Journal of Shandong University (Health Sciences)

Under hypoxic conditions, prolyl hydroxylase domain-containing protein 2 regulates ubiquitin-specific protease 22 to participate in the invasive biological behavior of esophageal squamous cell carcinoma

WANG Shenghai, QI Yuhao, HUANG Yinghua, GONG Shaojun, LI Jun

Journal of Shandong University (Health Sciences). 2026, 64(6): 1-12. doi:10.6040/j.issn.1671-7554.0.2025.1227

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Objective To investigate the effects of prolyl hydroxylase domain-containing protein 2(PHD2)on the malignant biological behaviors of esophageal squamous cell carcinoma(ESCC)in a hypoxic microenvironment, and to elucidate its regulatory relationship with ubiquitin-specific protease 22(USP22). Methods The high-throughput public gene expression database, gene expression omnibus(GEO), was utilized to analyze the expression of PHD2 mRNA in ESCC tissues and normal tissues. Western blotting was performed to evaluate PHD2 expression levels in a panel of esophageal squamous cell carcinoma(ESCC)cell lines(KYSE-410, KYSE-30, KYSE-150, EC-9706 and TE-1), with normal immortalized human esophageal epithelial cells(HET-1A, immortalized by SV40)serving as the control. ESCC cell models with PHD2 silencing(knockdown)and overexpression were established via transfection. Under normoxic and hypoxic(1%O₂)conditions, the proliferative capacity of ESCC cells was evaluated using the CCK-8 assay, while the migratory ability was assessed via wound healing and Transwell migration assays. Furthermore, the effects of PHD2 silencing and overexpression on USP22 expression levels were evaluated to validate their regulatory relationship. Finally, co-immunoprecipitation(Co-IP)assays were performed to demonstrate the interaction between PHD2 and USP22. Results Analysis of public gene expression databases revealed that PHD2 mRNA expression levels were higher in normal tissues than in ESCC tissues. Compared with ESCC cells, the expression of PHD2 was significantly higher in normal esophageal squamous epithelial cells(HET-1A)(P<0.05). Hypoxia promoted the proliferation and migration abilities of ESCC cells. Silencing of PHD2 enhanced the proliferation and migration of ESCC cells, whereas PHD2 overexpression suppressed these abilities(P<0.05). After 24 hours of hypoxia, PHD2 expression decreased while USP22 expression increased(P<0.05). Furthermore, PHD2 silencing upregulated the expression of USP22(P<0.05), while PHD2 overexpression downregulated USP22 expression(P<0.05). Finally, Co-IP assays confirmed the physical interaction between PHD2 and USP22. Conclusion PHD2 is expressed at low levels in both ESCC tissues and cell lines, and its overexpression suppresses the proliferation and migration of ESCC cells. Under normoxic conditions, PHD2 overexpression downregulates USP22 expression; notably, under hypoxic conditions, PHD2 maintains its regulatory effect on USP22. This suggests that a regulatory relationship likewise exists between USP22 and PHD2 under the hypoxic conditions of solid tumors, and they synergistically contribute to the aggressive biological behaviors of ESCC. PHD2 may therefore serve as a novel therapeutic target for ESCC.

N-acetylheparin alleviates lipopolysaccharide-induced sepsis myocardial injury by inhibiting cardiomyocytes ferroptosis

HU Haoran, LI Jiankui, HUANG Xiao, WANG Lulu, CHEN Yanqing, XU Haixiao, HAO Dong, WANG Tao

Journal of Shandong University (Health Sciences). 2026, 64(6): 13-21. doi:10.6040/j.issn.1671-7554.0.2025.1015

