Background: Cardiovascular disease is the commonest cause of death worldwide and premature arterial stiffening is a key contributor to this risk. Stiffness is highly heritable, but despite a clear genetic basis, the precise molecular pathways regulating stiffness are poorly understood. We aimed to identify the possible genetic risk loci that associated with arterial stiffness in young healthy adults who have little evidence of atherosclerosis or other confounding factors.

Methods: In this candidate gene based association study, the most important tagging SNPs which influenced arterial stiffness were investigated in ENIGMA study. Genotyping was performed in two-stages. First, participants were selected for top and bottom deciles of PWV (n=480) and genotyping carried out using Illumina Golden Gate assays. Significant tSNPs were subsequently tested in additional ENIGMA participants (n=1400) using ABI Taqman assays.

Results: In primary analyses, a number of tSNPs were identified with a significance level of <0.001. However, only those tSNPs pertaining to extracellular matrix (ECM) are presented. Two tSNPs in Fibulin 1 (rs2018279, rs2238823) and three in Aggrecan (rs3743399, rs2882676, rs2293087) genes associated significantly with PWV after adjusting for confounding factors (adjusted R²=0.38; p<0.001) when subjects were selected for deciles of PWV. Similar findings were replicated when data was analysed including the whole cohort (adjusted R²=0.28; p<0.005).

Conclusions: These data demonstrate that genetic variants of key ECM proteins were significantly associated with increased risk of large artery stiffening in young healthy adults. However, additional studies are needed to determine whether variation in these marker genes is associated with other measures of arterial stiffness.