Adiponectin and Pulmonary Hypertension Risk: Mendelian Randomization and Receptor‐Side Genetic Evidence
- 1Guangzhou National Laboratory Guangzhou International Bio Island Guangzhou Guangdong China
- 2State Key Laboratory of Respiratory Diseases, National Center for Respiratory Medicine, Guangdong Key Laboratory of Vascular Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China
Abstract
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.
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BibTeX
@article{wu2026adiponectin,
title = {{Adiponectin and Pulmonary Hypertension Risk: Mendelian Randomization and Receptor‐Side Genetic Evidence}},
author = {Ruixian Wu and Yiwen Zhang and Shuang Fu and Yuanhui Xiong and Manman Fu and Jian Wang},
journal = {Pulmonary circulation},
year = {2026},
month = oct,
doi = {10.1002/pul2.70449},
url = {https://europepmc.org/article/PMC/PMC13722306},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Adiponectin and Pulmonary Hypertension Risk: Mendelian Randomization and Receptor‐Side Genetic Evidence
AU - Ruixian Wu
AU - Yiwen Zhang
AU - Shuang Fu
AU - Yuanhui Xiong
AU - Manman Fu
AU - Jian Wang
PY - 2026
DA - 2026/10/01
JO - Pulmonary circulation
DO - 10.1002/pul2.70449
UR - https://europepmc.org/article/PMC/PMC13722306
AB - 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.
SN - 2045-8932
SN - 2045-8940
ER -