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Objective To investigate the effect of N-acetylheparin(NAH)on sepsis-induced myocardial injury and its underlying molecular mechanisms. Methods C57BL/6 mice were randomly divided into to four groups: control group(Control group), LPS-induced model group(LPS group), LPS combined with N-acetylheparin treatment group(LPS+NAH group), and N-acetylheparin(NAH group)alone group. A mouse model of sepsis-induced myocardial injury was established via intraperitoneal injection of lipopolysaccharide(LPS)at a dose of 10 mg/kg. Blood samples were collected by orbital venous puncture 18 hours post-injection, followed by serum separation and heart tissue harvesting. Cardiac function was evaluated using small animal echocardiography, while the extent of myocardial injury was assessed through hematoxylin-eosin(HE)staining, the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling(TUNEL)was used to observe the apoptosis rate of cardiomyocytes. The serum levels of creatine kinase isoenzyme MB(CK-MB), cardiac troponin I(cTnI)and high-mobility group box 1(HMGB1)were quantified using enzyme-linked immunosorbent assay(ELISA). The concentrations of total glutathione peroxidase(GSH), superoxide dismutase(SOD), malondialdehyde(MDA), and tissue iron in myocardial tissue were determined using commercial assay kits. Western blotting analysis was employed to quantify the protein expression levels of high mobility group box-1(HMGB1)and glutathione peroxidase 4(GPX4)in myocardial tissue. Results Compared with the Control group, mice in the LPS group exhibited significantly reduced left ventricular ejection fraction and fractional shortening at 18 hours post-injection. Serum CK-MB and cTnI levels were markedly elevated. HE staining revealed increased inflammatory cell infiltration and structural disarray in myocardial tissue, while TUNEL staining indicated a significantly higher rate of cardiomyocyte apoptosis. Additionally, myocardial iron content and MDA levels were significantly increased, whereas GSH, SOD, and GPX4 levels were decreased. Both serum and myocardial HMGB1 expression levels were upregulated. In contrast, NAH treatment in the LPS+NAH group effectively improved left ventricular systolic function, reduced myocardial enzyme release, and ameliorated histopathological damage. Furthermore, NAH administration attenuated cardiomyocyte apoptosis, lowered myocardial iron accumulation and MDA production, and restored antioxidant enzyme activities(GSH and SOD)as well as GPX4 expression. Notably, both serum and cardiac HMGB1 levels were significantly downregulated following NAH intervention, as confirmed by ELISA and Western blotting analysis. There was no statistically significant difference between the NAH group and the Control group. Conclusion NAH alleviates lipopolysaccharide-induced myocardial injury by suppressing HMGB1 expression, upregulating GSH and GPX4 levels and total SOD activity, reducing iron and MDA content in myocardial tissues, and thereby attenuating cardiomyocyte ferroptosis.

Correlation between the myocardial protection solution infusion strategies and the new-onset postoperative atrial fibrillation after acute Stanford type A aortic dissection surgery

CHENG Shaopeng, YANG Zhihao, WANG Yilin, YANG Jie, WANG Dongjin

Journal of Shandong University (Health Sciences). 2026, 64(6): 22-29. doi:10.6040/j.issn.1671-7554.0.2026.0273

