Objective:To identify genetic etiology of ischemic stroke(IS)based on pleiotropy of obe-sity related genes.Methods:A discordant sib-pair study was designed based on the Fangshan family co-hort in Beijing.Body mass index(BMI)polygenic risk score(PRS)was first constructed under different P values.Using the polygenic transmission disequilibrium test(pTDT),we then compared the actual BMI genetic risk of siblings with IS to their expected risk,to analyze whether higher BMI was over-trans-mitted to siblings with IS.The single nucleotide polymorphism(SNP)that comprised the PRS over-trans-mitted with IS and that corresponded to the highest heritability of IS were identified as a pleiotropy SNPs set between BMI and IS.This set was then utilized as a candidate set to identify and verify risk SNPs as-so-ciated IS by transmission disequilibrium test.Finally,we identified independent genomic risk loci and mapped to genes,we then explored the biological function of the identified risk loci and genes by func-tional annotation and pathway enrichment.Results:A total of 541 participants were enrolled,with an average age of(58.4±8.1)years,including 326 discordant sib pairs of ischemic stroke.Compared with non-IS participants,IS participants with males,education level below junior high school,hypertension and hyperlipidemia accounted for a higher proportion(P＜0.05).For all the BMI PRS,we found that the actual genetic risk of BMI in siblings with IS was higher than their expectation,suggesting that genetic risk associated with high BMI was over-transmitted with IS.Compared with other SNP sets,the set(P＜5 × 10-4)corresponded to the best analytical statistics of pTDT and the highest heritability of IS and was identified as the pleiotropy SNP set between BMI and IS.Within this set,there were 45 SNPs having linkage and association with IS,which were located in 43 independent genomic risk loci and mapped to 40 genes.These genes were significantly enriched in the lipid metabolism pathway.The rs2232852 cor-rected by multiple tests was mapped to CYB5R1 and ADIPOR1,which were related to lipid metabolism and the ferroptosis pathway.Conclusion:Pleiotropy between BMI-related genes and IS was observed.Forty-five SNPs were found with linkage and association with IS in the pleiotropy gene set and mapped to 40 genes,which were functionally enriched in lipid metabolic pathways.The rs2232852 corrected by multiple tests during association analysis validation was mapped to CYB5R1 and ADIPOR1,which were related to lipid metabolism and the ferroptosis pathway,suggesting that lipid metabolism and ferroptosis played an important role in the development of IS.

Objective:To explore the spousal correlations of total cholesterol(TC),total triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C),and to investigate the reasons behind these spousal correlations.Methods:Participants and data were from the baseline survey of family-based cohort studies in Fangshan,Beijing and Tulou,Fujian.The ori-gin of spousal correlations were explored from perspectives of convergence,assortative mating,social ho-mogamy.Pearson's correlation and generalized linear models(GLM)were used to estimate the spousal correlation.Convergence was assessed by Pearson's correlation between the phenotypic differences be-tween couples and the duration of marriage,with GLM used for further validation.Pearson's correlation of genetic risk scores(GRS)and couple-specific Mendelian randomization(MR)were calculated to assess the genetic correlation and possible causal relationships between spouses.Two-independent-sample t-tests were used to compare GRS consistency across subgroups divided by education attainment,couple-specific MR and Q statistics used to test assortative mating in subgroups and intergroup differences.Results:In the study,342 couples(287 couples from Fangshan and 55 couples from Fujian)were included,with the average age of(64.91±8.76)years.Spousal correlations of TC,TG,HDL-C,and LDL-C showed statistically significant associations both before and after adjusting for covariates,with effect sizes of 0.229(95％CI:0.125-0.327),0.257(95％CI:0.155-0.354),0.179(95％CI:0.074-0.280),and 0.181(95％CI:0.076-0.282).For convergence,for each additional year of marriage,ΔTC increased by 0.016 mmol/L(95％CI:0.001-0.033 mmol/L),and ΔLDL-C increased by 0.017 mmol/L(95％CI:0.002-0.031 mmol/L).For assortative mating,GRS correlations and results of couple specific MR didn't show any statistical significance.For social homogamy,no differences in GRS or assortative mating were found between subgroups stratified by education attainment.Conclusion:The blood lipid in participants exhibit spousal phenotypic correlations,however,no effects of convergence,assortative mating or social homogamy were observed.More independent studies with larger sample sizes are warranted to further validate these findings in the future.

