Tuberculosis Pharmacogenetics

Lead Research Organisation: MRC Unit, The Gambia

Abstract

There is evidence to suggest that inherited factors play a part in determining the response to treatment for TB. We will study whether variation in one gene NAT2, predicts treatment response in the largest study of its kind yet conducted.

Technical Summary

This study aims to relate genetic variation in NAT2, a gene involved in the metabolism of isoniazid to response to treatment for tuberculosis. A fine density SNP assay will be designed to capture genetic variation in NAT2 and genotype and haplotype will be related to response to treatment measured by reversion of Elispot responses to TB antigens ESAT6 and CP10. There have been several studies on adverse effects related to NAT2 genotype but none has yet demonstrated effects on treatment outcome. The study will be conducted in TB case contacts treated with isoniazid alone.

Publications

10 25 50

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Griffiths C (2012) Need to test impact of DNA-based risk scores in Thorax

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Grigg J (2017) Urinary prostanoids in preschool wheeze. in The European respiratory journal

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Jolliffe DA (2016) Environmental and genetic determinants of vitamin D status among older adults in London, UK. in The Journal of steroid biochemistry and molecular biology

 
Description Assessor for European Commission calls Global Alliance for Chronic Diseases. Prevention and treatment of lung diseases
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Assessor for European Commission. SC1-PM-10-2017 Comparing the effectiveness of existing healthcare interventions in the adult population. SC1-PM-08-2017 New therapies for rare diseases
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
 
Description Informing NICE guidance on expanding role of the pharmacist
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
URL https://www.nice.org.uk/guidance/indevelopment/gid-ng10008
 
Description Asthma UK Centre for Applied Research. £2,000,000. Programme 2: How do we help people with asthma to treat and manage their symptoms, and maximise the benefits they get from treatment?
Amount £2,000,000 (GBP)
Organisation Asthma UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2013 
End 08/2018
 
Description EDCTP PhD Studentship Louis-Marie Yindom
Amount £60,000 (GBP)
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 05/2005 
End 05/2009
 
Description In practice Fellowship
Amount £100,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 03/2017 
End 04/2021
 
Description Investigating the impact of London's Ultra Low Emission Zone on children's respiratory health
Amount £2,979,366 (GBP)
Organisation Public Heath Research (PHR) Progrmame 
Sector Charity/Non Profit
Country Unknown
Start 03/2018 
End 05/2023
 
Description NIHR Global Health Research
Amount £1,998,507 (GBP)
Funding ID 17/63/38 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 09/2018 
End 07/2021
 
Description NIHR Programme Chronic viral hepatitis in ethnic minorities. Strategies to prevent the predicted increase in mortality. Co Applicant
Amount £2,199,373 (GBP)
Funding ID RP-PG-1209-10038 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 08/2012 
End 08/2018
 
Description e-cigaretes for smoking cessation in pregnancy- a randomised controlled trial
Amount £1,671,212 (GBP)
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start 07/2017 
End 08/2021
 
Title Database of West African NAT2 variants 
Description 171 DNA samples typed by sequencing for NAT2 polymorphisms with clinical outcomes of treatment with isoniazid for latent TB. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Used for a study on elispot reversion following isoniazid treatment. Paper is currently under preparation. 
 
Title Complex intervention to promote uptake of the NHS Smoking Cessation Service in Community Pharmacies 
Description Background Smoking causes more than 100,000 deaths annually in the UK and is a major preventable cause of heart disease, stroke, chronic respiratory disease and cancer. [1] In East London the health burden from tobacco is high: 47% of residents smoke and 22% of deaths in Tower Hamlets are due to tobacco compared to 18% in London overall. [2] Importantly, a smoker who stops smoking at age 30 is likely to live as long as someone who has never smoked. [3] Thus smoking cessation is a major public health priority.[4] Pharmacists are an important and easily accessible front line service for NHS primary care. Pharmacy staff have contact with healthy people, those who are ill, young people and those less likely to attend more formal healthcare settings. NHS policy is to strengthen primary care delivery through the pharmacies. [5] Smoking cessation was one of the first clinical areas taken up by pharmacists and 35,000 quit attempts occur in pharmacies in London each year. [6] To date however there has been very little research to find the best ways of helping people to stop smoking in this setting and while a large proportion of service users quit, a significant number do not after passing through the pharmacy Stop Smoking programme. We aim to increase capacity of the pharmacy based Stop Smoking service by designing and testing a new training programme to build on pharmacists' consultation skills and knowledge, aiming to increase the numbers of smokers enrolling and staying in the Stop Smoking programme and successfully quitting. Allender, S., et al., The burden of smoking related ill health in the UK. Tob Control, 2009. 18(4): p. 2627. Anon, Tower Hamlets Primary Care Trust Annual Report. 2008. Peto, R., et al., Smoking, smoking cessation, and lung cancer in the UK since 1950: combination of national statistics with two case control studies. BMJ, 2000. 321(7257): p. 3239. Anon, Consultation on the future of tobacco control. 2008: Department of Health. Anon. Pharmacy based stop smoking services: optimising commissioning. NHS employers, London, 2009 Anon, Statistics on NHS Stop Smoking Services: England, April 2008 to March 2009, in NHS Information Centre. 2010, Health and Social Care Lifestyles Statistics. Research Plans PHASE 1: A Cochrane systematic review and meta-analysis of studies on changing health behaviours in pharmacies. The aim of this phase is to identify aspects of successful interventions that could be applied to smoking cessation, particularly underlying theories, as well as a review of reviews and a qualitative meta-synthesis. We will also update our review of computer advice on drug dosing to identify features of successful systems that might be used in future to help pharmacists to select the most appropriate drug therapy and dose to help someone to stop smoking. PHASE 2: Qualitative research involving pharmacy NHS Stop Smoking advisors and their service users to identify key elements of their interactions that are associated with success. We will audio record consultations, with some limited non-participant observation, and interview participants. We may also interview smokers who decide not to join the Stop Smoking Programme if further funding is obtained. Cheek swabs and saliva samples will be taken at baseline and to determine smoking status at 6 months from the set quit date. Genetic predictors of successful cessation (nicotine metabolism and DNA profiles) may also be explored as we will have the DNA to enable this, subject to further funding. We will make this clear on the consent forms. We will undertake detailed analysis of transcripts of informative consultations using a special conversation analysis technique to Identify strategies to promote recruitment to smoking cessation services and provide effective support during the quit attempt. PHASE 3: Development of an educational programme for pharmacists. The systematic reviews and qualitative work will feed directly into development of the educational intervention. The framework for the intervention is likely to be PACE methodology which we used successfully previously to promote effective use of medication for treatment of asthma. Elements of effective interventions identified in the reviews will be added eg motivational interviewing. The intervention has been tested in a pilot study in East London. PHASE 4: A randomised controlled trial to evaluate effectiveness and cost effectiveness of the educational intervention in practice. 
Type Preventative Intervention - Behavioural risk modification
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact Tested in feasibility studies and a pilot trial in east London 
URL http://www.blizard.qmul.ac.uk/research-project/1419-stop.html
 
Title e-cigaretes for smoking cessation in pregnancy 
Description e-cigaretes for smoking cessation in pregnancy - HTA funded trial starting 2017 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2017
Development Status Under active development/distribution
Impact Pending results of trial 
 
Description MRC Gambia Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Visitors discussed research over posters and demonstrations at the MRC Gambia.

Increase knowledge locally of the work of the MRC and thus potential for dissemination of outputs locally and trial recruitment,
Year(s) Of Engagement Activity 2006,2007,2008