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Objective To investigate the correlation between myocardial protection solution infusion strategies and the occurrence of new-onset postoperative atrial fibrillation in patients with acute Stanford type A aortic dissection(AAAD), with the aim of reducing the incidence of atrial fibrillation. Methods This retrospective study included 207 patients diagnosed with AAAD at Drum Tower Hospital from January 1, 2020, to December 31, 2024. Patients were categorized into an antegrade cardioplegia group(n=121)and a retrograde cardioplegia group(n=86)based on the myocardial protection solution infusion strategy. The primary endpoint was the incidence of new-onset atrial fibrillation, and secondary endpoints included mechanical ventilation duration and Intensive Care Unit(ICU)stay. Multivariate logistic regression analysis was used to assess the correlation between myocardial protection solution infusion strategy and new-onset atrial fibrillation, and three propensity score methods were used for adjustment. Subgroup analyses were conducted on different surgical methods, and the number needed to treat was analyzed. In addition, multivariate logistic regression analysis was used to explore the independent risk factors for new-onset atrial fibrillation after AAAD. Results The overall incidence of atrial fibrillation was 38.65%, showing no significant statistical difference between the two groups(39.67% vs. 37.21%, P=0.831). Regarding secondary endpoints, there was no statistically significant difference in the duration of mechanical ventilation on a ventilator between the antegrade perfusion group and the retrograde perfusion group(27.00 h vs. 21.50 h, P=0.075). However, the ICU stay in the antegrade perfusion group was shorter than that in the retrograde perfusion group, and the different was statistically significant(128.00 h vs. 160.50 h, P=0.012). Multivariate logistic regression and propensity score adjustment analyses also did not show a significant correlation between myocardial protection solution infusion methods and the incidence of new-onset atrial fibrillation(P>0.05). Subgroup analysis revealed no significant difference in atrial fibrillation occurrence between the two infusion methods. The analysis of the number of patients benefiting from treatment also did not find that different perfusion methods brought clinical benefits to the new-onset atrial fibrillation after surgery( number needed to treat: 40, 95%CI: -9-6). In addition, multivariate logistic regression analysis showed that advanced age(OR=1.08,95%CI:1.03-1.14,P=0.003), suffering from coronary heart disease(OR=2.45,95%CI:1.28-4.69,P=0.007), longer operation time(OR=1.02,95%CI:1.01-1.04,P=0.032)and longer ICU stay(OR=1.15,95%CI:1.06-1.25,P=0.011)were independent risk factors for new-onset atrial fibrillation after AAAD surgery. Conclusion In patients with AAAD, there is no significant correlation between myocardial protection solution infusion strategy and the incidence of new-onset atrial fibrillation. Antegrade cardioplegia can be recommended as the standard strategy. However, given that advanced age, comorbid coronary artery disease, prolonged operative duration, and extended ICU stay are independent risk factors, the choice of cardioplegia strategy should still be individualized.

Influencing factors and prediction model of Klebsiella pneumoniae infection in patients with pyogenic liver abscess

LIN Hua, HUANG Qingxian, SUN Yanpei, LI Xuemei, SUN Jing, LIU Yuantao

Journal of Shandong University (Health Sciences). 2026, 64(6): 30-42. doi:10.6040/j.issn.1671-7554.0.2025.1110

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Objective To analyze the factors associated with Klebsiella pneumoniae(KP)infection in patients with pyogenic liver abscess(PLA)and to develop and validate an early prediction tool for KP infection. Methods The clinical, laboratory, and imaging data of 287 patients with PLA who were admitted to Qilu Hospital of Shandong University(Qingdao)from December 2016 to October 2025 were retrospectively analyzed. Missing data were handled using multiple imputation by chained equations(MICE). Candidate variables were screened using Lasso regression, and a logistic regression model was subsequently constructed. Model performance was evaluated using receiver operating characteristic(ROC)curves, calibration curves, the Hosmer-Lemeshow test, and 5-fold cross-validation. Sensitivity analyses were also performed. Results Logistic regression analysis showed that a history of diabetes and higher CRP levels were positively associated with KP infection, whereas older age, higher neutrophil(NEU)levels, and a history of abdominal surgery were negatively associated with KP infection. The model achieved an area under the curve(AUC)of 0.837, with a sensitivity of 0.807 and a specificity of 0.767. The directions of association for the key predictors remained stable across different sensitivity analyses. Conclusion History of diabetes, CRP level, age, NEU level, and history of abdominal surgery are associated factors for KP infection in patients with PLA. The predictive model constructed based on these variables shows acceptable discrimination and calibration abilities, and may provide a reference for empirical antimicrobial therapy. However, further validation and optimization using multicenter, larger-sample, and multimodal data are still needed.

Comparison of coronal plane alignment of the knee phenotypes between knee osteoarthritis patients and asymptomatic controls

JIN Tong, WEI Xingzhou, JIN Chenyang, RAO Zhaobin, XIA Hanrong, ZHU Feng, WANG Yijun, ZHANG Lianfang, CHEN Guangdong, LI Rongqun, XU Yaozeng, ZHOU Jun

Journal of Shandong University (Health Sciences). 2026, 64(6): 43-49. doi:10.6040/j.issn.1671-7554.0.2026.0090

