Shared genetic susceptibility between autoimmune diseases and ischemic stroke implicates SH2B3 and a JAK-sensitive aldehyde stress response in rheumatoid arthritis

Autoimmune diseases (ADs) are associated with increased risk of ischemic stroke (IS), but whether distinct ADs share inherited susceptibility to IS and how such susceptibility is translated into disease mechanisms remain unclear. We evaluated genetic overlap between IS and 16 ADs using genome-wide and locus-level analyses, followed by regulatory, network, single-cell and computational perturbation analyses. Human validation focused on rheumatoid arthritis (RA), using serum metabolomics in 30 patients with RA and 30 healthy controls, including RA with IS ( n = 6) and RA without IS ( n = 24), and primary leukocyte perturbation in healthy controls (HC) and patients with RA and IS ( n = 3 each). Evidence for shared genetic susceptibility to IS varied across ADs. HDL identified positive genetic correlations for RA, systemic lupus erythematosus, Hashimoto’s thyroiditis (HT) and psoriasis (PsO), but the RA and IS correlation was not significant with LDSC. RA, PsO and HT colocalized with IS at a recurrent 12q24 (PP.H4.abf = 98.99%-99.92%). Regulatory analyses prioritized SH2B3 as the leading candidate at 12q24.12, whereas ALDH2 showed weaker genetic support but belonged to a conserved network enriched for JAK-STAT signaling and oxidative stress. Single-cell analyses localized overlapping JAK-STAT remodeling and reactive oxygen species programs to T cells. Our serum metabolomics showed lipid and redox alterations in RA and suggested additional alterations involving ω-6 lipid, oxidized lipid and ferroptosis-related pathways in RA with IS. RA with IS leukocytes showed increased ALDH2 and 4-hydroxynonenal (4-HNE). SH2B3 silencing reproduced this coupled response in HC CD3⁺ T cells and further increased both markers in RA with IS leukocytes; JAK inhibition ruxolitinib attenuated both responses. A recurrent 12q24 susceptibility signal links IS with selected ADs, with SH2B3 as the leading regulatory candidate and ALDH2 as part of a conserved inflammatory and oxidative stress network. In RA, these findings support a JAK-sensitive aldehyde stress response associated with reduced SH2B3 restraint, 4-HNE accumulation and accompanying ALDH2 upregulation.