Causal Relationship Between Sjögren's Syndrome and Atherosclerosis: A Bidirectional, Two-Sample, Mendelian Randomization Study.

Background: There is growing evidence that Sjögren's syndrome (SS) and atherosclerosis (AS) might share underlying immunological and inflammatory processes. Observational data have pointed toward a potential association between SS and a heightened likelihood of developing AS, though the causal direction and specific dynamics of this relationship have not been clearly verified. This Mendelian randomization (MR) investigation opts to investigate potential bidirectional causality between SS and three types of AS: coronary, cerebral, and peripheral.

Methods: Genetic variants significantly linked to SS and multiple AS subtypes were obtained from large-scale genome-wide association studies (GWAS). The main approach used for causal estimation was the inverse-variance weighted (IVW) method. To ensure robustness, additional methods such as the weighted median, MR-Egger regression, simple mode, and weighted mode were also applied. To test result stability and detect pleiotropy, tools including Cochran's Q test, MR-Egger intercept analysis, MR-Pleiotropy Residual Sum and Outlier (PRESSO) method, and leave-one-out analysis were performed.

Results: The results showed a notable genetic link between SS as well as an elevated coronary likelihood (OR = 1.046, 95%CI, 1.024-1.069; = 5.52×10⁻⁵), cerebral (OR = 1.320, 95%CI, 1.040-1.677 = 0.023), and peripheral (OR = 1.154, 95%CI, 1.082-1.231;  = 1.188×10⁻⁵) AS. Such findings imply that SS could independently elevate the risk for atherosclerotic disease. Conversely, reverse MR analysis suggested that peripheral AS could have a causal role in SS onset (OR = 1.751, 95%CI, 1.009-3.038;  = 0.046), whereas no significant reverse effect was observed from coronary or cerebral AS.

Conclusion: This study presents genetic evidence supporting a bidirectional causal link between SS and peripheral AS, and a unidirectional causal influence from SS toward both coronary and cerebral AS. The outcomes emphasize the importance of early cardiovascular screening and integrated management strategies addressing immune-vascular comorbidities in individuals diagnosed with SS.