Novel classes of porphyrazine macrocycles: effect of -delocalization, exocyclic coordination and quaternization processes

The pyrazinoporphyrazine macrocycles having formula [Py8TPyzPzH2], (Figure 1B) and its metal complexes [Py8TPyzPzM], with M = bivalent first transition series and non transition series metal ions, were extensively investigated by our group [1]. Structural and electronic features were studied by single crystal X-ray work, spectral (IR, UV-visible, NMR) and electrochemical investigations, and contributed by detailed theoretical DFT and TDDFT studies. The important role of the external pyridine rings has been examined by considering their capability of electronic contact with the central pyrazinoporphyrazine core. Their ability to coordinate metal centers [2] or to undergo quaternization processes at the N atoms [1b,c] has also been studied. The attention for applicative aspects has been particularly devoted to learn about their behavior as photosensitizers in PDT and their potentialities as multimodal anticancer agents [3, 2b-d]. The present thesis work has selected as the main subject the synthesis of two novel types of porphyrazine macrocycles, strictly related to the above considered “pyrazinoporphyrazines”, but showing a narrower (“restricted” macrocycle) or more extended porphyrazine core (“expanded” macrocycle”). The two compounds, in the form of unmetalated species are schematically shown in Figures 1A and 1C respectively. The targets of the present project were to explain: a) how the change in the expansion or contraction of the central planar or quasi-planar -conjugated skeleton, with respect to that of the pyrazinoporphyrazine core, will modify stability, solubility, tendency to aggregation, general physicochemical and redox behaviour of the new species and their applicative potentialities, with attention centered on their photoactivity properties; b) how the presence of the external pyridine rings, directly attached to the porphyrazine core (“restricted” macrocycle; Figure 1A) or more far away than in the already studied “pyrazinoporphyrazine” macrocycle (“expanded” macrocycle; Figure 1C) added of local metal coordination or quaternization processes, can produce consistent effects on the structural and electronic features of the new macrocyclic skeletons; c) how do the data concerning the response of the new species as photosensitizers compare with those already known for the original “pyrazinoporphyrazine” macrocycles. UV-visible spectral data in the low-donor nonaqueous solvents indicate that there is a progressive highly remarkable bathochromic shift of the barycentre of the overall spectrum in the direction pyridylporphyrazines pyrazinoporphyrazines quinoxalinoporphyrazines, in line with the parallel enhanced extension of the -conjugated system of the macrocycles in the order given. The eight external pyridines allow the accomplishment of exocyclic coordination and formation of pentanuclear species carrying externally PdCl2 and PtCl2. Figure 2 shows the pentametallic species for the pyridyl- (A) and quinoxalinoporphyrazines (B). Data at hand indicate that coordination of the PdII or PtII units takes place in all cases at the pyridine N atoms, and sites of the type N2(pyr)MCl2 (M = PdII, PtII; “py-py” coordination) are generated, displaying a square planar geometry and directed nearly perpendicularly to the plane of the central -conjugated macrocyclic system. External ligation modifies the UV-visible spectrum of the initial mononuclear species, the effect evidencing a bathochromic shift of the original main Q band by an average value of 15-20 nm. This remarkable shift is surprising if account is taken that exocyclic coordination of PdII and PtII, particularly for the pyrazino- and even more for the quinoxalinoporphyrazine compounds, takes place at the extreme periphery of the macrocycle and progressively more far away from the central metal. Further extension of the work focused on the synthesis of supercharged macrocycles for the pyridyl- and quinoxalinoporphyrazines. The new octacationic compounds which are moderately water soluble, were prepared from the mononuclear species upon reaction with CH3I, a process which results in the full N-methylation of the pyridine rings (Figure 3). The UV-visible spectra in water solution and in the low-donor solvents pyridine, DMSO and DMF show interesting effects which parallel those determined by the external metalation. The spectra evidence in the process from neutral to octacationic species a bathochromic shift of the Q bands about of the same order observed for the change mononuclear pentanuclear species. This means that the charged macrocycles enhance their electron deficiency; a fact that should be confirmed by the electrochemical behaviour in terms of the expected less negative half-wave potentials with respect to those pertinent to the neutral mononuclear species. The final challenge of some of the pyridyl- and quinoxalinoporphyrazines, especially those carrying centrally ZnII and MgII (closed shell metal ions) is their measured photoactivity for the generation in DMF of singlet oxygen, 1O2, the cytotoxic agent in the photodynamic therapy of cancer (PDT). The quantum yields of 1O2 measured, particularly for the two pyridylporphyazines having centrally ZnII and MgII, qualify these compounds as excellent photosensitizers. A combination of purity of the samples, water solubility, stability under the appropriate irradiation (600-750 nm), absence of aggregation in solution may be profitable for application in the PDT curative modality. The species carrying outside PtCl2 units may open perspectives for applications as bimodal PDT/cis-platin anticancer agents. Concomitant work was conducted on “pyrazinoporphyrazine” macrocycles carrying externally thienyl rings (Figure 4). The work on the thienyl pyrazinoporphyrazines involved modifications of the peripheral part of the macrocycle, focusing on the coordination properties of the S atoms inserted in the external 2-thienyl rings, in an interesting comparison with those seen for the pyridine rings in the pyridinated “pyrazinoporphyrazines” [4]. On the other hand the singlet oxygen and fluorescence response of the mono- and pentametallic complexes open perspectives for their potential use in PDT of cancer and for medical imaging and diagnosis. References: [1] a) Donzello, M. P.; Ou, Z.; Monacelli, F.; Ricciardi, G.; Rizzoli, C.; Ercolani, C.; Kadish, K. M. Inorg. Chem. 2004, 43, 8626; b) Donzello, M. P.; Ou, Z.; Dini, D.; Meneghetti, M.; Ercolani, C.; Kadish, K. M. Inorg. Chem., 2004, 43, 8637; c) Bergami, C.; Donzello, M. P.; Ercolani, C.; Monacelli, F.; Kadish, K. M.; Rizzoli, C. Inorg. Chem., 2005, 44, 9852; d) Bergami, C.; Donzello M. P.; Monacelli, F.; Ercolani, C.; Kadish, K. M. Inorg. Chem., 2005, 44, 9862. [2] a) Donzello, M. P.; Viola, E.; Cai, X.; Mannina, L.; Rizzoli, C.; Ricciardi, G.; Ercolani, C.; Kadish, K. M.; Rosa, A. Inorg. Chem., 2008, 47, 3903; b) Donzello, M. P.; Viola, E.; Cai, X.; Mannina, L.; Ercolani, C.; Kadish, K. M. Inorg. Chem., 2010, 49, 2447; c) Donzello, M. P.; Viola, E.; Mannina, L.; Barteri, M.; Fu, Z.; Ercolani, C. J. Porphyrins Phthalocyanines, 2011, 15, 984; d) Donzello, M. P.; Vittori, D.; Viola, E.; Manet, I.; Mannina , L.; Cellai, L.; Monti, S.; Ercolani, C. Inorg. Chem., 2011, 50, 7391. [3] Donzello, M. P.; Viola, E.; Bergami, C.; Dini, D.; Ercolani, C.; Giustini, M.; Kadish, K. M.; Meneghetti, M.; Monacelli, F.; Rosa, A.; Ricciardi, G. Inorg. Chem., 2008, 47, 8757. [4] a) De Mori, G.; Fu, Z.; Viola, E.; Cai, X.; Ercolani, C.; Donzello, M. P.; Kadish, K. M. Inorg. Chem., 2011, 50, 8225; b) Donzello, M.P.; De Mori, G.; Viola, E.; Ercolani, C.; Bodo, E.; Mannina, L.; Capitani, D.; Rizzoli, C.; Gontrani, L.; Aquilanti, G.; Kadish, K. M.; D’Angelo, P. Inorg. Chem., 2011, 50, 12116