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Objective To compare the distribution of coronal plane alignment of the knee(CPAK)phenotypes between patients with knee osteoarthritis(KOA)and asymptomatic controls,and to identify the phenotypic characteristics of CPAK distribution in patients with KOA. Methods This retrospective study included 2,166 individuals who underwent standing full-length lower-extremity radiography at The First Affiliated Hospital of Soochow University between January 1, 2019 and December 31, 2024. Among them, 1,785 patients were diagnosed with KOA as the primary diagnosis, who underwent total knee arthroplasty(TKA), involving 1,418 knees, and 486 patients who underwent unicompartmental knee arthroplasty(UKA), involving 551 knees. In addition, 381 normal controls were included. Medial proximal tibial angle(MPTA), lateral distal femoral angle(LDFA), arithmetic hip-knee-ankle angle(aHKA), and joint line obliquity(JLO)were measured, and CPAK phenotypes were assigned according to the established CPAK classification system. Preoperative anatomical parameters and CPAK phenotype distributions were compared among the control, TKA, and UKA groups. In patients with available postoperative images, preoperative-to-postoperative changes in anatomical parameters and CPAK phenotypes were further analyzed. Results CPAK phenotype distribution differed significantly among the three groups (P<0.001). The predominant phenotypes were type Ⅲ(281 knees, 36.88%)and type Ⅱ(216 knees, 28.35%)in the control group, type Ⅰ(605 knees, 42.67%)and type Ⅳ(286 knees, 20.17%)in the TKA group, and type Ⅰ(232 knees, 42.11%)and type Ⅱ(119 knees, 21.60%)in the UKA group. Preoperative MPTA, LDFA, aHKA, and JLO also differed significantly among the three groups(P<0.001). Postoperative imaging follow-up was available for 768 patients(858 knees)in the TKA group and 222 patients(265 knees)in the UKA group. CPAK phenotype distribution changed significantly from preoperative to postoperative in both groups(Bowkers symmetry test, both P<0.001), and postoperative phenotype distribution differed significantly between the two groups(P<0.001). Postoperatively, the TKA group mainly shifted to type Ⅳ(242 knees, 28.21%)and type Ⅴ(248 knees, 28.90%), whereas the UKA group remained predominantly type Ⅰ(102 knees, 38.49%)and type Ⅱ(83 knees, 31.32%). Conclusion CPAK phenotypes may help characterize KOA-related coronal alignment features and morphological changes before and after surgery; however, its value in assessing KOA risk and surgical decision-making still requires further validation in prospective studies.

Application of rapid immunohistochemistry in the detection of sentinel lymph node low-volume micrometastases after neoadjuvant chemotherapy for breast cancer

QI Xiumin, XIAO Yan, SUN Ping

Journal of Shandong University (Health Sciences). 2026, 64(6): 50-59. doi:10.6040/j.issn.1671-7554.0.2025.0136

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Objective To assess the size and type of sentinel lymph node(SLN)metastases after neoadjuvant chemotherapy(NAC)for breast cancer using rapid immunohistochemistry(RD-IHC)technology, and to analyze the accuracy and false negative rate(FNR)of RD-IHC detection, as well as its correlation with clinical pathological characteristics. Methods The one-step RD-IHC method was used to detect the expression of CK(pan)in intraoperative frozen sections of SLNs after NAC for breast cancer. The detection rates(DR)of three methods-intraoperative hematoxylin and eosin(IH), RD-IHC, and routine hematoxylin and eosin(HE)plus immunohistochemistry(RHPI)-for SLN macro-metastases, micro-metastases, and isolated tumor cells(ITCs)were compared and analyzed, and the clinical pathological characteristics associated with FNR were further investigated. Results A total of 393 SLN biopsy specimens from patients undergoing NAC were collected, and 1,106 lymph nodes were detected, with an average of 1 to 5 SLN biopsies per case. IH detected 98 cases of SLN metastases, RD-IHC detected 123 cases, and RHPI detected 133 cases. Among them, the DR of IH for SLN micro-metastases and ITCs was 4.6% and 3.1%, respectively, with an FNR of 26.3%(35/133)and 22 delayed diagnoses, the DR of RD-IHC for SLN micro-metastases and ITCs was 8.8% and 6.2%, respectively, with an FNR of 7.5%(10/133)and no delayed diagnosis cases, the DR of RHPI for SLN micro-metastases and ITCs was 8.9% and 7.6%, respectively. Compared with IH, RD-IHC improved the DR of low-volume micro-metastases and reduced the FNR. In subgroup analysis, RD-IHC false negatives were mainly observed in cases with estrogen receptor(ER)-positive, progesterone receptor(PR)-positive, HER2-negative, P53 wild-type, and low Ki67 expression, and the FNR of SLN biopsy specimens containing micro-metastases was significantly higher than that of the macro-metastasis group. When the number of SLN biopsies per case reached more than 3, the DR of SLN biopsy significantly increased and the FNR decreased. Conclusion RD-IHC can significantly improve the intraoperative diagnostic accuracy of SLN metastasis after NAC in breast cancer within a short period of time, especially for cases with low-volume micro-metastasis. RD-IHC can effectively reduce the rate of delayed diagnosis and maintain the FNR within a controllable range, thereby avoiding unnecessary secondary surgery and effectively guiding the selection of clinical surgical methods.

