, adipocyte metabolism, and body fat accumulation. At a basal state, perilipin protects the lipid core from lipases (e.g. hormonesensitive lipase and adipocyte TAG lipase) by sequestering the enzymes from the lipid droplet surfaces(2). However, once phosphorylated, perilipin allows or even recruits lipases to access lipid droplets(2), and hence causes active lipolysis References: Corella D et al. Perilipin gene variation determines higher susceptibility to insulin resistance in Asian women when consuming a high-saturated fat, low-carbohydrate diet. Diabetes Care Jun;29(6): (1) Caren E. Smith et al. Perilipin Polymorphism Interacts with Dietary Carbohydrates to Modulate Anthropometric Traits in Hispanics of Caribbean Origin J Nutr. Oct 2008; 138(10): Corella et al. Obese subjects carrying the 11482G>A polymorphism at the perilipin locus are resistant to weight loss after dietary energy restriction. J Clin Endocrinol Metab Sep; 90(9):

24 A significant amount of starch digestion occurs in the mouth during mastication. For example, blood glucose levels have been shown to be significantly higher when highstarch foods such as corn, rice, and potatoes (but not apples) are first chewed and then swallowed, rather than swallowed directly Salivary amylase persists in the stomach and intestines after swallowing thereby augmenting the enzymatic activity of pancreatic amylase in the small intestine. Higher AMY1 copy number and a concomitant increase in salivary amylase protein level are therefore likely to improve the efficiency with which high-starch foods are digested in the mouth, stomach, and intestines Those with a low copy number <4 had an 8X increased risk of obesity to those with high copy number >9 Might have even a greater affect than FTO gene Higher copy number in higher starch pops like US & Japan and lower in pops like rainforest tribes who eat mainly protein and low starch carbs Interestingly enough animals like chimpanzees who don t eat a lot of starch have low copy number of AMY1 References:

25 Look at multiple genes: a gene panel must look at multiple genes and what the aggregate results are of these genes. For the panel we are creating we will do that assessment for you. Context: As I have mentioned a number of times you need to continue to do what you are already doing and look at any test results in context to what has been working and what might work for a client and their particular lifestyle. Moderation: If you look at most of the research they are getting results with moderate rather than extreme diets which probably doesn t surprise you Monitor and adjust: You will likely need to monitor and adjust the macronutrient ratios and exercise plan based on the results that your client gets. Healthy principals still apply: Regardless of the results, healthy eating is healthy eating. This as you are already doing needs to be stressed with your clients. 24

26 Reassure: People often feel guilty about being overweight. You can help make them feel better and reassure them that there may be genetic factors that could be making it more difficult for them to lose weight. Empower: But what can be empowering is the knowledge that they can work with their genes rather than against them. Experiment: If your client is not interested in testing and is having difficulties losing weight then you might want to experiment with macronutrient ratios if you are not already doing so. For example, try a high fat, Mufa diet for a couple of weeks and see how they respond. Then switch to another alternative if they don t respond. Test: The other option is of course to do a DNA test. 25

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