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3. A Pilot Genome-Wide Analysis Study Identifies Loci Associated With Response to Obeticholic Acid in Patients With NASH.

Author

Gawrieh, Samer, Guo, Xiuqing, Tan, Jingyi, Lauzon, Marie, Taylor, Kent D, Loomba, Rohit, Cummings, Oscar W, Pillai, Sreekumar, Bhatnagar, Pallav, Kowdley, Kris V, Yates, Katherine, Wilson, Laura A, Chen, Yii-Der Ida, Rotter, Jerome I, Chalasani, Naga, and NASH Clinical Research Network

Subjects
NASH Clinical Research Network
Abstract

A significantly higher proportion of patients with nonalcoholic steatohepatitis (NASH) who received obeticholic acid (OCA) had histological improvement relative to placebo in the FLINT (farnesoid X nuclear receptor ligand obeticholic acid for noncirrhotic, NASH treatment) trial. However, genetic predictors of response to OCA are unknown. We conducted a genome-wide association study (GWAS) in FLINT participants to identify variants associated with NASH resolution and fibrosis improvement. Genotyping was performed using the Omni2.5 content GWAS chip. To avoid false positives introduced by population stratification, we focused our GWAS on white participants. Six regions on chromosomes 1, 4, 6, 7, 15, and 17 had multiple single nucleotide polymorphisms (SNPs) with suggestive association (P

Published
2019

4. Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Author

't Hart, L.M., Abdalla, M., Adam, J., Adamski, J., Adragni, K., Allin, K.H., Arumugam, M., Atabaki Pasdar, N., Baltauss, T., Banasik, K.B., Baum, P., Bell, J.D., Bergstrom, M., Beulens, J.W., Bianzano, S., Bizzotto, R., Bonneford, A., Brorsson, C.A.B., Brown, A.A., Brunak, S.B., Cabrelli, L., Caiazzo, R., Canouil, M., Dale, M., Davtian, D., Dawed, A.Y., De Masi, F.M., de Preville, N., Dekkers, K.F., Dermitzakis, E.T., Deshmukh, H.A., Dings, C., Donnelly, L., Dutta, A., Ehrhardt, B., Elders, P.J.M., Engel Thomas, C.E.T., Engelbrechtsen, L., Eriksen, R.G., Eriksen, R.E., Fan, Y., Fernandez, J., Ferrer, J., Fitipaldi, H., Forgie, I.M., Forman, A., Franks, P.W., Frau, F., Fritsche, A., Froguel, P., Frost, G., Gassenhuber, J., Giordano, G.N., Giorgino, T., Gough, S., Graefe-Mody, U., Grallert, H., Grempler, R., Groeneveld, L., Groop, L., Gudmundsdóttir, V.G., Gupta, R.G., Haid, M., Hansen, T., Hansen, T.H., Hattersley, A.T., Haussler, R.S., Heggie, A.J., Hennige, A.M., Hill, A.V., Holl, R.W., Hong, M.-G., Hudson, M., Jablonka, B., Jennison, C., Jiao, J., Johansen, J.J., Jones, A.G., Jonsson, A., Karaderi, T.K., Kaye, J., Klintenberg, M., Koivula, R.W., Kokkola, T., Koopman, A.D.M., Kurbasic, A, Kuulasmaa, T., Laakso, M., Lehr, T., Loftus, H., Lundbye Allesøe, R.L.A, Mahajan, A., Mari, A., Mazzoni, G.M., McCarthy, M.I., McDonald, T.J., McEvoy, D., McRobert, N., McVittie, I., Mourby, M., Musholt, P., Mutie, P, Nice, R., Nicolay, C., Nielsen, A.M.N., Nilsson, B.N., Palmer, C.N., Pattou, F., Pavo, I., Pearson, E.R., Pedersen, O., Pedersen, H.K.P., Perry, M.H., Pomares-Millan, H., Ramisch, A., Rasmussen, S.R., Raverdi, V., Ridderstrale, M., Robertson, N., Roderick, R.C., Rodriquez, M., Ruetten, H., Rutters, F., Sackett, W., Scherer, N., Schwenk, J.M., Shah, N., Sharma, S., Sihinevich, I., Sondertoft, N.B., Staerfeldt, H., Steckel-Hamann, B., Teare, H., Thomas, M.K., Thomas, E.L., Thomsen, H.S., Thorand, B., Thorne, C.E., Tillner, J., Troen Lundgaard, A.T.L., Troll, M., Tsirigos, K.D.T., Tura, A., Uhlen, M., van Leeuwen, N., van Oort, S., Verkindt, H., Vestergaard, H., Viñuela, A., Vogt, J.K, Wad Sackett, P.W.S, Wake, D., Walker, M., Wesolowska-Andersen, A., Whitcher, B., White, M.W., Wu, H., Dawed, Adem Y, Mari, Andrea, Brown, Andrew, McDonald, Timothy J, Li, Lin, Wang, Shuaicheng, Hong, Mun-Gwan, Sharma, Sapna, Robertson, Neil R, Mahajan, Anubha, Wang, Xuan, Walker, Mark, Gough, Stephen, Hart, Leen M ‘t, Zhou, Kaixin, Forgie, Ian, Ruetten, Hartmut, Pavo, Imre, Bhatnagar, Pallav, Jones, Angus G, and Pearson, Ewan R

