Proteome-wide Mendelian randomization study implicates inflammaging biomarkers in retinal vasculature, cardiometabolic diseases and longevity

Abstract

With the increasing proportion of elderly individuals, improving understanding of the biological mechanisms involved in healthy aging is of utmost importance. Retinal vascular complexity obtained from retinal fundus photographs, and evaluated as fractal dimension (ie, Df), a measure of the geometric pattern of the retinal vasculature, has recently emerged as a valuable indicator of diseases and aging processes. The purpose of our study was to elucidate possible mechanisms underlying those relationships. By integrating retinal Df with genomic and plasma proteome biomarkers, we uncovered novel pathways involved in determining Df and its links with cardiometabolic diseases and longevity. First, we performed a genome wide association study (GWAS) of retinal vascular Df by meta-analysing signals from 74,434 participants from three large epidemiological cohorts, the Canadian Longitudinal Study of Aging (CLSA), the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS), and the UK Biobank (UKBB). We replicated four known loci associated with Df, and identified one novel locus within or near DAAM1, as well as found seven suggestive associations within or near CSNK1A1L, MAST4, HIVEP1, LOC283038, FNDC3A, SP100, and SUGP1 genes. GWAS summary statistics confirmed a negative correlation between Df and cardiovascular disease, stroke, and inflammation, but a positive correlation with longevity. Next, employing Mendelian randomization which combined genetic determinants of Df, and cis-protein Quantitative Trait Loci from 1,159 circulating proteins from the Prospective Urban and Rural Epidemiological (PURE) cohort (n=12,066), we identified eight causal mediators for Df, namely IgG Fc receptorIIb, BST1, LILRB2, IL16, MMP12, PON2, ALPP, and PDL2. Notably, MMP12 and IgG Fc receptorIIb have been suggested to connect Df to cardiometabolic outcomes (i.e., coronary artery disease, stroke, peripheral artery disease, and type 2 diabetes) and longevity, respectively. Pathway enrichment analyses highlighted the role of IgG Fc receptorIIb in immune and inflammatory responses to aging processes, referred to as inflammaging. This multi-pronged approach unveils IgG Fc recIIb and MMP12 as key mediators in immune and inflammation pathways, linking lower Df to a higher risk of cardiometabolic diseases and a shorter lifespan. Therefore, retinal Df may be a convenient way to estimate inflammaging, such that lower retinal Df, may indicate a higher inflammaging status. Targeting MMP12 and IgG Fc ReceptorIIb may promote healthy aging and mitigating the occurrence of cardiometabolic diseases in the elderly population.