Individually the UK and not the WA case vs
control cohort were sufficiently powered to assess an association between AAA and rs10757278 (in the United Kingdom, 88.7% and in WA, 73.1% power to detect a difference at 5% significance, based on the findings of Helgadottir et al1
). However, the reported association between rs10757278-G and AAA,1
was only confirmed statistically (P
>0.03) in the combined group with an overall effect of 1.38 (1.04–1.82), demonstrating the importance of combining cohorts to improve power in candidate gene analysis. When patients with CAD were excluded from the analysis as a potential confounder, the sizes of the effects were essentially unchanged. The size of the association found in our study is consistent with that of Helgadottir et al1
(), suggesting that the original report did not overestimate the true effect, as has been described for other associations.10
Combining the published data and ours (3558 cases and 18108 controls), results in an overall is OR=1.31 (1.22–1.41, P
Figure 1 Meta-analysis combining odds ratios for rs10757278-G and AAA association, with current data (highlighted in grey) and previously published data.1 Combined odds ratio is 1.31 (1.22–1.41) P<0.0001. Test for heterogeneity between studies (more ...)
We also assessed the relationship between the 9p21 variant and AAA growth rate using the previously employed multilevel model.9
Helgadottir et al1
reported a borderline significant association between the rs10757278-G allele and slower AAA growth in the UK small aneurysm trial cohort (AAA growth GG compared with AG −0.46
=0.05), and suggested that the sequence variation predisposed to atherosclerosis (important in AAA) formation but subsequently slowed AAA growth. This theory was supported by previous data from the UK small aneurysm trial, which was associated reduced ankle pressure with slower AAA progression.9
In contrast, in both of our cohorts (combined power >80% to detect 0.46
mm/year decrease in AAA growth rate, at the 5% level), there was no significant association between AAA growth and rs10757278-G allele. The smaller initial mean aortic diameters and longer surveillance periods in our patients than patients in the UK small aneurysm trial may explain the difference between these observations; clearly larger studies will be needed to confirm any genotype effect on AAA growth, which at best appears to be modest. This can only be achieved through the collaboration of AAA surveillance data.
Our confirmation of the association between AAA and the 9p21 variant has added to the urgency to understand this highly significant region of the genome for both occlusive and degenerative vascular disease. It might be expected that different genes would play a role in the progression of disease, which in any case appears to be more complex to assess.