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Meena Kumari 17 November 2008 English Longitudinal Study of Ageing (ELSA): An example of data use from the ELSA DNA Repository.

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Presentation on theme: "Meena Kumari 17 November 2008 English Longitudinal Study of Ageing (ELSA): An example of data use from the ELSA DNA Repository."— Presentation transcript:

1 Meena Kumari 17 November 2008 English Longitudinal Study of Ageing (ELSA): An example of data use from the ELSA DNA Repository

2 ELSA DNA Repository (EDNAR) Wave 1 (2002-3) Wave 2 (2004-5) Wave 2 nurse 7666 Wave 3 (2006-7) Refresher 1892 issued Wave 4 (2008-9) Wave 4 nurse DNA consent 6551 HSE 98, 99, 2001

3 AIMS: EDNAR Using genetics to understand social and psychosocial processes impact health –Gene-environment interactions Using genetics to understand biological pathways –Mendelian randomisation approach contribution of data to the wider academic community –Within UCL as part of London based consortium (n=35,000) –Wider academic community in the form of the repository Genetic repository (EDNAR)

4 Progress in the EDNAR Funded in November 2005 by NIA 16 applications ( as of October 2008 ) 1,450 SNPs measured 2 papers published –Caulfield et al., Plos Med –Rice et al., J. Allergy. Exp. Immunol papers under review

5 Randomisation to test causality the Mendelian randomisation approach Drug intervention RCT Sample Randomisation InterventionControl Biomarker lower Biomarker higher CV event rate lower CV event rate higher Mendelian randomisation Population Random allocation of alleles Genotype aaGenotype AA Biomarker lower Biomarker higher CV event rate lower CV event rate higher Genetics

6 Application of mendelian randomisation Separating the mechanism-based and off- target actions of torcetrapib using cholesteryl ester transfer protein gene polymorphisms (Sofat et al., under review) –Torcetrapib is a drug that raises good cholesterol by its action on cholesteryl ester transfer protein (CETP) –Recently the Illuminate trial was stopped because the drug was found to have increased adverse cardiovascular outcomes in the treatment arm compared to the control arm –Torcetrapib associated with increases in systolic and diastolic blood pressure

7 Adverse effects of torcetrapib on CVD risk factors Is the adverse effect due to the mechanism of the drug or something off target about this particular drug? Can we use genetic variation in the CETP gene to understand whether the effect of Torcetrapib is due to its mechanism of action (on target) or to an idiosyncracy of the drug itself (off target)? Is genetic variation in the CETP gene associated with changes in systolic and diastolic blood pressure?

8 Association of CETP TaqIB and CVD risk factors Examination of the association of CETP TaqIB (B1B1, B1B2 vs B2B2) and -629C>A variants (rs and rs respectively on –CETP –HDL-cholesterol (good cholesterol) –Diastolic and systolic blood pressure A total of 31 studies and 67,687 individuals of mean age 55.8 (SD 9.6) years

9 Association of genetic variation in CETP and CETP protein Genotype stratified by ethnicity Caucasian Japanese Caucasian Japanese Mean Difference (95% CI) B1B2* B2B2* Individuals (No of studies) 2,763 (6) 1,149 (5) 4,086 (6) 750 (5) p value for 2 test of heterogeneity CETP Concentration mg/ ml <0.001 a (-0.32, -0.14) (-0.32, -0.16) (-0.67, -0.26) (-0.74, -0.31)

10 Association of genetic variation in CETP and HDL-cholesterol

11 Is CETP variation associated with blood pressure? (-0.64, 0.10) 0.16 (-0.28, 0.60) 0.23 (-0.02, 0.69) (-1.90, 0.95) (-1.64, 1.33) (-0.10, 0.90) 0.28 (-0.24, 0.80) 0.15 (-0.55, 0.85) (-1.59, 0.89) 0.31 (-0.38, 0.99) 0.23 (-0.22, 0.69) (-2.49, 0.90) (-1.86, 0.38) 0.15 (-1.93, 2.23) B1B2 v B1B1 27,877 (20) Low LDL High LDL B2B2 v B1B1 >1000 <1000 Affected Unaffected Mixed-affected & unaffected Male only Female only Males and Females rs rs Stratified analyses B2B2 v B1B1 Study Size Baseline coronary disease status Gender SNP 46,412 (21) 29,050 (21) 28,047(16) 1,711(6) 2,551(3) 4,312(5) 23,184(14) 9,489 (11) 4,793 (6) 15,270 (11) 2,070 (2) SBP by LDL level 6,596 (6) 6,587 (6) Group Comparisons Individuals (No of studies) Mean Difference (95% CI) p value for 2 test of heterogeneity Systolic Blood Pressure 0.15 mmHg a

12 Is CETP variation associated with blood pressure? (-0.43, -0.04) (-0.35, 0.28) (-0.27, 0.26) 0.02 (-0.15, 1.62) (-1.42, 0.23) (-1.03, 0.86) 0.08 (-0.28, 0.44) (-0.60, 0.35) (-0.07, 0.67) (-0.58, 0.53) 0.05 (-0.26, 0.36) (-2.08, -0.17) (-1.69, 0.54) 0.24 (-0.37, 0.84) B1B2 v B1B1 27,877 (20) Low LDL High LDL B2B2 v B1B1 >1000 <1000 Affected Unaffected Mixed-affected & unaffected Male only Female only Males and Females rs rs Stratified analyses B2B2 v B1B1 Study Size Baseline coronary disease status Gender SNP 46,412 (21) 29,050 (21) 28,047(16) 1,711(6) 2,551(3) 4,312(5) 23,184(14) 9,489 (11) 4,793 (6) 15,270 (11) 2,070 (2) SBP by LDL level 6,596 (6) 6,587 (6) Group Comparisons Mean Difference (95% CI) Individuals (No of studies) p value for 2 test of heterogeneity Diastolic Blood Pressure mmHg b

13 Comparing the effect of gene and drug Observed from genetic studies Expected, as calculated from trials DBP 5mg B1B2 allele 10mg B2B2 allele Diastolic Blood Pressure (mmHg) SBP 5mg B1B2 allele 10 mg B2B2 allele Systolic Blood Pressure (mmHg) HDL-C 5 mg B1B2 allele 10 mg B2B2 allele HDL (mmol/L)

14 Conclusions 1. Discordance in the effect of CETP SNPs and torcetrapib treatment on blood pressure, despite the concordant effects of gene variants and drug on eight blood lipid and lipoprotein traits indicates that the hypertensive effect of torcetrapib is unlikely to be due to CETP-inhibition. 2. The findings are important for regulators and manufacturers considering randomised trials of other CETP inhibitor molecules in development. 3. Using genetic studies as a type of natural trial could have wider application in drug development, helping to validate targets, model drug effects, and distinguish on and off-target effects in man.


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