Cross-Trait Meta-Analysis Reveals a Genetic Link between Inflammation and Aging in Giant Cell Arteritis.

Abstract

Giant cell arteritis (GCA) is a complex inflammatory disease affecting individuals over 50 suggesting a strong link with aging-related immune and vascular changes. However, the precise mechanisms underlying this age-related susceptibility remain poorly understood. Considering the relevance of aging in GCA, genetic factors influencing biological aging markers, such as telomere shortening and epigenetic age acceleration (EAA), might also contribute to its development. This study investigated the shared genetic basis between GCA and these markers to enhance understanding of the role of aging in this vasculitis. Data from approximately 6.6 million variants obtained from previously published genome-wide association studies (GWASs) of GCA (3,498 cases and 15,550 controls), telomere length (472,174 individuals), and EAA (34,710 individuals) were meta-analysed using ASSET. Significant variants (p<5×10^-8) were functionally annotated, and causal genes were prioritized using FUMA. Potential therapeutic candidates were identified through drug repurposing. This study identified 21 genetic variants shared between GCA and at least one aging marker. Two pleiotropic signals were annotated at PTPN22 and PLG, known risk factors for GCA, whereas the remainder represent potentially new susceptibility loci for this vasculitis. Several prioritized causal genes, such as SERPING1, SAR1B, SESN1, and SMC4, are involved in both inflammation and senescence, shedding light on the molecular pathways linking aging and GCA. Interestingly, expression levels of some of the prioritized genes PDE1B, ATXN2, and CNEP1R1, were dysregulated in immune cells from active patients. Drug repurposing analysis highlighted promising therapeutic candidates for GCA, including sulfasalazine, an anti-inflammatory agent, and investigational drugs targeting inflammatory pathways like NF-κB. These findings uncover significant genetic overlap between GCA and aging markers, offering insights into shared molecular pathways and potential new therapies targeting both inflammation and cellular senescence.