MRI based radiomics nomogram differentiate between hepatocellular carcinoma and intrahepatic mass-forming cholangiocarcinoma in HBV patients

WANG Linxiang, CUI Jin, WANG Lianbang, QI Xu, WANG Gongzheng, WANG Ximing

Journal of Shandong University (Health Sciences). 2026, 64(6): 60-67. doi:10.6040/j.issn.1671-7554.0.2025.0946

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Objective To evaluate the performance of differentiating hepatocellular carcinoma(HCC)and intrahepatic mass-forming cholangiocarcinoma(IMCC)based on multiparametric MRI radiomics nomogram. Methods The retrospective, multicenter study involved 206 patients with either HCC or IMCC, who were enrolled from three hospitals between August 2016 and September 2022. Patients were divided into a training cohort(126 cases)and a testing cohort(80 cases)based on different hospitals. And the radiomics features of three sequences(T1-FS, T2-FS, and DWI)were extracted. The four machine learning algorithms were used to construct radiomics models. The optimal model was selected for further analysis. Independent clinical features were identified through univariate and multivariate analysis, which were then used to construct the clinical model. Subsequently, the radiomics nomogram was established by integrating independent clinical features with the selected radiomics model. The validation of all models was conducted through 5-fold cross-validation for hyperparameter optimization in the training cohort and evaluated in the external testing cohort. The receiver operating characteristic(ROC)curve was used to evaluate the model performance. The Delong test was used to compare the model differences. Results ROC analysis of the testing cohort demonstrated that the optimal radiomics model(T1+T2+DWI)by employing linear support vector machine achieved an area under curve(AUC)of 0.929(95%CI: 0.872-0.986), with sensitivity of 0.879, specificity of 0.894, and accuracy of 0.888. In conjunction with alpha fetoprotein, carbohydrate antigen 199 and sex, the clinical-radiomics nomogram exhibited superior performance, achieving an AUC of 0.951(95%CI: 0.910-1.000), with sensitivity of 0.909, specificity of 0.936, and accuracy of 0.925. These results were statistically superior to both the clinical model(AUC=0.822, 95%CI: 0.730-0.910; P=0.008)and the radiomics model(P=0.038), indicating significant added value from the integration of clinical and radiomic features. Conclusion The radiomics nomogram can distinguish between IMCC and HCC in patients with hepatitis B virus, thus facilitating more precise treatment plan, particularly for patients who are not able to tolerate enhanced scanning procedures.

