Browsing by Author "Kumar, Rahul"

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    Hypobaric hypoxia drives selection of altitude-associated adaptative alleles in the Himalayan population
    (Elsevier, 2024) Sharma, Samantha; Koshy, Remya; Kumar, Rahul; Mohammad, Ghulam; Thinlas, Tashi; Graham, Brian B.; Pasha, Qadar; Medical and Molecular Genetics, School of Medicine
    Genetic variants play a crucial role in shaping the adaptive phenotypes associated with high-altitude populations. Nevertheless, a comprehensive understanding of the specific impacts of different environments associated with increasing altitudes on the natural selection of these genetic variants remains undetermined. Hence, this study aimed to identify genetic markers responsible for high-altitude adaptation with specific reference to different altitudes, majorly focussing on an altitude elevation range of ∼1500 m and a corresponding decrease of ≥5 % in ambient oxygen availability. We conducted a comprehensive genome-wide investigation (n = 192) followed by a validation study (n = 514) in low-altitude and three high-altitude populations (>2400 m) of Nubra village (NU) (3048 m), Sakti village (SKT) (3812 m), and Tso Moriri village (TK) (4522 m). Extensive genetic analysis identified 86 SNPs that showed significant associations with high-altitude adaptation. Frequency mapping of these SNPs revealed 38 adaptive alleles and specific haplotypes that exhibited a strong linear correlation with increasing altitude. Notably, these SNPs spanned crucial genes, such as ADH6 and NAPG along with the vastly studied genes like EGLN1 and EPAS1, involved in oxygen sensing, metabolism, and vascular homeostasis. Correlation analyses between these adaptive alleles and relevant clinical and biochemical markers provided evidence of their functional relevance in physiological adaptation to hypobaric hypoxia. High-altitude population showed a significant increase in plasma 8-isoPGF2α levels as compared to low-altitude population. Similar observation showcased increased blood pressure in NU as compared to TK (P < 0.0001). In silico analyses further confirmed that these alleles regulate gene expression of EGLN1, EPAS1, COQ7, NAPG, ADH6, DUOXA1 etc. This study provides genetic insights into the effects of hypobaric-hypoxia on the clinico-physiological characteristics of natives living in increasing high-altitude regions. Overall, our findings highlight the synergistic relationship between environment and evolutionary processes, showcasing physiological implications of genetic variants in oxygen sensing and metabolic pathway genes in increasing high-altitude environments.
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    Liver injury after SARS-CoV-2 vaccination: Features of immune-mediated hepatitis, role of corticosteroid therapy and outcome
    (Wolters Kluwer, 2022) Efe, Cumali; Kulkarni, Anand V.; Beretta-Piccoli, Benedetta Terziroli; Magro, Bianca; Stättermayer, Albert; Cengiz, Mustafa; Clayton-Chubb, Daniel; Lammert, Craig; Bernsmeier, Christine; Gül, Özlem; Higuera-de la Tijera, Fatima; Anders, Margarita; Lytvyak, Ellina; Akın, Mete; Purnak, Tugrul; Liberal, Rodrigo; Peralta, Mirta; Ebik, Berat; Duman, Serkan; Demir, Nurhan; Balaban, Yasemin; Urzua, Álvaro; Contreras, Fernando; Venturelli, Maria Grazia; Bilgiç, Yılmaz; Medina, Adriana; Girala, Marcos; Günşar, Fulya; Londoño, Maria-Carlota; Androutsakos, Theodoros; Kisch, Ayelen; Yurci, Alper; Güzelbulut, Fatih; Çağın, Yasir Furkan; Avcı, Enver; Akyıldız, Murat; Dindar-Demiray, Emine Kübra; Harputluoğlu, Murat; Kumar, Rahul; Satapathy, Sanjaya K.; Mendizabal, Manuel; Silva, Marcelo; Fagiuoli, Stefano; Roberts, Stuart K.; Soylu, Neşe Karadağ; Idilman, Ramazan; Yoshida, Eric M.; Montano-Loza, Aldo J.; Dalekos, George N.; Ridruejo, Ezequiel; Schiano, Thomas D.; Wahlin, Staffan; Medicine, School of Medicine
