A susceptibility locus on chromosome 9p21 has become the most consistently reproduced genetic risk marker for myocardial infarction1, 2. The locus has also now been associated with an increased risk of aneurysm formation via different underlying pathological processes, in distinct vascular beds; the abdominal aorta and intracranial arteries3. Together these observations point towards an underlying biological mechanism that operates at the level of the arterial wall4.

We have completed a comprehensive vascular phenotype study in around 2500 individuals to study the impact of genotype on the arterial wall in young people and compared the findings to those with established coronary artery disease. As well as associations with vascular phenotypes we have demonstrated an unexpected association between blood pressure and genotype in young people (based on a sample of 1354 adolescents from the Ten Towns Study) (see below). While unexpected, the direction of effect fits with our observations of vascular phenotype in young subjects. Other studies in older subjects have not demonstrated associations between this genotype and conventional risk factors, including blood pressure.

We wish to undertake a collaborative project to establish whether we can replicate this finding in a second cohort of young people of similar age. At the same time the lack of association with other risk factors during childhood could be verified. Our analysis has been based on the rs2891168 SNP (which effectively tags the 9p21 risk haplotype4) and we propose the joint analysis with ALSPAC be based on the same SNP or the most closely associated proxy SNP within the available ALSPAC genome wide association study dataset of 2000 subjects. We propose that we study associations with blood pressure levels at both age 11 and during adolescence (as performed for the Ten Towns Study) and with other risk factors at these time points.

This collaboration would provide a unique opportunity to present data from two different populations on the association between this specific genetic locus and risk factors during childhood. Furthermore, the collaboration with ALSPAC provides the possibility for rapid analysis based on existing data for both blood pressure and genome-wide association.

Adolescence

AA

AG

GG

p

Number of male (%)

199 (55)

350 (55)

193 (55)

0.9

Median age in years (range)

15 (13-16)

15 (13-16)

15 (13-16)

0.7

Systolic blood pressure in mmHg

122.6 (14.1)

120.9 (13.2)

120.4 (13.2)

0.03

Diastolic blood pressure in mmHg

67.8 (7.8)

66.8 (7.2)

66.5 (7.1)

0.02

Aged 10-11 years

AA

AG

GG

p

Systolic blood pressure in mmHg

113.3 (11.2)

112.4 (11.1)

111.9 (10.8)

0.1

Diastolic blood pressure in mmHg

66.1 (6.8)

65.5 (7.0)

65.0 (6.9)

0.03

Values expressed as mean (SD) unless otherwise stated. p represents the significance level of an ANOVA.

1. Samani NJ, Erdmann J, Hall AS, et al. Genomewide association analysis of coronary artery disease. N Engl J Med. Aug 2 2007;357(5):443-453.

2. McPherson R, Pertsemlidis A, Kavaslar N, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. Jun 8 2007;316(5830):1488-1491.

3. Helgadottir A, Thorleifsson G, Magnusson KP, et al. The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nat Genet. Feb 2008;40(2):217-224.

4. Broadbent HM, Peden JF, Lorkowski S, et al. Susceptibility to coronary artery disease and diabetes is encoded by distinct, tightly linked SNPs in the ANRIL locus on chromosome 9p. Hum Mol Genet. Mar 15 2008;17(6):806-814.