Objective To study the immune regulatory effect of total flavonoids from houttuynia cordata on herpes simplex keratitis(HSK)mice and preliminarily explore its mechanism.Methods A surgical blade to mark the"#"character on the corneal epithelial layer of Balb/c mice and inoculate with I type herpes simplex virus(HSV-1)was used to construct an HSK model.The successfully identified HSK mice were randomly divided into model group,low(75 mg/kg)and high-dose(300 mg/kg)total flavonoids from houttuynia cordata groups,and high-dose total flavonoids from houttuynia cordata+toll like receptor(TLR)2 agonist Pam3CSK4(0.3 mg/kg)group.A control group was also established with 12 mice in each group.During the modeling and administration period,the corneal lesions in mice were observed daily using a slit-lamp microscope and scored.After administration,HE staining was used to observe the pathological changes of the mouse cornea.ELISA was used to detect the levels of interferon-γ(INF-γ),interleukin-2(IL-2),IL-4,and IL-6 in mouse serum.Western blot was used to detect the protein expression levels of TLR2,myeloid differentiation factor 88(MyD88),nuclear factor-kappaB p65(NF-κB p65)and p-NF-κB p65 in mouse corneal tissue.Results Compared with the control group,the model group mice showed corneal edema,ulcers,and neovascularization,with severe corneal damage and a large number of inflammatory cell infiltration.The serum levels of INF-γ and IL-2 significantly decreased,while the levels of IL-4 and IL-6 significantly increased(P<0.01).The protein expression levels of TLR2 and MyD88 and protein ratios of p-NF-κB p65/NF-κB p65 in corneal tissue significantly increased(P<0.01).Compared with the model group,the low and high dose of total flavonoids from houttuynia cordata groups showed improved corneal injury,the corneal lesion score significantly dereased(P<0.01).The serum levels of INF-γ and IL-2 significantly increased,while the levels of IL-4 and IL-6 significantly decreased(P<0.01).The protein expression levels of TLR2 and MyD88 and protein ratios of p-NF-κB p65/NF-κB p65 in corneal tissue significantly decreased(P<0.01).However,the TLR2 agonist Pam3CSK4 partially reversed the improvement effects of total flavonoids from houttuynia cordata on keratitis and immune imbalance in HSK mice.Conclusion The total flavonoids of houttuynia cordata can effectively improve corneal damage,regulate immune response,and suppress inflammation levels in HSK mice.Its mechanism of action may be related to the regulation of TLR2/NF-κB signaling pathway.

Objective To explore the medication patterns as well as the potential mechanism of action of traditional Chinese medicine in the treatment of presbycusis based on data mining and network pharmacology.Methods Search for the literatures on the treatment of presbycusis with traditional Chinese medicine in CNKI,Wanfang Data Knowledge Service Platform and VIP,conduct visual analyses such as association rule analysis and cluster analysis on them,and summarize the medication patterns and core drug combinations.Predict the action targets of drugs and diseases through network pharmacology,and obtain core targets and pathways.Results A total of 22 literatures were included,and 22 traditional Chinese medicine prescriptions were obtained,involving 72 kinds of traditional Chinese medicines,with a total frequency of administration of 238 times.The four natures of the medicine were mainly warm,the five flavors were mainly sweet,bitter and pungent,and channel tropism were mainly liver meridian and kidney meridian.The core drug combination was Shanzhuyu and Shudihuang.Network pharmacological analysis showed that this combination may improve presbycusis by influencing core targets such as protein kinase B(Akt)1 and interleukin-6,thereby intervening in related pathways such as advanced glycation end product/advanced glycation end product receptor signaling pathway and the phosphoinositide 3-kinase/Akt signaling pathway.Conclusion The treatment of presbycusis with traditional Chinese medicine mainly focuses on invigorating kidney for consolidating semen,while also circulate and nourish blood.Network pharmacology predicts the key mechanisms of core high-frequency drug treatment for presbycusis,providing data support and theoretical basis for the clinical treatment of traditional Chinese medicine.

Genomic imprinting refers to the phenomenon of differential expression of two alleles due to their different parental origins. Genes that produce genomic imprinting are usually called imprinted genes. The genetic effect caused by the presence of imprinted genes is called parent-of-origin effect. Parent-of-origin effect and genomic imprinting play important roles in the pathophysiological mechanism and occurrence and development of cardio-metabolic diseases. In-depth exploration of the law and potential roles of imprinted genes and parent-of-origin effects will help to better understand the mechanism of cardio-metabolic diseases, and also provide important theoretical basis for the precise treatment of diseases related to imprinted genes.

