Abstract
Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke. Yet its genetics is complex and little is known about its molecular drivers. We have identified for the first time, tagSNPs in the genes for extracellular matrix proteins, aggrecan and fibulin-1, that modulate stiffness in young healthy adults. We confirmed SNP associations with ex vivo stiffness measurements and expression studies in human donor aortic tissues. Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan reflecting loss of chondroitin-sulphate binding domains. These differences were age-dependent but the striking finding was the acceleration of this process in stiff versus elastic young aortas. These findings suggest that aggrecan and fibulin-1 have critical roles in determining the biomechanics of the aorta and their modification with age could underpin age-related aortic stiffening.
Highlights
Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke
We found that the two groups in the primary study chosen based on their extreme Aortic pulse wave velocity (aPWV) were well matched for age, gender, body mass index and systolic pressure (Table 1)
Of the 384 tagging single nucleotide polymorphisms (tagSNPs) genotyped (Supplementary Table 2), we identified 35 SNPs in 20 genes that significantly associated with aPWV with an unadjusted p-value of
Summary
Stiffening of the aorta is an important independent risk factor for myocardial infarction and stroke. We confirmed SNP associations with ex vivo stiffness measurements and expression studies in human donor aortic tissues Both aggrecan and fibulin-1 were found in the aortic wall, but with marked differences in the distribution and glycosylation of aggrecan reflecting loss of chondroitin-sulphate binding domains. Aortic stiffness has a multi-factorial aetiology and a polygenic pattern of inheritance (~40% heritability) This reflects the impact of many genes that influence processes such as cell signalling, the cytoskeleton, mechanical regulation of vascular structure[4], and vascular smooth muscle tone[5]. To identify genetic risk alleles for stiffness it is key to study relatively young people to isolate ‘pure’ genetic contribution and minimise atherosclerotic related influences[10,11] To this end, we have performed a candidate-gene based association study using the phenotypic extremes from a cohort of young healthy adults (the ENIGMA cohort) with low cardiovascular risk. Body mass index; SBP-systolic blood pressure; DBP-diastolic blood pressure; MAP-mean arterial pressure; HDL-high density lipoprotein; LDL-low density lipoprotein; aPWV-aortic pulse wave velocity. *Refers to Top and Bottom deciles of the cohort
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