Genetically proxied sex hormones, Sjögren's disease, and broad dry eye disease: A bidirectional two-sample mendelian randomization study.

ObjectiveTo evaluate bidirectional associations of genetically proxied total testosterone and estradiol with Sjögren's disease (SjD) and broad dry eye disease (DED) using female-derived, male-derived, and sex-combined hormone GWASs.MethodsWe conducted bidirectional two-sample Mendelian randomization using European-ancestry genome-wide association studies (GWASs). Forward analyses evaluated total-testosterone and estradiol traits from female-derived, male-derived, and sex-combined GWASs against FinnGen SjD (3,309 cases and 484,260 controls) and Million Veteran Program broad DED (84,262 cases and 314,374 controls); reverse analyses used disease instruments to estimate disease-to-hormone associations. Primary instruments met P < 5 × 10-8 and F > 10. Secondary forward SjD analyses used bioavailable-testosterone and testosterone-cluster instruments. Inverse-variance-weighted (IVW) estimates were complemented by weighted median, pleiotropy diagnostics, major histocompatibility complex (MHC) exclusion, Steiger orientation, and direction-specific LDtrait analyses.ResultsSex-combined total testosterone was inverse for SjD by IVW (26 variants; odds ratio [OR], 0.41; 95% confidence interval [CI], 0.23-0.72; P = 0.002) and weighted median (OR, 0.30; 95% CI, 0.14-0.68; P = 0.004). The IVW estimate remained inverse after LDtrait exclusion. Male- and female-derived total-testosterone estimates were null and directionally discordant. Sex-combined bioavailable testosterone was also inverse (73 variants; OR, 0.50; 95% CI, 0.33-0.76; P = 0.001); the other four secondary IVW estimates did not meet correction, and all five secondary sets were heterogeneous. No estradiol-SjD, hormone-DED, or reverse IVW estimate met correction. Reverse sensitivity signals were not robust to MHC exclusion.ConclusionsSex-combined total- and bioavailable-testosterone estimates were concordantly inverse for SjD, but sex-specific estimates were null. The data establish neither a common effect across sex strata, independence from sex hormone-binding globulin, nor a disease-to-hormone association. Sparse estradiol and reverse instruments constrain inference. Larger sex-stratified SjD datasets are needed; these findings do not support hormone testing or treatment.