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Mendelian randomization finds genetically proxied CETP inhibition sharply raises the risk of primary Sjögren's syndrome (Curr Pharm Biotechnol 2026)
Original title: Genetic Evidence for Causal Effects of Lipid-lowering Drug Targets on Primary Sjögren's Syndrome Risk: A Mendelian Randomization Study
To test whether lipid-lowering drug targets causally affect risk of primary Sjögren's syndrome, a chronic autoimmune disease of the lacrimal and salivary glands, researchers performed drug-target Mendelian randomization using genetic instruments for HMGCR, PCSK9, NPC1L1, APOB, CETP and LDLR, sourced from the Global Lipids Genetics Consortium and UK Biobank, applying inverse variance weighted, weighted median, MR-Egger, simple mode and weighted mode methods with heterogeneity and sensitivity analyses. Genetically proxied inhibition of both HMGCR (odds ratio 3.602, 95% CI 1.051 to 12.344, P equals 0.041) and CETP (odds ratio 12.251, 95% CI 2.599 to 57.743, P equals 0.002) was significantly associated with increased risk of primary Sjögren's syndrome, while the other targets showed no significant association. The authors suggest HMGCR and CETP may affect Sjögren's syndrome risk through non-lipid pathways, distinct from other lipid-lowering drug targets.
Original abstract
Introduction: Primary Sjögren's Syndrome (pSS) is a chronic autoimmune condition affecting lacrimal and salivary glands. While previous studies suggest potential associations between dyslipidemia and autoimmune diseases, the causal relationship between lipid-lowering medications and pSS remains unclear.
Methods: This study employed drug-targeted Mendelian randomization (MR) analysis to assess the impact of lipid-lowering drugs on pSS risk, focusing on genetic targets including HMGCR, PCSK9, NPC1L1, APOB, CETP, and LDLR. Data were sourced from the Global Lipids Genetics Consortium and UK Biobank. Significant single-nucleotide polymorphisms linked to LDL cholesterol were utilized as instrumental variables. Causal effects were estimated using Inverse Variance Weighted, Weighted Median, MR Egger, Simple Mode, and Weighted Mode methods. Robustness was ensured through heterogeneity and sensitivity analyses.
Results: The inhibition of HMGCR and CETP genes was found to be significantly associated with an increased risk of developing pSS (HMGCR: OR = 3.602, 95% CI (1.051, 12.344), p = 0.041; CETP: OR = 12.251, 95% CI (2.599, 57.743), p = 0.002).
Discussion: HMGCR and CETP may affect pSS risk via non-lipid pathways, suggesting distinct mechanisms among different lipid-lowering drug targets.
Conclusion: This study provides compelling evidence suggesting that lipid-lowering drugs may contribute to the risk of pSS, thus offering new insights for clinical intervention strategies.
the classgeneticsinflammationsafety
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.