Adiponectin and Pulmonary Hypertension Risk: Mendelian Randomization and Receptor-Side Genetic Evidence

Circulating adiponectin is generally considered metabolically protective, but higher levels have been associated with adverse outcomes in some cardiovascular diseases and states of high disease burden, a pattern referred to as the adiponectin paradox. This study assessed genetic evidence relating the adiponectin axis to pulmonary arterial hypertension (PAH) and pulmonary hypertension (PH)-related phenotypes, with consideration of body mass index (BMI) and ADIPOR1/ADIPOR2-related regulation. We integrated publicly available GWAS data for adiponectin, BMI, and PAH/PH with GTEx quantitative trait locus data. The primary two-sample Mendelian randomization (MR) analysis used the GCST90293086 adiponectin GWAS as the exposure and the Rhodes/GCST007228 PAH GWAS as the outcome. Supplementary analyses included FinnGen Release 12, BMI-adjusted multivariable MR, receptor-side cis-MR and MRBEE, ADIPOR2 colocalization, local linkage disequilibrium and proxy variant annotation, and lung tissue sQTL analysis. The primary IVW analysis included 21 variants and indicated a nominally significant positive association between genetically predicted adiponectin and PAH risk (OR = 1.452, 95% CI: 1.033-2.042; p = 0.03195). Complementary MR estimates were similar in direction but did not reach statistical significance. In BMI-adjusted multivariable MR using a different FinnGen PH-related outcome, the adiponectin estimate was negative. Because the outcomes differed, this contrast cannot be attributed to BMI adjustment alone. Receptor-side analyses provided supportive genetic evidence involving ADIPOR1/ADIPOR2, including ADIPOR2 colocalization and lung tissue sQTL findings. These exploratory findings do not establish a direct harmful causal effect of circulating adiponectin or confirm a receptor-mediated molecular mechanism.