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

2. ELSA DNA Repository (EDNAR)
HSE ’98, ’99, 2001
Wave 1 (2002-3)
11391
Wave 2 (2004-5)
Wave 2 nurse
7666
Wave 3 (2006-7)
DNA consent
6551
Refresher
1892 issued
Wave 4 (2008-9)
Wave 4 nurse

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. 2008
Rice et al., J. Allergy. Exp. Immunol. 2008
4 papers under review

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

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
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.
-0.23 (-0.32, -0.14)
-0.24 (-0.32, -0.16)
-0.47 (-0.67, -0.26)
-0.52 (-0.74, -0.31)
-0.25
-0.5
-0.75

10. Association of genetic variation in CETP and HDL-cholesterol
0.06
0.06 (0.05, 0.07)
0.06 (0.05, 0.06)
0.13 (0.11, 0.14)
0.16 (0.10, 0.22)
0.12 (0.08, 0.15)
0.10 (0.08, 0.13)
0.14 (0.12, 0.17)
0.11 (0.09, 0.13)
0.16 (0.14, 0.18)
0.12 (0.10, 0.14)
0.12 (0.11, 0.14)
0.15 (0.10, 0.20)
0.13
B1B2 v B1B1 Caucasian
B1B2 v B1B1 Japanese
B2B2 v B1B1 Caucasian
B2B2 v B1B1 Japanese
>1000
<1000
Affected
Unaffected
Mixed-affected & unaffected
Male only
Female only
Males and Females
rs708272 rs
Stratified analyses: Caucasians only, B2B2 v B1B1
Study Size
Baseline coronary disease status
Gender
SNP
54,971 (30)
1,876 (6)
34,432 (30)
1,179 (6)
31,772 (20)
3,664 (10)
4,385 (9)
6,538 (10)
23,083 (13)
12,822 (16)
6,343 (9)
16,749 (12)
33,208 (27)
2,706 (3)
Group Comparisons
Mean Difference
(95% CI)
Individuals
(No of studies)
HDL-Cholesterol
p value for
2 test of
heterogeneity
0.002
<0.001
0.008
0.494
0.198
0.003
mmol/L c.

11. Is CETP variation associated with blood pressure?
-0.27 (-0.64, 0.10)
0.16 (-0.28, 0.60)
0.23 (-0.02, 0.69)
-0.47 (-1.90, 0.95)
-0.16 (-1.64, 1.33)
-0.10 (-0.10, 0.90)
0.28 (-0.24, 0.80)
0.15 (-0.55, 0.85)
-0.35 (-1.59, 0.89)
0.31 (-0.38, 0.99)
0.23 (-0.22, 0.69)
-0.80 (-2.49, 0.90)
-0.74 (-1.86, 0.38)
0.15 (-1.93, 2.23) -4 -2 2 4
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
rs708272 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
0.72
0.65
0.26
0.46
0.36
Systolic Blood Pressure
0.15
mmHg a

12. Is CETP variation associated with blood pressure?
-0.23 (-0.43, -0.04)
-0.04 (-0.35, 0.28)
-0.00 (-0.27, 0.26)
0.02 (-0.15, 1.62)
-0.60 (-1.42, 0.23)
-0.09 (-1.03, 0.86)
0.08 (-0.28, 0.44)
-0.12 (-0.60, 0.35)
-0.02 (-0.07, 0.67)
-0.02 (-0.58, 0.53)
0.05 (-0.26, 0.36)
-1.13 (-2.08, -0.17)
-0.58 (-1.69, 0.54)
0.24 (-0.37, 0.84) -4 -2 2 4
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
rs708272 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
0.33
0.86
0.02
0.21
0.10
0.29
0.55
mmHg b

13. Comparing the effect of gene and drug
DBP
5mg
B1B2 allele
10mg
B2B2 allele
-0.50
-0.25
0.00
0.25
0.50
Diastolic Blood Pressure (mmHg)
1.0
SBP
0.5
Systolic Blood Pressure (mmHg)
0.0
-0.5
-1.0
5mg
B1B2 allele
10 mg
B2B2 allele
HDL-C
5 mg
B1B2 allele
10 mg
B2B2 allele
0.025
0.075
0.125
0.175
HDL (mmol/L)
Observed from genetic studies
Expected, as calculated from trials

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.