Nutrigenetics and Nutrigenomics in Clinical Research and Practice

Nutrigenetics and Nutrigenomics in Clinical Research and Practice Mar$n Kohlmeier, MD, PhD University of North Carolina at Chapel Hill Department of Nutri7on and UNC Nutri7on Research Ins7tute mkohlmeier@unc.edu

Outline NGx lessons for clinical research Analyzing study data Op$mizing study design Applica$ons for clinical prac$ce U$lity in prac$ce Some genotype- nutrient interac$ons Nutri$on guidance

Applica$on in Clinical Research

Application in clinical research Analyzing study data Jacob et al., J Nutr 1994

Application in clinical research Analyzing study data Jacob et al., J Nutr 1994

Application in clinical research Statistical analysis 5 0 n 0 0>4 4>8 8>12 12>16 >16

Application in clinical research Design and analysis Controlled feeding trial of 126 adults for 4 months at four folate intake levels % change of Hcys levels 0-5 226 282 660 814 µg DFE Intakes - 10 CC - 15-20 - 25 CT TT MTHFR Genotypes - 30-35 Ashfield-Watt et al., Am J Clin Nutr 2002

Application in clinical research Optimizing study design TT prevalence is 10-30% Lakoff et al., Am J Clin Nutr 2015

Application in clinical research Optimizing study design Lakoff et al., Am J Clin Nutr 2015

Application in clinical research Optimizing study design It might have been bexer to select par$cipants with the same PCFT rs2239907 genotype (minor allele frequency 0.33) since blood was the targeted compartment. Intes$ne Blood Cytosol

Application in clinical research Design and analysis Key point: Once a gene$cally heterogeneous response has been credibly observed, from then on it cannot be ignored.

Applica$ons for Clinical Prac$ce

Applications for clinical practice Evalua$on of gene$c informa$on Before a gene$c test can be generally accepted in clinical prac$ce, data must be collected to demonstrate the benefits and risks that accrue from both posi$ve and nega$ve results. Final Report of the Task Force on Gene$c Tes$ng: Promo%ng Safe and Effec%ve Gene%c Tes%ng in the United States Na7onal Ins7tutes of Health- Department of Energy Working Group on Ethical, Legal and Social Implica7ons of Human Genome Research, September 2007

Evaluation of genetic information Analy7cal validity (is the result correct) Clinical validity (sensi7vity/specificity) Clinical u7lity (is it worth it) Founda7on for Blood Research/CDC, 2004

Evaluation of genetic information Clinical u$lity of gene$c informa$on Clinical u7lity takes into account the impact and usefulness of the test results to the individual, the family, and society. The benefits and risks to be considered include the psychological, social, and economic consequences of tes7ng as well as the implica7ons for health outcomes. Secretary s Advisory Commi]ee on Gene7c Tes7ng, 2008

Evaluation of genetic information Clinical u$lity of gene$c informa$on Clinical u7lity takes into account the impact and usefulness of the test results to the individual, the family, and society. The benefits and risks to be considered include the psychological, social, and economic consequences of tes7ng as well as the implica7ons for health outcomes. Secretary s Advisory Commi]ee on Gene7c Tes7ng, 2008 Clinical u$lity = net benefit

Evaluation of genetic information U$lity of gene$c informa$on In how many cases is the outcome better with the information than without it? Outcome is the balance of benefits and harms

Evaluation of genetic information A brief digression about nutrigenetic harms Such harms are mostly related to Expenditures and opportunity costs Misguided use of risky therapies Psychological and social burdens Insurance and employment risks

Evaluation of genetic information How to reduce harms By elimina$ng exposure to gene$c informa$on benefits and harms

Evaluation of genetic information How to reduce harms By elimina$ng exposure to gene$c informa$on Pa$ents and clients need nutri$on guidance, not DNA sequence data!

Evaluation of genetic information How to reduce harms By protec$ng sensi$ve gene$c informa$on In many cases it is best not to record gene$c informa$on in pa$ent files because privacy cannot be ensured.

