Biomarkers and Therapeutic Drugs for Pregnancy Complications in patients with PCOS
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical-Adult
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Secondary Categories:
- Clinical-Adult & Pediatric
Introduction:
Women with polycystic ovary syndrome (PCOS) are prone to pregnancy complications, including gestational diabetes, gestational hypertension, preeclampsia, and sponteneous abortion. However, biomarkers and therapeutic drugs in predicting pregnancy complications in PCOS patients are limited.
Methods:
Our study acquired PCOS from FinnGen biobank. Gestational hypertension, gestational diabetes, sponteneous abortion, and preeclampsia GWAS summary statistics were acquired from UK biobank. Metabolome, gut microbiota, and immunocytes were obtained for two-step Mendelian randomization (MR), with aim to identify metabolites, gut microbiota and immunocytes mediating the PCOS and pregnancy complications. pQTL, and eQTL data were employed for MR and summary-data-based Mendelian Randomization (SMR), respectively, with aim to identify therapeutic targets. Specifically, we employed the inverse variance weighted (IVW) method to calculate the MR effect estimates, and P<0.05 was used as statistical significance. HEIDI tests were leveraged to verify the results of SMR. P_SMR<0.05 and p_HEIDI >0.01 were used as statistical significance. At last, Drug-Gene Interaction Database (DGIdb) was used to predict drugs based on therapeutic targets.
Results:
PCOS has causal effect on 24 metabolites, 16 gut microbiota, and 19 immunocytes. 54 metabolites, 15 gut microbiota, and 31 immunocytes have causal effect on gestational hypertension. 53 metabolites, 9 gut microbiota, and 29 immunocytes have causal effect on gestational diabetes. 72 metabolites, 16 gut microbiota, and 43 immunocytes have causal effect on preeclampsia. 75 metabolites, 23 gut microbiota, and 24 immunocytes have causal effect on sponteneous abortion.
One metabolites (Iminodiacetate (IDA) levels), but no gut microbiota or immunocyte, serve as mediators between PCOS and gestational hypertension, indicating IDA levels may be biomarkers for gestational hypertension in PCOS. No metabolites, gut microbiota, or immunocyte serve as mediators between PCOS and gestational diabetes. No metabolites, gut microbiota, or immunocyte serve as mediators between PCOS and preeclampsia. One metabolites (N-acetyl-isoputreanine levels), one gut microbiota (Bacteroides abundance) but no immunocyte serve as mediators between PCOS and sponteneous abortion, indicating N-acetyl-isoputreanine levels and Bacteroides abundance may be biomarkers for sponteneous abortion in PCOS. Based on pQTL and eQTL, 43 genes (SWP70, ASIC1, EMC9, ERC1, FLI1, GCLC, GPX1, MED29, METTL7A, MYO1B, NOMO3, NR1H3, PPIP5K2, PSME1, RAB33B, SLC39A13, SLC9B2, TLE3, TMEM214, UBN1, ABHD1, AGBL5, CGREF1, CTTNBP2, DGKZ, DNAAF1, EPS15L1, KHK, KLHL7, MAD2L1BP, MAPRE3, MIER1, OSTM1, PDRG1, PLCH1, RBM47, RPL10A, SLCO4A1, SMARCD1, SRGAP1, SRGAP2C, XKR6, ZNF497) were identified as therapeutic targets for gestational hypertension in PCOS. 19 genes (TIMD4, FLI1, HAUS2, HEATR5B, NSMCE2, PHC3, PIK3R4, PLGRKT, UBN1, VAPB, FLI1, HAUS2, HEATR5B, NSMCE2, PHC3, PIK3R4, PLGRKT, UBN1, VAPB) were identified as therapeutic targets for gestational diabetes in PCOS. 14 genes (BUD31, CKS2, FAM228B, MAFF, NPL, RPRD2, SGTA, SNAPC4, ZSCAN25, FKBP1B, NDUFAF6, SPP1, ZBTB17) were identified as therapeutic targets for preeclampsia in PCOS. 29 genes (DPEP2, DRD4, HERC4, KAT8, KCNQ4, KRTCAP2, NDUFAF6, RAD9B, SETD1A, STX4, VPS29, YPEL5, ZNF431, C1orf21, DUSP28, EFNA1, ESRP2, IL2RA, IMMT, KBTBD7, MTX1, NAA30, PRR14, RAPSN, SLC7A6OS, TANK, THBS3, ZNF646) were identified as therapeutic targets for sponteneous abortion in PCOS. Based on common therapeutic targets, 1 (Icatibant), 4 (Copanlisib, Infigratinib, Quercetin, Alpelisib), 28 (Capmatinib, Haloperidol lactate, Tepotinib, Amifampridine phosphate, Guanidine hydrochloride, Amifampridine, Loxapine hydrochloride, Olanzapine pamoate, Dalfampridine, Loxapine succinate, Droperidol, Promazine hydrochloride, Clothiapine, Alectinib, Trifluoperazine, Hydrochloride loxapine, Methotrimeprazine, Amoxapine, Chlorpromazine, Hydrochloride, Cabozantinib s-malate, Olanzapine, Crizotinib, Thioridazine, Pimozide, Chlorpromazine, Haloperidol, and Decanoate) were identified as potential drugs for pregnancy hypertension, pregnancy diabetes, and sponteneous abortion in PCOS, respectively. However, no drugs were identified for preeclampsia in PCOS.