Novel classes of porphyrazine macrocycles: effect of -delocalization, exocyclic coordination and quaternization processes

The pyrazinoporphyrazine macrocycles having formula [Py8TPyzPzH2], (Figure 1B) and its metal complexes [Py8TPyzPzM], with M = bivalent first transition series and non transition series metal ions, were extensively investigated by our group [1]. Structural and electronic features were studied by single crystal X-ray work, spectral (IR, UV-visible, NMR) and electrochemical investigations, and contributed by detailed theoretical DFT and TDDFT studies. The important role of the external pyridine rings has been examined by considering their capability of electronic contact with the central pyrazinoporphyrazine core. Their ability to coordinate metal centers [2] or to undergo quaternization processes at the N atoms [1b,c] has also been studied. The attention for applicative aspects has been particularly devoted to learn about their behavior as photosensitizers in PDT and their potentialities as multimodal anticancer agents [3, 2b-d]. The present thesis work has selected as the main subject the synthesis of two novel types of porphyrazine macrocycles, strictly related to the above considered “pyrazinoporphyrazines”, but showing a narrower (“restricted” macrocycle) or more extended porphyrazine core (“expanded” macrocycle”). The two compounds, in the form of unmetalated species are schematically shown in Figures 1A and 1C respectively. The targets of the present project were to explain: a) how the change in the expansion or contraction of the central planar or quasi-planar -conjugated skeleton, with respect to that of the pyrazinoporphyrazine core, will modify stability, solubility, tendency to aggregation, general physicochemical and redox behaviour of the new species and their applicative potentialities, with attention centered on their photoactivity properties; b) how the presence of the external pyridine rings, directly attached to the porphyrazine core (“restricted” macrocycle; Figure 1A) or more far away than in the already studied “pyrazinoporphyrazine” macrocycle (“expanded” macrocycle; Figure 1C) added of local metal coordination or quaternization processes, can produce consistent effects on the structural and electronic features of the new macrocyclic skeletons; c) how do the data concerning the response of the new species as photosensitizers compare with those already known for the original “pyrazinoporphyrazine” macrocycles. UV-visible spectral data in the low-donor nonaqueous solvents indicate that there is a progressive highly remarkable bathochromic shift of the barycentre of the overall spectrum in the direction pyridylporphyrazines pyrazinoporphyrazines quinoxalinoporphyrazines, in line with the parallel enhanced extension of the -conjugated system of the macrocycles in the order given. The eight external pyridines allow the accomplishment of exocyclic coordination and formation of pentanuclear species carrying externally PdCl2 and PtCl2. Figure 2 shows the pentametallic species for the pyridyl- (A) and quinoxalinoporphyrazines (B). Data at hand indicate that coordination of the PdII or PtII units takes place in all cases at the pyridine N atoms, and sites of the type N2(pyr)MCl2 (M = PdII, PtII; “py-py” coordination) are generated, displaying a square planar geometry and directed nearly perpendicularly to the plane of the central -conjugated macrocyclic system. External ligation modifies the UV-visible spectrum of the initial mononuclear species, the effect evidencing a bathochromic shift of the original main Q band by an average value of 15-20 nm. This remarkable shift is surprising if account is taken that exocyclic coordination of PdII and PtII, particularly for the pyrazino- and even more for the quinoxalinoporphyrazine compounds, takes place at the extreme periphery of the macrocycle and progressively more far away from the central