Objective:To evaluate the efficacy and safety of endoscopic submucosal dissection (ESD) for the treatment of ileocecal valve lipoma.Methods:A retrospective cohort study was performed on data of ileocecal lipoma patients who underwent ESD at the Endoscopy Center of Zhongshan Hospital, Fudan University from December 2013 to June 2023. According to the lesion location, the patients were divided into ileocecal valve group and cecum group. The operation time, operation speed, en bloc resection rate, complications, and follow-up outcomes between the two groups were compared.Results:A total of 59 patients with ileocecal lipoma were enrolled, including 31 patients in the ileocecal valve group and 28 patients in the cecum group.There were no significant differences in gender, age, specimen size, or lesion size between the two groups ( P>0.05). Lipomas in both the ileocecal valve group and the cecum group were successfully resected by ESD. The en bloc resection rates were 100.0% (31/31) and 92.9% (26/28) respectively, and the difference was not statistically significant ( χ2=0.033, P=0.133). Median operative duration significantly differed between the two groups ( ileocecal valve group 26 min VS cecum group 20 min, Z=-0.136, P=0.027), as did resection speed (ileocecal valve group 0.14 cm2/min VS cecum group 0.24 cm2/min, Z=-0.223, P=0.022). Adverse events included one postoperative fever in the ileocecal valve group and one delayed bleeding in the cecum group. During the median follow-up of 38 months (7-106 months), there was no case of residual tumor or recurrence. Conclusion:Despite technical challenges in ESD of ileocecal valve lipoma, it is still a safe, feasible and effective treatment method.

Genomic imprinting refers to the phenomenon of differential expression of two alleles due to their different parental origins. Genes that produce genomic imprinting are usually called imprinted genes. The genetic effect caused by the presence of imprinted genes is called parent-of-origin effect. Parent-of-origin effect and genomic imprinting play important roles in the pathophysiological mechanism and occurrence and development of cardio-metabolic diseases. In-depth exploration of the law and potential roles of imprinted genes and parent-of-origin effects will help to better understand the mechanism of cardio-metabolic diseases, and also provide important theoretical basis for the precise treatment of diseases related to imprinted genes.

Objective To study the immune regulatory effect of total flavonoids from houttuynia cordata on herpes simplex keratitis(HSK)mice and preliminarily explore its mechanism.Methods A surgical blade to mark the"#"character on the corneal epithelial layer of Balb/c mice and inoculate with I type herpes simplex virus(HSV-1)was used to construct an HSK model.The successfully identified HSK mice were randomly divided into model group,low(75 mg/kg)and high-dose(300 mg/kg)total flavonoids from houttuynia cordata groups,and high-dose total flavonoids from houttuynia cordata+toll like receptor(TLR)2 agonist Pam3CSK4(0.3 mg/kg)group.A control group was also established with 12 mice in each group.During the modeling and administration period,the corneal lesions in mice were observed daily using a slit-lamp microscope and scored.After administration,HE staining was used to observe the pathological changes of the mouse cornea.ELISA was used to detect the levels of interferon-γ(INF-γ),interleukin-2(IL-2),IL-4,and IL-6 in mouse serum.Western blot was used to detect the protein expression levels of TLR2,myeloid differentiation factor 88(MyD88),nuclear factor-kappaB p65(NF-κB p65)and p-NF-κB p65 in mouse corneal tissue.Results Compared with the control group,the model group mice showed corneal edema,ulcers,and neovascularization,with severe corneal damage and a large number of inflammatory cell infiltration.The serum levels of INF-γ and IL-2 significantly decreased,while the levels of IL-4 and IL-6 significantly increased(P<0.01).The protein expression levels of TLR2 and MyD88 and protein ratios of p-NF-κB p65/NF-κB p65 in corneal tissue significantly increased(P<0.01).Compared with the model group,the low and high dose of total flavonoids from houttuynia cordata groups showed improved corneal injury,the corneal lesion score significantly dereased(P<0.01).The serum levels of INF-γ and IL-2 significantly increased,while the levels of IL-4 and IL-6 significantly decreased(P<0.01).The protein expression levels of TLR2 and MyD88 and protein ratios of p-NF-κB p65/NF-κB p65 in corneal tissue significantly decreased(P<0.01).However,the TLR2 agonist Pam3CSK4 partially reversed the improvement effects of total flavonoids from houttuynia cordata on keratitis and immune imbalance in HSK mice.Conclusion The total flavonoids of houttuynia cordata can effectively improve corneal damage,regulate immune response,and suppress inflammation levels in HSK mice.Its mechanism of action may be related to the regulation of TLR2/NF-κB signaling pathway.

