Meena Kumari17 November 2008

English Longitudinal Study of Ageing (ELSA):

An example of data use from the ELSA DNA Repository

ELSA DNA Repository (EDNAR)

Wave 1 (2002-3)11391

Wave 2 (2004-5)Wave 2 nurse

7666

Wave 3 (2006-7) Refresher1892 issued

Wave 4 (2008-9)Wave 4 nurse

DNA consent6551

HSE ’98, ’99, 2001

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)» m.kumari@ucl.ac.uk

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

Randomisation to test causality

the Mendelian randomisation approach

Drug intervention

RCT

Sample

Randomisation

Intervention Control

Biomarker lower

Biomarker higher

CV eventrate lower

CV eventrate higher

Mendelian randomisation

Population

Random allocation of alleles

Genotype aa Genotype AA

Biomarker lower

Biomarker higher

CV eventrate lower

CV eventrate higher

Genetics

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

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?

Association of CETP TaqIB and CVD risk factors

• Examination of the association of CETP TaqIB (B1B1, B1B2 vs B2B2) and -629C>A variants (rs708272 and rs1800775 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

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 for2 test of

heterogeneityCETP Concentration

mg/ ml

<0.001

<0.001

<0.001

<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)

0-0.25-0.5-0.75

Association of genetic variation in CETP and HDL-cholesterol

0 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)

0.13 (0.11, 0.14)0.12 (0.08, 0.15)

0.10 (0.08, 0.13) 0.14 (0.12, 0.17)

0.13 (0.11, 0.14)

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

rs1800775

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-Cholesterolp value for2 test of

heterogeneity

0.002

<0.001

<0.001

0.008

<0.001

0.494

0.198

0.003

mmol/L

c.

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 0 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

rs1800775

Stratified analyses B2B2 v B1B1Study 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 for2 test of

heterogeneity

0.72

0.65

0.26

0.46

0.46

0.36

Systolic Blood Pressure

0.15

mmHg

a

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)

0-4 -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

rs1800775

Stratified analyses B2B2 v B1B1Study 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 ComparisonsMean Difference

(95% CI)Individuals

(No of studies)

p value for 2 test of

heterogeneityDiastolic Blood Pressure

0.33

0.86

0.02

0.21

0.10

0.29

0.55

mmHg

b

Comparing the effect of gene and drug

Observed from genetic studies

Expected, as calculated from trials

DBP

5mgB1B2 allele

10mgB2B2 allele

-0.50

-0.25

0.00

0.25

0.50

Dia

stol

ic B

lood

Pre

ssur

e (m

mH

g)

SBP

5mgB1B2 allele

10 mgB2B2 allele

-1.0

-0.5

0.0

0.5

1.0

Sys

tolic

Blo

od P

ress

ure

(mm

Hg)

HDL-C

5 mgB1B2 allele

10 mgB2B2 allele

0.025

0.075

0.125

0.175

HD

L (

mm

ol/L

)

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.