    Background and aims: A few case reports of autoimmune hepatitis-like liver injury have been reported after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. We evaluated clinical features, treatment response and outcomes of liver injury following SARS-CoV-2 vaccination in a large case series. Approach and results: We collected data from cases in 18 countries. The type of liver injury was assessed with the R-value. The study population was categorized according to features of immune-mediated hepatitis (positive autoantibodies and elevated immunoglobulin G levels) and corticosteroid therapy for the liver injury. We identified 87 patients (63%, female), median age 48 (range: 18-79) years at presentation. Liver injury was diagnosed a median 15 (range: 3-65) days after vaccination. Fifty-one cases (59%) were attributed to the Pfizer-BioNTech (BNT162b2) vaccine, 20 (23%) cases to the Oxford-AstraZeneca (ChAdOX1 nCoV-19) vaccine and 16 (18%) cases to the Moderna (mRNA-1273) vaccine. The liver injury was predominantly hepatocellular (84%) and 57% of patients showed features of immune-mediated hepatitis. Corticosteroids were given to 46 (53%) patients, more often for grade 3-4 liver injury than for grade 1-2 liver injury (88.9% vs. 43.5%, p = 0.001) and more often for patients with than without immune-mediated hepatitis (71.1% vs. 38.2%, p = 0.003). All patients showed resolution of liver injury except for one man (1.1%) who developed liver failure and underwent liver transplantation. Steroid therapy was withdrawn during the observation period in 12 (26%) patients after complete biochemical resolution. None had a relapse during follow-up. Conclusions: SARS-CoV-2 vaccination can be associated with liver injury. Corticosteroid therapy may be beneficial in those with immune-mediated features or severe hepatitis. Outcome was generally favorable, but vaccine-associated liver injury led to fulminant liver failure in one patient.
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    MYBL1 rearrangements and MYB amplification in breast adenoid cystic carcinomas lacking the MYB–NFIB fusion gene
    (Wiley, 2017) Kim, Jisun; Geyer, Felipe C.; Martelotto, Luciano G.; Ng, Charlotte K. Y.; Lim, Raymond S.; Selenica, Pier; Li, Anqi; Pareja, Fresia; Fusco, Nicola; Edelweiss, Marcia; Kumar, Rahul; Gularte-Merida, Rodrigo; Forbes, Andre N.; Khurana, Ekta; Mariani, Odette; Badve, Sunil; Vincent-Salomon, Anne; Norton, Larry; Reis-Filho, Jorge S.; Weigelt, Britta; Pathology and Laboratory Medicine, School of Medicine
    Breast adenoid cystic carcinoma (AdCC), a rare type of triple-negative breast cancer, has been shown to be driven by MYB pathway activation, most often underpinned by the MYB–NFIB fusion gene. Alternative genetic mechanisms, such as MYBL1 rearrangements, have been reported in MYB–NFIB-negative salivary gland AdCCs. Here we report on the molecular characterization by massively parallel sequencing of four breast AdCCs lacking the MYB–NFIB fusion gene. In two cases, we identified MYBL1 rearrangements (MYBL1–ACTN1 and MYBL1–NFIB), which were associated with MYBL1 overexpression. A third AdCC harboured a high-level MYB amplification, which resulted in MYB overexpression at the mRNA and protein levels. RNA-sequencing and whole-genome sequencing revealed no definite alternative driver in the fourth AdCC studied, despite high levels of MYB expression and the activation of pathways similar to those activated in MYB–NFIB-positive AdCCs. In this case, a deletion encompassing the last intron and part of exon 15 of MYB, including the binding site of ERG-1, a transcription factor that may downregulate MYB, and the exon 15 splice site, was detected. In conclusion, we demonstrate that MYBL1 rearrangements and MYB amplification probably constitute alternative genetic drivers of breast AdCCs, functioning through MYBL1 or MYB overexpression. These observations emphasize that breast AdCCs probably constitute a convergent phenotype, whereby activation of MYB and MYBL1 and their downstream targets can be driven by the MYB–NFIB fusion gene, MYBL1 rearrangements, MYB amplification, or other yet to be identified mechanisms. Copyright © 2017 Pathological Society of Great Britain and Ireland.