Conclusion:
Our results first suggested biomarkers in predicting pregnancy complications in PCOS based on MR. Therapeutic drugs might provide individualized treatment.
Women with polycystic ovary syndrome (PCOS) are prone to pregnancy complications, including gestational diabetes, gestational hypertension, preeclampsia, and sponteneous abortion. However, biomarkers and therapeutic drugs in predicting pregnancy complications in PCOS patients are limited.
Methods:
Our study acquired PCOS from FinnGen biobank. Gestational hypertension, gestational diabetes, sponteneous abortion, and preeclampsia GWAS summary statistics were acquired from UK biobank. Metabolome, gut microbiota, and immunocytes were obtained for two-step Mendelian randomization (MR), with aim to identify metabolites, gut microbiota and immunocytes mediating the PCOS and pregnancy complications. pQTL, and eQTL data were employed for MR and summary-data-based Mendelian Randomization (SMR), respectively, with aim to identify therapeutic targets. Specifically, we employed the inverse variance weighted (IVW) method to calculate the MR effect estimates, and P<0.05 was used as statistical significance. HEIDI tests were leveraged to verify the results of SMR. P_SMR<0.05 and p_HEIDI >0.01 were used as statistical significance. At last, Drug-Gene Interaction Database (DGIdb) was used to predict drugs based on therapeutic targets.
Results:
PCOS has causal effect on 24 metabolites, 16 gut microbiota, and 19 immunocytes. 54 metabolites, 15 gut microbiota, and 31 immunocytes have causal effect on gestational hypertension. 53 metabolites, 9 gut microbiota, and 29 immunocytes have causal effect on gestational diabetes. 72 metabolites, 16 gut microbiota, and 43 immunocytes have causal effect on preeclampsia. 75 metabolites, 23 gut microbiota, and 24 immunocytes have causal effect on sponteneous abortion.
One metabolites (Iminodiacetate (IDA) levels), but no gut microbiota or immunocyte, serve as mediators between PCOS and gestational hypertension, indicating IDA levels may be biomarkers for gestational hypertension in PCOS. No metabolites, gut microbiota, or immunocyte serve as mediators between PCOS and gestational diabetes. No metabolites, gut microbiota, or immunocyte serve as mediators between PCOS and preeclampsia. One metabolites (N-acetyl-isoputreanine levels), one gut microbiota (Bacteroides abundance) but no immunocyte serve as mediators between PCOS and sponteneous abortion, indicating N-acetyl-isoputreanine levels and Bacteroides abundance may be biomarkers for sponteneous abortion in PCOS. Based on pQTL and eQTL, 43 genes (SWP70, ASIC1, EMC9, ERC1, FLI1, GCLC, GPX1, MED29, METTL7A, MYO1B, NOMO3, NR1H3, PPIP5K2, PSME1, RAB33B, SLC39A13, SLC9B2, TLE3, TMEM214, UBN1, ABHD1, AGBL5, CGREF1, CTTNBP2, DGKZ, DNAAF1, EPS15L1, KHK, KLHL7, MAD2L1BP, MAPRE3, MIER1, OSTM1, PDRG1, PLCH1, RBM47, RPL10A, SLCO4A1, SMARCD1, SRGAP1, SRGAP2C, XKR6, ZNF497) were identified as therapeutic targets for gestational hypertension in PCOS. 19 genes (TIMD4, FLI1, HAUS2, HEATR5B, NSMCE2, PHC3, PIK3R4, PLGRKT, UBN1, VAPB, FLI1, HAUS2, HEATR5B, NSMCE2, PHC3, PIK3R4, PLGRKT, UBN1, VAPB) were identified as therapeutic targets for gestational diabetes in PCOS. 14 genes (BUD31, CKS2, FAM228B, MAFF, NPL, RPRD2, SGTA, SNAPC4, ZSCAN25, FKBP1B, NDUFAF6, SPP1, ZBTB17) were identified as therapeutic targets for preeclampsia in PCOS. 29 genes (DPEP2, DRD4, HERC4, KAT8, KCNQ4, KRTCAP2, NDUFAF6, RAD9B, SETD1A, STX4, VPS29, YPEL5, ZNF431, C1orf21, DUSP28, EFNA1, ESRP2, IL2RA, IMMT, KBTBD7, MTX1, NAA30, PRR14, RAPSN, SLC7A6OS, TANK, THBS3, ZNF646) were identified as therapeutic targets for sponteneous abortion in PCOS. Based on common therapeutic targets, 1 (Icatibant), 4 (Copanlisib, Infigratinib, Quercetin, Alpelisib), 28 (Capmatinib, Haloperidol lactate, Tepotinib, Amifampridine phosphate, Guanidine hydrochloride, Amifampridine, Loxapine hydrochloride, Olanzapine pamoate, Dalfampridine, Loxapine succinate, Droperidol, Promazine hydrochloride, Clothiapine, Alectinib, Trifluoperazine, Hydrochloride loxapine, Methotrimeprazine, Amoxapine, Chlorpromazine, Hydrochloride, Cabozantinib s-malate, Olanzapine, Crizotinib, Thioridazine, Pimozide, Chlorpromazine, Haloperidol, and Decanoate) were identified as potential drugs for pregnancy hypertension, pregnancy diabetes, and sponteneous abortion in PCOS, respectively. However, no drugs were identified for preeclampsia in PCOS.
Conclusion:
Our results first suggested biomarkers in predicting pregnancy complications in PCOS based on MR. Therapeutic drugs might provide individualized treatment.
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