Prac$ce- ready Examples

Practice-ready examples Case Study: Folate intake and homocysteine 15 RDA 2xRDA Homocysteine (µmol/l) 10 MTHFR 677TT MTHFR 677CC Δ Hcys 3.04 µmol/l 0.64 µmol/l Δ MI risk stroke risk - 15 % - 24 % - 3 % - 5% 5 200 400 600 800 Dietary Folate Equivalents (µg/day) 677CT 677CC 677TT

Practice-ready examples Case Study: Folate intake and homocysteine What you want to do in prac%ce: Guide individuals with two MTHFR 677 T alleles (rs1801133 TT) to get at least 600 µg dietary folate equivalents.

Case Study: Folic acid and breast cancer Practice-ready examples Breast Cancer Odds Ra$o 1.5 1.0 DHFR 19del+/+ 52% increase in breast cancer risk 5% decrease in breast cancer risk DHFR 19del- /- No Yes Mul$vitamin Use 19-/+ 19-/- 19+/+ Based on data from Xu et al. AJCN 2007;85:1098-1102

Case Study: Folic acid and breast cancer Practice-ready examples What you want to do in prac%ce: Guide women with a DHFR 19 bp del allele to get generous amounts of folate from plant sources and avoid supplements and for$fied foods with folic acid.

Practice-ready examples Case Study: Coffee and myocardial infarction Odds Ra$o risk of myocardial infarc$on 1 cup 2-3 cups Δ MI risk 1.5 1.0 2*(CYP1A2*1F) - 36 % ± 0 % 0.5 CYP1A2*1A <1 1 2-3 4+ Preven$on poten$al: Screen 2200 middle- aged men, adapt recommenda$on for 1000, to prevent 2-4 MI per year. Addi$onal benefits are possible. "slow" "fast" Coffee consump$on (cups per day) Data from Cordelis et al. JAMA 2006;295:1135-1141 Prevalence Benefit 0.1 0.01 0.001

Practice-ready examples Case Study: Coffee and myocardial infarction What you want to do in prac%ce: Guide men with a CYP1A2*1F allele (rs762551 C) to caffeine intakes of less than 200 mg/day

Case Study: Saturated fat and obesity Practice-ready examples 30 ApoA2-265 T BMI (kg/m 2 ) BMI difference of 2.1 25 ApoA2-265 CC 20 Preven$on poten$al: Screen 1,000 people, adapt recommenda$on for 150, prevent 12-14 pounds weight gain in more than half of them. 10 20 30 40 Saturated Fat (g/day) Prevalence Benefit -265CT -265CC -265TT Based on data from Corella et al. Arch Int Med 2009;169:1897-1906 0.1 0.01 0.001

Case Study: Saturated fat and obesity Practice-ready examples What you want to do in prac%ce: Guide carriers of two APOA2 alleles C (rs5082 CC) to limit their saturated fat intake to less than 12 g/day

Nutri$on Guidance

Nutrition guidance Assessment Targets Planning

Nutrition guidance Assessment Targets Planning Age Gender Weight Height Exercise Condi7ons Medica7ons. Gene7cs Diet pa]ers Food groups Macronutrients Fats Minerals Micronutrients Bioac7ves Behavioral Change (limit snacking) General guidelines (eat more vegetables) Specific direc7ons (limit to 1 cup of coffee) Meal plans and 7ps Dietary supplements (300 IU Vitamin E)

So far, so good, now they know the targets Nutrition guidance DNA Gene$cs Targets Client Lab Website Die$$an

Let the personal nutri$on counseling begin Nutrition guidance Nutri$on guidance DNA Gene$cs Targets Client Lab Website Die$$an

Now the difficult part: making food choices Nutrition guidance Nutri$on guidance DNA Gene$cs Targets Client Lab Website Die$$an

Nutrition guidance Genotype- specific Gluten- free Lactose- free Vegetarian Vegan Low- Carb

Nutrition guidance A version for mobile devices Also provides plans for gluten- free, lactose- free, vegetarian and vegan combina$ons

Ques$ons?