Riboflavin to lower blood pressure, a targeted nutrition approach

Transcription

1 Riboflavin to lower blood pressure, a targeted nutrition approach Mary Ward RD, PhD Northern Ireland Centre for Food & Health (NICHE) / The Nutrition Society (UK) ulster.ac.uk

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3 Outline Background: Hypertension / MTHFR Role of a novel gene-nutrient interaction RCT evidence Population based evidence Potential for impact / translation Take home messages

4 Mortality due to global risk factors Attributable Deaths in Thousands High Blood Pressure Lopez et al Lancet 367,

5 Hypertension The major risk factor for CVD and stroke in particular Defined as a blood pressure (BP) of greater than 140/90 mmhg Multiple lifestyle, nutritional and genetic factors known to affect BP Antihypertensive drugs are highly effective yet hypertension remains a global problem Dietary approaches to lower BP Weight loss; salt reduction; DASH diet; alcohol

6 Nutrition and Lifestyle factors targeted to reduce BP Lifestyle factor SBP decrease (mmhg) Weight loss (per 10 kg) 5-20 Physical activity 4-9 Sodium reduction 2-8 Limit alcohol 2-4 Modified from Chobanian et al JNC 7 report

7 Newton-Cheh C, Johnson T, Gateva V et al. (2009) Nat Genet 41,

8 One Carbon 1-Carbon metabolism Metabolism

9 MTHFR 677C T Polymorphism Polymorphic mutations in MTHFR: MTHFR 677C T Polymorphism C to T substitution at base pair 677 Alanine/valine change in the amino acid sequence Functionally defective enzyme Homozygosity (TT genotype) results in lower MTHFR enzyme activity and increased homocysteine concentrations in vivo Meta-analyses 1-4 estimate excess risk of CVD (by 14-21%) risk in individuals with the TT genotype, but large geographical variation between countries 1 Wald DS et al. BMJ 2002;. 2 Klerk et al. JAMA 2002; 3 Lewis et al. BMJ 2005; 4 Holmes et al. Lancet 2011

10 MTHFR 677TT genotype frequency Wilcken et al J Med Genet 40,

11 Genotype-specific response to riboflavin Mean homocysteine (µmol/l) CC (n = 27) CT (n = 26) TT (n = 34) Baseline Riboflavin 1.6mg/d 12 weeks After intervention * McNulty et al Circulation 113(1), 74-80

12 MTHFR 677TT genotype and hypertension Meta-analysis of 20 studies ; 4461 participants OR 1.87 (95% CI ); P=0.001 Niu WQ, You YG, Qi Y. (2012) J Hum Hypertens. 26,

13 SBP (mmhg) DBP (mmhg) This Role gene-nutrient of this gene-nutrient interaction interaction may have in BP a 145 b 90 b Pre 140 ab a a * 80 a * CC CT TT CC CT TT Horigan et al Journal of Hypertension; 28:

14 SBP (mmhg) DBP (mmhg) Role of this gene-nutrient interaction in BP 145 b 90 b Pre 140 ab Post a a * 80 a * CC CT TT CC CT TT Horigan et al Journal of Hypertension; 28:

15 SBP (mmhg) Baseline systolic BP by MTHFR genotype p=0.002 b p=0.009 b a ab a a CC CT 125 TT Differences between genotype groups at each time point determined by 1-way ANOVA and Tukey post hoc test (p<0.05) Wilson et al, 2012 AJCN

16 Systolic BP response in patients with the TT genotype Wilson et al, 2012 AJCN

17 Hypertensive cohort of TUDA Screened for the MTHFR 677C T polymorphism (n=1427) Hypertensive patients identified as having the MTHFR 677TT genotype (n=157) Participants stratified by systolic BP and randomised to treatment group (n=91) Deceased =1 Not contactable=12 Declined to participate=37 Failed to meet inclusion criteria = 16 Riboflavin 1.6 mg/d (n=46) Week 0 Placebo (n=45) Dropouts (n=2) Dropouts (n=1) Riboflavin (n=44) Week 16 Placebo (n=44) Completed (n=88) Flow diagram of study design and completion rates

18 Systolic BP (mmhg) Diastolic BP (mmhg) BP Response to Intervention Pre Post P= P= * Placebo Riboflavin 1.6mg/d Placebo Riboflavin 1.6mg/d Time x treatment interaction (repeated measures ANOVA) * Statistical significance (p<0.05) Wilson et al Hypertension

19 Responses of riboflavin and systolic BP to intervention with riboflavin (1.6 mg/d for 16 weeks) or placebo in patients with the MTHFR 677TT genotype Wilson et al, Hypertension 2013

20 % Participants achieving Goal BP Response to Intervention GOAL BP P= Placebo Riboflavin Statistical significance (p<0.05) determined by chi-square