metal. Further extension of the work focused on the synthesis of supercharged macrocycles for the pyridyl- and quinoxalinoporphyrazines. The new octacationic compounds which are moderately water soluble, were prepared from the mononuclear species upon reaction with CH3I, a process which results in the full N-methylation of the pyridine rings (Figure 3). The UV-visible spectra in water solution and in the low-donor solvents pyridine, DMSO and DMF show interesting effects which parallel those determined by the external metalation. The spectra evidence in the process from neutral to octacationic species a bathochromic shift of the Q bands about of the same order observed for the change mononuclear pentanuclear species. This means that the charged macrocycles enhance their electron deficiency; a fact that should be confirmed by the electrochemical behaviour in terms of the expected less negative half-wave potentials with respect to those pertinent to the neutral mononuclear species. The final challenge of some of the pyridyl- and quinoxalinoporphyrazines, especially those carrying centrally ZnII and MgII (closed shell metal ions) is their measured photoactivity for the generation in DMF of singlet oxygen, 1O2, the cytotoxic agent in the photodynamic therapy of cancer (PDT). The quantum yields of 1O2 measured, particularly for the two pyridylporphyazines having centrally ZnII and MgII, qualify these compounds as excellent photosensitizers. A combination of purity of the samples, water solubility, stability under the appropriate irradiation (600-750 nm), absence of aggregation in solution may be profitable for application in the PDT curative modality. The species carrying outside PtCl2 units may open perspectives for applications as bimodal PDT/cis-platin anticancer agents. Concomitant work was conducted on “pyrazinoporphyrazine” macrocycles carrying externally thienyl rings (Figure 4). The work on the thienyl pyrazinoporphyrazines involved modifications of the peripheral part of the macrocycle, focusing on the coordination properties of the S atoms inserted in the external 2-thienyl rings, in an interesting comparison with those seen for the pyridine rings in the pyridinated “pyrazinoporphyrazines” [4]. On the other hand the singlet oxygen and fluorescence response of the mono- and pentametallic complexes open perspectives for their potential use in PDT of cancer and for medical imaging and diagnosis. References: [1] a) Donzello, M. P.; Ou, Z.; Monacelli, F.; Ricciardi, G.; Rizzoli, C.; Ercolani, C.; Kadish, K. M. Inorg. Chem. 2004, 43, 8626; b) Donzello, M. P.; Ou, Z.; Dini, D.; Meneghetti, M.; Ercolani, C.; Kadish, K. M. Inorg. Chem., 2004, 43, 8637; c) Bergami, C.; Donzello, M. P.; Ercolani, C.; Monacelli, F.; Kadish, K. M.; Rizzoli, C. Inorg. Chem., 2005, 44, 9852; d) Bergami, C.; Donzello M. P.; Monacelli, F.; Ercolani, C.; Kadish, K. M. Inorg. Chem., 2005, 44, 9862. [2] a) Donzello, M. P.; Viola, E.; Cai, X.; Mannina, L.; Rizzoli, C.; Ricciardi, G.; Ercolani, C.; Kadish, K. M.; Rosa, A. Inorg. Chem., 2008, 47, 3903; b) Donzello, M. P.; Viola, E.; Cai, X.; Mannina, L.; Ercolani, C.; Kadish, K. M. Inorg. Chem., 2010, 49, 2447; c) Donzello, M. P.; Viola, E.; Mannina, L.; Barteri, M.; Fu, Z.; Ercolani, C. J. Porphyrins Phthalocyanines, 2011, 15, 984; d) Donzello, M. P.; Vittori, D.; Viola, E.; Manet, I.; Mannina , L.; Cellai, L.; Monti, S.; Ercolani, C. Inorg. Chem., 2011, 50, 7391. [3] Donzello, M. P.; Viola, E.; Bergami, C.; Dini, D.; Ercolani, C.; Giustini, M.; Kadish, K. M.; Meneghetti, M.; Monacelli, F.; Rosa, A.; Ricciardi, G. Inorg. Chem., 2008, 47, 8757. [4] a) De Mori, G.; Fu, Z.; Viola, E.; Cai, X.; Ercolani, C.; Donzello, M. P.; Kadish, K. M. Inorg. Chem., 2011, 50, 8225; b) Donzello, M.P.; De Mori, G.; Viola, E.; Ercolani, C.; Bodo, E.; Mannina, L.; Capitani, D.; Rizzoli, C.; Gontrani, L.; Aquilanti, G.; Kadish, K. M.; D’Angelo, P. Inorg. Chem., 2011, 50, 12116