Fertility motivation and reproductive intention among pregnant women: a moderated mediation and fsQCA analysis

YOU Jiaxin, ZHANG Dan, SU Yonggang

Journal of Shandong University (Health Sciences). 2026, 64(6): 68-76. doi:10.6040/j.issn.1671-7554.0.2025.1147

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Objective To investigate the association between fertility motivation and reproductive intention among pregnant women and to examine the mediating role of maternal-fetal attachment and the moderating role of spousal invalidating responses. Configurational pathways underlying reproductive intention were further identified using fuzzy-set qualitative comparative analysis(fsQCA). Methods Using convenience sampling, a total of 556 pregnant women were recruited from an antenatal clinic of Jinan Maternity and Child Care Hospital in Shandong Province between April 3 and August 23, 2025. Data were collected using a general information questionnaire, the Fertility Motivation Scale, the Maternal-Fetal Attachment Scale, and the Spousal Invalidating Responses Scale. A moderated mediation model, combined with Fuzzy-set qualitative comparative analysis, was used to explore the underlying mechanisms of reproductive intention. Results Among the participants, 193(34.7%)reported an intention to have another child. The moderated mediation analysis showed that, in the autonomous fertility motivation model, the direct effect of autonomous fertility motivation on re-fertility intention was not significant(P=0.061), while maternal-fetal attachment exerted a significant mediating effect(indirect effect=0.002, 95%CI: 0.001-0.005). Spousal invalidating responses significantly moderated the association between autonomous fertility motivation and reproductive intention(P=0.039). In the controlled fertility motivation model, controlled fertility motivation had a significant direct effect on reproductive intention(P<0.001), and maternal-fetal attachment also showed a significant mediating effect(indirect effect=0.001, 95%CI: 0.001-0.002). Spousal invalidating responses significantly moderated the relationship between maternal-fetal attachment and reproductive intention(p=0.039). The fsQCA identified several configurational pathways linked to the absence of reproductive intention. Two patterns were observed among primiparous women(multidimensional weakness and stress confrontation), and three among multiparous women(collaborative decision-making, multidimensional weakness, and transformation-disconnection). Conclusion To enhance fertility motivation, strengthen maternal-fetal attachment, and improve spousal emotional responses may help optimize the psychological context of pregnancy and support the development of reproductive intention.

Latent profile analysis of financial toxicity and its influencing factors in patients with enterostomy

WANG Jing, YAN Yishan, XIAO Lulu, WANG Ziling, LIU Yahong, LIU Rui, CHAO Qun

Journal of Shandong University (Health Sciences). 2026, 64(6): 77-85. doi:10.6040/j.issn.1671-7554.0.2025.0573

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Objective To explore the potential categories of financial toxicity in patients with enterostomy using latent profile analysis(LPA)and to analyze their influencing factors, aiming to provide a basis for developing targeted intervention strategies. Methods From April to September 2023, a total of 512 patients from the enterostomy clinic of a Grade A tertiary hospital in Tianjin were selected by convenience sampling. Data were collected using a general information questionnaire, the Family APGAR index, the Comprehensive score for Financial toxicity-functional assessment of chronic illness therapy, and the Functional assessment of chronic illness therapy-spiritual well-being scale. Latent profile analysis was performed using Mplus 8.3, and multivariate logistic regression analysis was conducted using SPSS 21.0 to identify influencing factors. Results The financial toxicity of enterostomy patients could be classified into three latent profiles: the non-financial toxicity group(17.19%), the mild financial toxicity group(47.27%), and the moderate financial toxicity group(35.54%). Multivariate logistic regression analysis revealed that lower family care, lower spiritual well-being, lower educational level, medical payment methods of urban resident medical insurance or new rural cooperative medical care, and a per capita monthly household income in the range of 1,001-3,000 yuan were independent factors influencing patients classification into higher financial toxicity profiles(P<0.05). Conclusion There is significant heterogeneity in financial toxicity among enterostomy patients, influenced by both objective economic conditions and subjective psychosocial resources. Healthcare professionals should implement stratified management based on the characteristics of different profiles and construct a comprehensive intervention model integrating medical, psychological, and family support to precisely alleviate patients financial toxicity.

Genetic evidence on the association of metformin targets with risk of fetal congenital nervous system malformations

JI Hanbing, WU Yutong, WU Sijia, HUANG Xin, LI Hongkai, CHEN Hao

Journal of Shandong University (Health Sciences). 2026, 64(6): 86-93. doi:10.6040/j.issn.1671-7554.0.2025.0928

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Objective To systematically and separately evaluate whether genetic perturbations of the five established targets of metformin are causally associated with the risk of fetal congenital nervous system malformations(CNSM). Methods This study employed a drug-target Mendelian randomization approach. Summary data for five target genes(PRKAB1, GPD1, ETFDH, SLC47A1, and ACACB)were utilized, with their quantitative trait loci at transcriptomic and proteomic levels serving as instrumental variables. Causal inference was estimated using various methods, including inversevariance weighted. Key findings were then validated through colocalization analysis. Results Among the five targets examined, only metformins core pharmacodynamic target, PRKAB1, and its downstream target, ACACB, showed a significant causal association with a reduced risk of CNSM. This protective effect was validated at both transcriptomic level(OR=0.897, 95%CI: 0.808-0.997, P=0.043)and proteomic level(OR=0.709, 95%CI: 0.521-0.964, P=0.028). Analysis of the other three targets revealed no significant signals. Colocalization analysis supported the possibility that PRKAB1 and CNSM may share a common causal variant(PP.H4=0.654). Conclusion Among the multiple metformin-related pathways, the pathway mediated by its core target PRKAB1 may play a protective role in the development of the fetal nervous system. This finding provides novel, pathway-specific genetic evidence supporting the safety of metformin use during pregnancy.

Causal associations of lipid-lowering drugs with skeletal diseases: a transethnic drug-target Mendelian randomization analysis

YU Haorui, CHEN Changhai, ZHANG Xiumei, YUAN Zhongshang

Journal of Shandong University (Health Sciences). 2026, 64(6): 94-103. doi:10.6040/j.issn.1671-7554.0.2025.1276

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Objective To assess the causal associations of five lipid-lowering drug classes—statins, cholesterol absorption inhibitors, proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors, ATP citrate lyase(ACL)inhibitors, and angiopoietin-like 3(ANGPTL3)inhibitors—with the risk of osteoporosis and osteoarthritis using a drug-target Mendelian randomization approach. Methods Summary statistics from publicly available genome-wide association studies were used. Five lipid-lowering drug classes were considered as exposures, and osteoporosis and osteoarthritis as outcomes. Drug-target Mendelian randomization analyses were conducted using inverse-variance weighting as the primary method, supplemented by seven additional methods. The false discovery rate(FDR)method was applied to correct for multiple comparisons. Heterogeneity tests, pleiotropy tests, and leave-one-out analyses were performed to assess robustness. Results PCSK9 inhibitor use showed a positive causal association with increased osteoporosis risk in both European(OR=1.169, 95%CI: 1.025-1.332, P_FDR=0.040)and East Asian populations(OR=1.370, 95%CI: 1.115-1.683, P_FDR=0.008). PCSK9 inhibitor use was also positively associated with osteoarthritis risk in the European population(OR=1.183, 95%CI: 1.102-1.271, P_FDR=1.46×10^-5). The causal association between statin use and osteoarthritis exhibited population heterogeneity: a positive association in the European population(OR=1.128, 95%CI: 1.01-1.259, P_FDR=0.040)and a negative association in the East Asian population(OR=0.440, 95%CI: 0.253-0.765, P_FDR=0.010). Cholesterol absorption inhibitor use was causally associated with reduced osteoarthritis risk in the European population(OR=0.723, 95%CI: 0.544-0.962, P_FDR=0.043). Conclusion PCSK9 inhibitor use increases the risk of osteoporosis in both European and East Asian populations, while the effect of statins on osteoarthritis is population-specific. These findings suggest that skeletal safety evaluation of lipid-lowering drugs should consider target specificity and population heterogeneity.