21 Modified from Chobanian et al JNC 7 report Lifestyle factors targeted to reduce BP Lifestyle factor SBP decrease (mmhg) Weight loss (per 10 kg) 5-20 Riboflavin (genotype-specific) 6-13 Physical activity 4-9 Sodium reduction 2-8 Limit alcohol 2-4

22 Study design: combined TUDA and NANS studies NANS study (n 1500) TUDA study (n 5205) Excluded: Taking B-vitamin supplements (n 226) MTHFR genotype unavailable (n 348) Cognitive cohort (n 1703) Hypertensive cohort (n 2100) Bone cohort (n 1402) Excluded: Taking B-vitamin supplements (n 792) MTHFR genotype unavailable (n 113) Available NANS sample (n 925) Available TUDA sample (n 4300) Combined NANS and TUDA cohorts (n 5225) MTHFR genotype CC (n 2350) CT (n 2261) TT (n 615) Figure 1. Flow diagram of study design; 1 National Adult Nutrition Survey of Ireland; 2 Trinity, Ulster, Department of Agriculture cohort study; 3 CC (wild type), CT (heterozygous) TT (homozygous) genotypes for the MTHFR 677C T polymorphism.

23 Systolic BP (mmhg) Effect of MTHFR genotype on BP by age (n 6148) CC CT TT Age by decile Reilly et al unpublished

24 Hazard ration (95% CI) Gene-Nutrient interaction and risk of hypertension 3,5 3 2,5 2 High Riboflavin Low Riboflavin 1,5 1 0,5 Non TT TT MTHFR C677T genotype Reilly et al unpublished

25 Impact

26 Cardiovascular Mortality Risk CVD mortality risk increases as BP rises x 2x 115/75 135/85 155/95 175/105 Systolic/Diastolic Blood Pressure (mmhg) 8x Lewington S et al. Lancet 2002;360: Chobanian AV et al. JAMA 2003;289:

27 Impact of BP reduction Meta-analysis of 61 prospective, observational studies including over 1 million adults 1 2 mmhg decrease in SBP 10% reduction in risk of stroke mortality Potential public health significance of this genenutrient interaction on BP Lewington et al Lancet; 360:

28 Nutrition and Lifestyle factors to reduce BP Lifestyle factor SBP decrease (mmhg) Weight loss (per 10 kg) 5-20 Riboflavin (genotype-specific) 6-13 Physical activity 4-9 Sodium reduction 2-8 Limit alcohol 2-4 Modified from Chobanian et al JNC 7 report

29 Attitude of General Practitioners to riboflavin as a treatment for hypertension P= <0.000

30 Riboflavin Status: Global Picture Author Location AGE (yrs) N= EGRAC Intake (mg/d) Developing Countries Boisvert et al Barnouin et al Developed Countries Horigan et al Bailey et al Rai et al Shi et al Guatemala > Cuba % EGRAC > % EGRAC >1.6 Havana:1.65 Guantanamo:1.45 N.Ireland UK Developed and Developing Countries Whitfield et al Men 1.33 Women 1.32 Havana 0.85 Guantanamo: 1.02 Men: 1.87 Women: 1.69 USA China > Cambodia and Vancouver Cambodia 1.80 Vancouver 1.37

31 Riboflavin Status NANS (n=1130) 36% 23% 41% Young Canadians (n=51) TUDA (n=5192) 29% 19% 52% Elderly Canadians (n=226) Adequate ( 1.30) Suboptimal ( ) Deficient ( 1.40) 38% 33% 25% 29% 14% 61% Cambodia, urban (n=146) 13% 9% Cambodia, rural (n=156) 9% 10% 78% 81%

32 Take-home messages The MTHFR 677TT genotype is a risk factor for hypertension and is associated with higher (compared with non-tt) BP across the life cycle Riboflavin can play an important role in prevention and treatment of hypertension specifically in people with the TT genotype Independent of current antihypertensive therapy Potential for a personalised approach Future work Mechanistic studies Confirmation of these findings in other populations Effect of higher doses

33 Helene McNulty Sean Strain Kristina Pentieva Catherine Hughes Leane Hoey Liadhan McAnena Anne Molloy John Scott Tim Green Angela Devlin Adrian McCann PhD students Paula Tighe Geraldine Horigan Carol Wilson Eamon Laird Rosie Reilly Emma Hughes Amy McMahon PhD student Kyly Whitfield The TUDA and JINGO project teams

34 Riboflavin Sources Source mg/average serving Milk 0.45 Yoghurt 0.35 Egg 0.26 Fortified Breakfast Cereal 0.22 Spinach 0.21 Beef (cooked roast) 0.15 Cheddar Cheese 0.11 Bread (Whole-wheat/White)