Shifts of Faecal Microbiota during Sporadic Colorectal Carcinogenesis

Gut microbiota has been implicated in the etiopathogenesis of colorectal cancer. The development of colorectal cancer is a multistep process by which healthy epithelium slowly develops into preneoplastic lesions, which in turn progress into malignant carcinomas over time. In particular, sporadic colorectal cancers can arise from adenomas (about 85% of cases) or serrated polyps through the "adenoma-carcinoma" or the "serrated polyp-carcinoma" sequences, respectively. In this study, we performed 16 S rRNA gene sequencing of bacterial DNA extracted from faecal samples to compare the microbiota of healthy subjects and patients with different preneoplastic and neoplastic lesions. We identified putative microbial biomarkers associated with stage-specific progression of colorectal cancer. In particular, bacteria belonging to the Firmicutes and Actinobacteria phyla, as well as members of the Lachnospiraceae family, proved to be specific of the faecal microbiota of patients with preneoplastic lesions, including adenomas and hyperplastic polyps. On the other hand, two families of the Proteobacteria phylum, Alcaligeneaceae and Enterobacteriaceae, with Sutterella and Escherichia/Shigella being the most representative genera, appeared to be associated with malignancy. These findings, once confirmed on larger cohorts of patients, can represent an important step towards the development of more effective diagnostic strategies

Analogous Mechanisms of Resistance to Benzothiazinones and Dinitrobenzamides in Mycobacterium smegmatis