Integrative cross-omics analysis identifies pleiotropic genes shared by coronary artery disease and chronic obstructive pulmonary disease

CHEN Xinyi, HUANG Xin, SUN Xiubin, WANG Shukang, YUAN Zhongshang

Journal of Shandong University (Health Sciences). 2026, 64(6): 104-114. doi:10.6040/j.issn.1671-7554.0.2025.1159

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Objective To integrate transcriptome-wide association studies(TWAS)with pleiotropy analysis under a composite null hypothesis and to explore potential pleiotropic genes for coronary artery disease(CAD)and chronic obstructive pulmonary disease(COPD)from a transcriptomic perspective, providing new insights into the comorbid mechanisms of CAD and COPD. Methods Genome-wide association study(GWAS)summary data for CAD and COPD were obtained from the Million Veteran Program of The Department of Veterans Affairs, and gene expression reference weights for whole blood were derived from GTEx V8. TWAS was conducted using FUSION, and potential pleiotropic genes for CAD and COPD were analyzed using the gPLACO method developed in this study. Furthermore, enrichment analysis, protein-protein interaction analysis, Mendelian randomization analysis, and differential gene expression analysis were conducted on the CAD-COPD pleiotropic genes. Results After Benjamini-Hochberg correction, FUSION identified a total of 794 genes associated with CAD and 463 genes associated with COPD. gPLACO identified 79 pleiotropic genes shared between CAD and COPD, of which 62 were simultaneously significant in TWAS results for both diseases. GO enrichment analysis and transcription factor target gene enrichment further revealed potential biological pathways underlying CAD-COPD comorbidity, including carnitinetransmembrane transporter activity(P=6.03×10^-7)and MEF2C target gene(P=5.01×10^-3). Further protein-protein interaction analysis, Mendelian randomization analysis, and differential gene expression analysis also suggested STARD3 as a potential pleiotropic gene for CAD-COPD. Conclusion STARD3 is a potential pleiotropic gene for CAD-COPD, underscoring the critical roles of carnitine metabolism and endothelial function in their shared pathophysiology.

Association between multimorbidity of chronic diseases and subjective and objective cognitive function in rural middle-aged and older adults

MENG Kexin, WANG Qi, YU Ruihong, XU Ruiqi, FU Chunying, XIE Bo, ZHU Dongshan

Journal of Shandong University (Health Sciences). 2026, 64(6): 115-126. doi:10.6040/j.issn.1671-7554.0.2025.1162

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Objective To investigate the association between chronic diseases/multimorbidity and subjective/objective cognitive function among middle-aged and older adults in rural China, providing evidence for developing targeted intervention strategies. Methods Utilizing data from the Pingyin Chronic Disease and Cognitive Aging Cohort, 3,132 rural residents aged 45-70 years were enrolled through multi-stage sampling. Subjective cognitive decline was assessed using the subjective cognitive decline questionnaire-9(SCD-Q9), while objective cognitive function was evaluated with the Montreal cognitive assessment-basic(MoCA-B). Based on 19 chronic diseases, participants were categorized by multimorbidity level: no multimorbidity(0-1 disease), low-level multimorbidity(2-3 diseases), and high-level multimorbidity(≥4 diseases). Logistic regression and multiple linear regression models were applied to examine the associations. Results The prevalence rates of abnormal subjective and objective cognitive scores were 57.5% and 60.5%, respectively. Univariate analysis showed that both subjective and objective cognitive impairment rates increased with higher multimorbidity levels(P<0.001). Multivariable logistic regression analysis revealed that, after adjusting for demographic characteristics, lifestyle factors, and depression status, multimorbidity level was independently and positively associated with abnormal SCD-Q9 scores(low-level multimorbidity: OR=1.52, 95%CI: 1.27-1.82; high-level multimorbidity: OR=3.00, 95%CI: 1.80-5.03), but showed no independent association with abnormal MoCA-B scores(P>0.05). Multiple linear regression analysis further confirmed a linear dose-response relationship between the number of chronic diseases and SCD-Q9 scores(β=0.34, 95%CI: 0.27-0.42), whereas no significant association was found with MoCA-B scores. Advanced age, low education level, and depression were common risk factors for both subjective and objective cognitive impairment, while females exhibited higher susceptibility specifically to subjective cognitive decline. Conclusion Multimorbidity is significantly associated with subjective cognitive decline in a dose-response manner among rural middle-aged and older adults, but shows no independent association with objective cognitive impairment.

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