Objective:To identify genetic etiology of ischemic stroke(IS)based on pleiotropy of obe-sity related genes.Methods:A discordant sib-pair study was designed based on the Fangshan family co-hort in Beijing.Body mass index(BMI)polygenic risk score(PRS)was first constructed under different P values.Using the polygenic transmission disequilibrium test(pTDT),we then compared the actual BMI genetic risk of siblings with IS to their expected risk,to analyze whether higher BMI was over-trans-mitted to siblings with IS.The single nucleotide polymorphism(SNP)that comprised the PRS over-trans-mitted with IS and that corresponded to the highest heritability of IS were identified as a pleiotropy SNPs set between BMI and IS.This set was then utilized as a candidate set to identify and verify risk SNPs as-so-ciated IS by transmission disequilibrium test.Finally,we identified independent genomic risk loci and mapped to genes,we then explored the biological function of the identified risk loci and genes by func-tional annotation and pathway enrichment.Results:A total of 541 participants were enrolled,with an average age of(58.4±8.1)years,including 326 discordant sib pairs of ischemic stroke.Compared with non-IS participants,IS participants with males,education level below junior high school,hypertension and hyperlipidemia accounted for a higher proportion(P＜0.05).For all the BMI PRS,we found that the actual genetic risk of BMI in siblings with IS was higher than their expectation,suggesting that genetic risk associated with high BMI was over-transmitted with IS.Compared with other SNP sets,the set(P＜5 × 10-4)corresponded to the best analytical statistics of pTDT and the highest heritability of IS and was identified as the pleiotropy SNP set between BMI and IS.Within this set,there were 45 SNPs having linkage and association with IS,which were located in 43 independent genomic risk loci and mapped to 40 genes.These genes were significantly enriched in the lipid metabolism pathway.The rs2232852 cor-rected by multiple tests was mapped to CYB5R1 and ADIPOR1,which were related to lipid metabolism and the ferroptosis pathway.Conclusion:Pleiotropy between BMI-related genes and IS was observed.Forty-five SNPs were found with linkage and association with IS in the pleiotropy gene set and mapped to 40 genes,which were functionally enriched in lipid metabolic pathways.The rs2232852 corrected by multiple tests during association analysis validation was mapped to CYB5R1 and ADIPOR1,which were related to lipid metabolism and the ferroptosis pathway,suggesting that lipid metabolism and ferroptosis played an important role in the development of IS.

Objective:To explore the spousal correlations of total cholesterol(TC),total triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C),and to investigate the reasons behind these spousal correlations.Methods:Participants and data were from the baseline survey of family-based cohort studies in Fangshan,Beijing and Tulou,Fujian.The ori-gin of spousal correlations were explored from perspectives of convergence,assortative mating,social ho-mogamy.Pearson's correlation and generalized linear models(GLM)were used to estimate the spousal correlation.Convergence was assessed by Pearson's correlation between the phenotypic differences be-tween couples and the duration of marriage,with GLM used for further validation.Pearson's correlation of genetic risk scores(GRS)and couple-specific Mendelian randomization(MR)were calculated to assess the genetic correlation and possible causal relationships between spouses.Two-independent-sample t-tests were used to compare GRS consistency across subgroups divided by education attainment,couple-specific MR and Q statistics used to test assortative mating in subgroups and intergroup differences.Results:In the study,342 couples(287 couples from Fangshan and 55 couples from Fujian)were included,with the average age of(64.91±8.76)years.Spousal correlations of TC,TG,HDL-C,and LDL-C showed statistically significant associations both before and after adjusting for covariates,with effect sizes of 0.229(95％CI:0.125-0.327),0.257(95％CI:0.155-0.354),0.179(95％CI:0.074-0.280),and 0.181(95％CI:0.076-0.282).For convergence,for each additional year of marriage,ΔTC increased by 0.016 mmol/L(95％CI:0.001-0.033 mmol/L),and ΔLDL-C increased by 0.017 mmol/L(95％CI:0.002-0.031 mmol/L).For assortative mating,GRS correlations and results of couple specific MR didn't show any statistical significance.For social homogamy,no differences in GRS or assortative mating were found between subgroups stratified by education attainment.Conclusion:The blood lipid in participants exhibit spousal phenotypic correlations,however,no effects of convergence,assortative mating or social homogamy were observed.More independent studies with larger sample sizes are warranted to further validate these findings in the future.