Tuberculosis is still a leading cause of death worldwide. The selection and spread of Mycobacterium tuberculosis multidrug-resistant (MDR-TB) and extensively drug-resistant strains (XDR-TB) is a severe public health problem. Recently, two different classes of chemical series, the benzothiazinones (BTZ) and the dinitrobenzamide (DNB) derivatives have been found to be highly active against M. tuberculosis, including XDR-TB strains. The target of BTZs is DprE1 protein which works in concert with DprE2 to form the heteromeric decaprenylphosphoryl-β-D-ribose 2′-epimerase, involved in Decaprenyl-Phospho-Arabinose (DPA) biosynthesis. Interestingly, it has been shown that the DNBs block the same pathway thus suggesting that both drugs could share the same target. Moreover, in Mycobacterium smegmatis the overexpression of the NfnB nitroreductase led to the inactivation of the BTZs by reduction of a critical nitro-group to an amino-group. In this work several spontaneous M. smegmatis mutants resistant to DNBs were isolated. Sixteen mutants, showing high levels of DNB resistance, exhibited a mutation in the Cys394 of DprE1. Using fluorescence titration and mass spectrometry it has been possible to monitor the binding between DprE1 and DNBs, achieving direct evidence that MSMEG_6382 is the cellular target of DNBs in mycobacteria. Additionally, M. smegmatis mutants having low levels of resistance to DNBs harbor various mutations in MSMEG_6503 gene encoding the transcriptional repressor of the nitroreductase NfnB. By LC/MS2 analysis it has been demonstrated that NfnB is responsible for DNB inactivation. Taken together, our data demonstrate that both DNB and BTZ drugs share common resistance mechanisms in M. smegmatis

Prediction of early distant recurrence in upfront resectable pancreatic adenocarcinoma: A multidisciplinary, machine learning-based approach

Despite careful selection, the recurrence rate after upfront surgery for pancreatic adenocarcinoma can be very high. We aimed to construct and validate a model for the prediction of early distant recurrence (<12 months from index surgery) after upfront pancreaticoduodenectomy. After exclusions, 147 patients were retrospectively enrolled. Preoperative clinical and radiological (CT-based) data were systematically evaluated; moreover, 182 radiomics features (RFs) were extracted. Most significant RFs were selected using minimum redundancy, robustness against delineation uncertainty and an original machine learning bootstrap-based method. Patients were split into training (n = 94) and validation cohort (n = 53). Multivariable Cox regression analysis was first applied on the training cohort; the resulting prognostic index was then tested in the validation cohort. Clinical (serum level of CA19.9), radiological (necrosis), and radiomic (SurfAreaToVolumeRatio) features were significantly associated with the early resurge of distant recurrence. The model combining these three variables performed well in the training cohort (p = 0.0015,HR = 3.58,95%CI = 1.98–6.71) and was then confirmed in the validation cohort (p = 0.0178,HR = 5.06,95%CI = 1.75–14.58). The comparison of survival curves between low and high-risk patients showed a p-value <0.0001. Our model may help to better define resectability status, thus providing an actual aid for pancreatic adenocarcinoma patients’ management (upfront surgery vs. neoadjuvant chemotherapy). Independent validations are warranted

High Risk of Secondary Infections Following Thrombotic Complications in Patients With COVID-19

Background. This study’s primary aim was to evaluate the impact of thrombotic complications on the development of secondary infections. The secondary aim was to compare the etiology of secondary infections in patients with and without thrombotic complications. Methods. This was a cohort study (NCT04318366) of coronavirus disease 2019 (COVID-19) patients hospitalized at IRCCS San Raffaele Hospital between February 25 and June 30, 2020. Incidence rates (IRs) were calculated by univariable Poisson regression as the number of cases per 1000 person-days of follow-up (PDFU) with 95% confidence intervals. The cumulative incidence functions of secondary infections according to thrombotic complications were compared with Gray’s method accounting for competing risk of death. A multivariable Fine-Gray model was applied to assess factors associated with risk of secondary infections. Results. Overall, 109/904 patients had 176 secondary infections (IR, 10.0; 95% CI, 8.8–11.5; per 1000-PDFU). The IRs of secondary infections among patients with or without thrombotic complications were 15.0 (95% CI, 10.7–21.0) and 9.3 (95% CI, 7.9–11.0) per 1000-PDFU, respectively (P = .017). At multivariable analysis, thrombotic complications were associated with the development of secondary infections (subdistribution hazard ratio, 1.788; 95% CI, 1.018–3.140; P = .043). The etiology of secondary infections was similar in patients with and without thrombotic complications. Conclusions. In patients with COVID-19, thrombotic complications were associated with a high risk of secondary infections

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk