Using Genetics for Personal Nutritional Guidance Martin Kohlmeier, MD, PhD

Transcription

1 Using Genetics for Personal Nutritional Guidance Martin Kohlmeier, MD, PhD University of North Carolina at Chapel Hill Department of Nutrition and UNC Nutrition Research Institute

2 Disclosures AFFILIATION/FINANCIAL INTERESTS (prior 12 months) Grants/Research Support: Scientific Advisory Board/Consultant: Speakers Bureau: Stock Shareholder: Other CORPORATE ORGANIZATION NIH, Metagenics Inc None None None None

3 Objectives After this presentation you will be able to - explain how to assess the utility of a nutrigenetic variant - minimize adverse consequences of genetic information - use at least 5 high-utility nutrigenetic variants in practice

4 Nutrigenetics is the science of inherited nutritional individuality

5 What is nutrigenetics good for? Many nutrition interventions are only effective when they are targeted at responders

6 What is nutrigenetics good for? Knowing about the existence of genetically diverse responses to dietary interventions helps to see patients and clients as the individuals they are.

7 Where is nutrigenetic heterogeneity coming from? Some genetic adaptations that increase disease resistance cause food intolerance as an indirect effect. Example: G6PDH deficiency confers both malaria resistance and high sensitivity to broad beans (favism).

8 Where is nutrigenetic heterogeneity coming from? Humans have inhabited diverse nutritopes throughout history and have adapted to new food patterns. Xhosa in South Africa Arabs in Oman Vikings on Atlantic Islands LCT -14,010 C LCT -13,915 G LCT -13,910 T Small changes in the lactase gene of these people sustain enzyme expression into adulthood. This adaptation helped them to consume lots of milk and survive in environments with otherwise sparse food supplies.

9 Why you want to know about this: Lactose intolerance often mimics the symptoms of inflammatory bowel disease. You can use predictive genetic assessment to improve dietary guidance. The normal state (65-70% world-wide) is loss of lactase expression after infancy. Pastoral populations have evolved variants in the upstream enhancer region causing persistent expression in adulthood. The effects of the diverse persistence alleles are dominant T in more than 80% of Europeans G in more than 50% of Kuwaitis A in Xhosa, Brazilians G in Somalis C in Kenyans, Tanzanians

10 Evaluation of genetic information Ethical, legal and social implications Analytical validity Clinical validity Clinical utility Foundation for Blood Research/CDC, 2004

11 Clinical utility of genetic information Clinical utility 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 testing as well as the implications for health outcomes. Secretary s Advisory Committee on Genetic Testing, 2008

12 Clinical utility of genetic information Clinical utility 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 testing as well as the implications for health outcomes. Secretary s Advisory Committee on Genetic Testing, 2008 Clinical utility = net benefit

13 Utility of genetic information In how many cases is the outcome better with the information than without it?

14 Utility of genetic information In how many cases is the outcome better with the information than without it? Outcome is the balance of benefits and harms

15 A brief digression about nutrigenetic harms

16 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

17 How to reduce harms By eliminating exposure to genetic information

18 How to reduce harms By eliminating exposure to genetic information Patients and clients need nutrition guidance, not DNA sequence data!

19 Using anonymized information in practice by working with a healthcare professional who provides guidance without disclosing the information with an online meal planning tool that is self-administered fully anonymized (double masking)

20 Utility of genetic information In how many cases is the outcome better with the information than without it?

21 Utility of genetic information In how many cases is the outcome better with the information than without it? Outcome is the balance of benefits and harms

22 Utility of genetic information In how many cases is the outcome better with the information than without it? Outcome is the balance of benefits and harms The balance is better with fewer harms

23 How then can we assess clinical utility? By estimating the net benefit of genetic information

24 Case Study: Folate intake and homocysteine 15 Homocysteine (µmol/l) RDA Dietary Folate Equivalents (µg/day)

25 Case Study: Folate intake and homocysteine 15 Homocysteine (µmol/l) 10 MTHFR 677TT MTHFR 677CC RDA 2xRDA Dietary Folate Equivalents (µg/day) 677CT 677CC 677TT

26 Case Study: Folate intake and homocysteine 15 RDA 2xRDA Homocysteine (µmol/l) 10 MTHFR 677TT MTHFR 677CC D Hcys 3.04 µmol/l 0.64 µmol/l D MI risk stroke risk -15 % -24 % - 3 % - 5% Dietary Folate Equivalents (µg/day) 677CT 677CC 677TT Data from Ashfield-Watt et al. Am J Clin Nutr 2002;76:

27 Case Study: Folate intake and homocysteine 15 RDA 2xRDA Homocysteine (µmol/l) 10 MTHFR 677TT MTHFR 677CC D Hcys 3.04 µmol/l 0.64 µmol/l D MI risk stroke risk -15 % -24 % - 3 % - 5% 5 Prevention potential: Screen 10,000 middle-aged men, adapt recommendation for 1000, to prevent about 1-2 events per year. Additional benefits are likely CT 677CC Dietary Folate Equivalents (µg/day) Prevalence Benefit TT

28 Case Study: Folate intake and homocysteine What you want to do in practice: Guide individuals with two MTHFR 677 T alleles (rs TT) to get at least 600 µg dietary folate equivalents.

29 Case Study: Folic acid and breast cancer Breast Cancer Odds Ratio DHFR 19del+/+ 52% increase in breast cancer risk 5% decrease in breast cancer risk DHFR 19del-/- Prevention potential: Screen 1000 women, adapt recommendation for 200, prevent breast cancer in 6-7. No Yes 19-/+ 19-/- Multivitamin Use Prevalence Benefit /+ Based on data from Xu et al. AJCN 2007;85:

30 Case Study: Folic acid and breast cancer What you want to do in practice: Guide women with a DHFR 19 bp del allele to get generous amounts of folate from plant sources and avoid supplements and fortified foods with folic acid.

31 Case Study: Calcium and bone health Absorbed calcium, mg (estimated) RDA 1.5 * RDA D absorbed calcium VDR bb VDR BB 92 mg 90 mg Prevention potential: Too small for meaningful estimate bb bb Calcium intake (mg/day) Prevalence Benefit BB Data from Dawson-Hughes et al. J Clin Endocrinol Metab 1995;80:

32 Case Study: Calcium and bone health Change in femoral neck BMD (% per yr) 1 VDR bb RDA VDR BB Prevention potential: Outcome different only when well below current intake recommendation bb bb Calcium intake (mg/day) Prevalence Benefit BB Data from Krall et al. J Bone Min Res 1995;10:

33 Case Study: Calcium and bone health What you want to do in practice: Do not use the VDR B allele (rs A) to suggest higher vitamin D intake to carriers.

34 Case Study: Calcium and colorectal cancer 2.0 Odds Ratio CR cancer risk >1129 Calcium intake (mg/day) Based on data from Dai et al. AJCN 2007;86:

35 Case Study: Calcium and colorectal cancer 2.0 Odds Ratio CR cancer risk 1.0 TRPM7 A G = 1482T A = 1482 I TRPM7 GG AG GG >1129 Calcium intake (mg/day) GG Based on data from Dai et al. AJCN 2007;86:

36 Case Study: Calcium and colorectal cancer 2.0 Odds Ratio CR cancer risk 1.0 G = 1482T A = 1482 I TRPM7 A TRPM7 GG Potentially a 82% decrease in CR cancer risk AG GG >368 Magnesium intake (mg/day) Prevalence Benefit GG Based on data from Dai et al. AJCN 2007;86:

37 Case Study: Minerals and colorectal cancer What you want to do in practice: Guide carriers of a TRPM7 A allele (rs A) to keep their Ca/Mg ratio below 2.5

38 Case Study: Coffee and myocardial infarction Odds Ratio risk of myocardial infarction 1 cup 2-3 cups D MI risk *(CYP1A2*1F) -36 % ± 0 % 0.5 CYP1A2*1A < Prevention potential: Screen 2200 middle-aged men, adapt recommendation for 1000, to prevent 2-4 MI per year. Additional benefits are possible. Coffee consumption (cups per day) Prevalence Benefit 0.1 "slow" "fast" Data from Cordelis et al. JAMA 2006;295:

39 Case Study: Coffee and myocardial infarction What you want to do in practice: Guide men with a CYP1A2*1F allele (rs C) to caffeine intakes of less than 200 mg/day

40 Case Study: PUFA and cardiovascular health Carotid intima-media thickness (µm) 800 ALOX5 var RDA total w3 ~500 mg/1000 kcal 100 g (3.5 oz) salmon/week provides about mg/1000 kcal 600 ALOX5 W Prevention potential: Equal benefits at RDA level intake? Higher than average risk for variant carriers who don t eat fish variant EPA+DHA intake (mg/1000 kcal) Prevalence Benefit W Data from Dwyer et al. New Engl J Med 2004;350:

41 Essential fats Case Study: PUFA and cardiovascular health Carotid intima-media thickness (µm) ALOX5 W ALOX5 var Average intake ~65 mg/1000 kcal Reducing daily meat intake by 4 oz or eating one egg less typically reduces AA intake by about mg/1000 kcal. Prevention potential: The effect on artery thickness of decreasing AA intake from high to average may be comparable to that of smoking cessation or curing diabetes variant Arachidonic acid intake (mg/1000 kcal) Prevalence Benefit W Data from Dwyer et al. New Engl J Med 2004;350:

42 Case Study: PUFA and cardiovascular health What you want to do in practice: Guide carriers of an ALOX5 indel variant to limit arachidonic acid intake (meat/eggs) to less than 65 mg/day (4 oz meat or one large egg contain mg arachidonic acid)

43 Case Study: Saturated fat and obesity 30 ApoA2-265 T BMI (kg/m 2 ) BMI difference of ApoA2-265 CC 20 Prevention potential: Screen 1,000 people, adapt recommendation for 150, prevent pounds weight gain in more than half of them Saturated Fat (g/day) Prevalence Benefit -265CT -265CC -265TT Based on data from Corella et al. Arch Int Med 2009;169:

44 Case Study: Saturated fat and obesity What you want to do in practice: Guide carriers of two APOA2 alleles C (rs5082 CC) to limit their saturated fat intake to less than 12 g/day

45 Case Study: Choline and organ dysfunction Response to choline intake % of men developing signs of organ dysfunction MTHFD1 1958GA/AA 25 MTHFD1 1958GG GG Daily choline intake (mg/kg) AG/AA Data from Kohlmeier et al. PNAS 2005;102:

46 Case Study: Choline and organ dysfunction What you want to do in practice: Guide men with an MTHFD1 A allele (rs A) to get about 800 mg choline per day

47 Some genes for tailoring nutrition guidance IL6 UCP1 UCP3 FABP2 LCT ADH1B ALDH2 CYP1A2 ADORA2A MTHFD1 PEMT F2 F5 AGT ADD1 GRK4 GSTM1 SEP15 ALOX5 CETP FADS1 FADS2 OTC GFOD2 CYP4F2 VDR GC FUT2 TCN2 HP COX2 MTHFR DHFR PTGS2 MGMT CASR GSTP1 UGT1A1 PON1 ALPL SIRT1 ESR2 HFE TMPRSS6 SLC40A1 HAMP NAT1 NAT2 XPC TRPM7 CUBN SLC23A1 SLC23A2 PLA2G4A XRCC1 MPO MTP MnSOD CD36 PAPOLG TAS2R38 TAS2R50 TAS1R3 TAS1R2 TAS2R3 TAS2R4 TAS2R5 TAS2R5 TAS2R19 [OR10A2] HLA-DQA1 HLA-DQB1 OR2M7 CFTR APOA2 PLIN CLOCK TCF7L2 PNPLA3 FTO MC4R TFAP2B FABP2 PPARG ADRB2 ADRB3 TNFA IRS1 AMY1 SLC30A3

48 Information overload? Laboratory Client

49 Personalized Online Nutrition Guidance (PONG) How can genetic information be used in practice? with an online meal planning tool that is self-administered fully anonymized (double masking) based on individual intake targets

50 The first step is to look at potential meal plans. The traffic-light color code indicates how close the match is.

51 Users can develop alternative meal plans for their personal intake targets.

52 Each meal item can be deleted or replaced. Other foods can be added. The traffic-light color code always indicates how close the match will be.

53 Nutrition details of every meal item can be viewed. External links provide recipe details for many items.

54

55 Final comments Intervention effects in genetic subgroups are easily obscured by the lack of significant response of the majority. Many dietary interventions are only effective, if they are targeted to genetically susceptible individuals. The likely effect size of some genotype-specific interventions is as large as that of medical treatments.

56

57 9 th Annual Congress of the International Society for Nutrigenetics and Nutrigenomic Chapel Hill, May 17-19, 2015 Register soon, space is limited!

58