Published
2023
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6. Pharmacogenomics of GLP-1 receptor agonists : a genome-wide analysis of observational data and large randomised controlled trials

Author

Dawed, Adem Y., Mari, Andrea, Brown, Andrew, McDonald, Timothy J., Li, Lin, Wang, Shuaicheng, Hong, Mun-Gwan, Sharma, Sapna, Robertson, Neil R., Mahajan, Anubha, Wang, Xuan, Walker, Mark, Gough, Stephen, Hart, Leen M. 't, Zhou, Kaixin, Forgie, Ian, Ruetten, Hartmut, Pavo, Imre, Bhatnagar, Pallav, Jones, Angus G., Pearson, Ewan R., DIRECT consortium, for the D. I. R. E. C. T. consortium, Dawed, Adem Y., Mari, Andrea, Brown, Andrew, McDonald, Timothy J., Li, Lin, Wang, Shuaicheng, Hong, Mun-Gwan, Sharma, Sapna, Robertson, Neil R., Mahajan, Anubha, Wang, Xuan, Walker, Mark, Gough, Stephen, Hart, Leen M. 't, Zhou, Kaixin, Forgie, Ian, Ruetten, Hartmut, Pavo, Imre, Bhatnagar, Pallav, Jones, Angus G., Pearson, Ewan R., and DIRECT consortium, for the D. I. R. E. C. T. consortium

Abstract

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1 receptor agonist treatment. Methods: In this genome-wide analysis we included adults (aged >= 18 years) with type 2 diabetes treated with GLP-1 receptor agonists with baseline HbA1c of 7% or more (53 mmol/mol) from four prospective observational cohorts (DIRECT, PRIBA, PROMASTER, and GoDARTS) and two randomised clinical trials (HARMONY phase 3 and AWARD). The primary endpoint was HbA1c reduction at 6 months after starting GLP-1 receptor agonists. We evaluated variants in GLP1R, then did a genome-wide association study and gene-based burden tests. Findings: 4571 adults were included in our analysis, of these, 3339 (73%) were White European, 449 (10%) Hispanic, 312 (7%) American Indian or Alaskan Native, and 471 (10%) were other, and around 2140 (47%) of the participants were women. Variation in HbA1c reduction with GLP-1 receptor agonists treatment was associated with rs6923761G -> A (Gly168Ser) in the GLP1R (0.08% [95% CI 0.04-0.12] or 0.9 mmol/mol lower reduction in HbA1c per serine, p=6.0 x 10(-5)) and low frequency variants in ARRB1 (optimal sequence kernel association test p=6.7 x 10(-8)), largely driven by rs140226575G -> A (Thr370Met; 0.25% [SE 0.06] or 2.7 mmol/mol [SE 0.7] greater HbA1c reduction per methionine, p=5.2 x 10(-6)). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian or Alaska Native populations who have a higher frequency of this variant (6-11%) than in White European populations. Combining these two genes i

Published
2023
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7. Efficacy of MCIMT with Auditory Cueing in order to Augment Functional Motor Recovery of Chronic Hemiparetic Arm

Author

Sharma, Himanshu, Bhatnagar, Pallav, jain, Kapila, Goyal, Bhupesh, Joshi, Nikita, Sharma, Himanshu, Bhatnagar, Pallav, jain, Kapila, Goyal, Bhupesh, and Joshi, Nikita

Abstract

Background: Stroke is a leading cause of functional impairments globally, often resulting in long-term disability and a substantial impact on individuals, families, and caregivers. Learned nonuse, a phenomenon where motor deficits persist after a stroke due to central nervous system suppression, is a significant challenge in stroke rehabilitation. Constraint-Induced Movement Therapy (CIMT) is a well-established neurorehabilitation approach based on behavioural training, which includes repetitive task-specific training, behavioural techniques, and constraining the use of the more affected upper extremity. CIMT has been successful in improving functionality in chronic hemiparetic stroke patients, promoting cortical reorganization and neural plasticity. Method: This study involved 60 stroke survivors aged 20 or older, selected purposively and meeting specific criteria. Participants underwent an 8-week Modified CIMT (M-CIMT) program with auditory cueing for the hemiparetic upper limb. Data collection included pre-test and post-test assessments using the Wolf Motor Function Test (WMFT) and the Motor Activity Log (MAL) to evaluate functional activity. The M-CIMT program comprised warm-up sessions, M-CIMT protocols, and cool-down exercises, conducted five days a week. Results: Following participation in the M-CIMT program, significant improvements were observed in WMFT and MAL scores. The mean pre-test score of 46.60 seconds decreased to a mean post-test score of 16.85 seconds, with highly significant t-values of 14.292 and -51.356 and a p-value of 0.0, indicating a strong correlation between the two datasets. The analysis revealed that M-CIMT effectively enhanced upper extremity function in chronic stroke patients. Conclusion: This study highlights the effectiveness of the Modified CIMT protocol, emphasizing repeated use and a distributed practice schedule, in reducing upper-limb impairment and improving upper-limb use and function in chronic stroke patients. The signific

Published
2023

8. Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials

Author

Dawed, Adem Y, primary, Mari, Andrea, additional, Brown, Andrew, additional, McDonald, Timothy J, additional, Li, Lin, additional, Wang, Shuaicheng, additional, Hong, Mun-Gwan, additional, Sharma, Sapna, additional, Robertson, Neil R, additional, Mahajan, Anubha, additional, Wang, Xuan, additional, Walker, Mark, additional, Gough, Stephen, additional, Hart, Leen M ‘t, additional, Zhou, Kaixin, additional, Forgie, Ian, additional, Ruetten, Hartmut, additional, Pavo, Imre, additional, Bhatnagar, Pallav, additional, Jones, Angus G, additional, Pearson, Ewan R, additional, 't Hart, L.M., additional, Abdalla, M., additional, Adam, J., additional, Adamski, J., additional, Adragni, K., additional, Allin, K.H., additional, Arumugam, M., additional, Atabaki Pasdar, N., additional, Baltauss, T., additional, Banasik, K.B., additional, Baum, P., additional, Bell, J.D., additional, Bergstrom, M., additional, Beulens, J.W., additional, Bianzano, S., additional, Bizzotto, R., additional, Bonneford, A., additional, Brorsson, C.A.B., additional, Brown, A.A., additional, Brunak, S.B., additional, Cabrelli, L., additional, Caiazzo, R., additional, Canouil, M., additional, Dale, M., additional, Davtian, D., additional, Dawed, A.Y., additional, De Masi, F.M., additional, de Preville, N., additional, Dekkers, K.F., additional, Dermitzakis, E.T., additional, Deshmukh, H.A., additional, Dings, C., additional, Donnelly, L., additional, Dutta, A., additional, Ehrhardt, B., additional, Elders, P.J.M., additional, Engel Thomas, C.E.T., additional, Engelbrechtsen, L., additional, Eriksen, R.G., additional, Eriksen, R.E., additional, Fan, Y., additional, Fernandez, J., additional, Ferrer, J., additional, Fitipaldi, H., additional, Forgie, I.M., additional, Forman, A., additional, Franks, P.W., additional, Frau, F., additional, Fritsche, A., additional, Froguel, P., additional, Frost, G., additional, Gassenhuber, J., additional, Giordano, G.N., additional, Giorgino, T., additional, Gough, S., additional, Graefe-Mody, U., additional, Grallert, H., additional, Grempler, R., additional, Groeneveld, L., additional, Groop, L., additional, Gudmundsdóttir, V.G., additional, Gupta, R.G., additional, Haid, M., additional, Hansen, T., additional, Hansen, T.H., additional, Hattersley, A.T., additional, Haussler, R.S., additional, Heggie, A.J., additional, Hennige, A.M., additional, Hill, A.V., additional, Holl, R.W., additional, Hong, M.-G., additional, Hudson, M., additional, Jablonka, B., additional, Jennison, C., additional, Jiao, J., additional, Johansen, J.J., additional, Jones, A.G., additional, Jonsson, A., additional, Karaderi, T.K., additional, Kaye, J., additional, Klintenberg, M., additional, Koivula, R.W., additional, Kokkola, T., additional, Koopman, A.D.M., additional, Kurbasic, A, additional, Kuulasmaa, T., additional, Laakso, M., additional, Lehr, T., additional, Loftus, H., additional, Lundbye Allesøe, R.L.A, additional, Mahajan, A., additional, Mari, A., additional, Mazzoni, G.M., additional, McCarthy, M.I., additional, McDonald, T.J., additional, McEvoy, D., additional, McRobert, N., additional, McVittie, I., additional, Mourby, M., additional, Musholt, P., additional, Mutie, P, additional, Nice, R., additional, Nicolay, C., additional, Nielsen, A.M.N., additional, Nilsson, B.N., additional, Palmer, C.N., additional, Pattou, F., additional, Pavo, I., additional, Pearson, E.R., additional, Pedersen, O., additional, Pedersen, H.K.P., additional, Perry, M.H., additional, Pomares-Millan, H., additional, Ramisch, A., additional, Rasmussen, S.R., additional, Raverdi, V., additional, Ridderstrale, M., additional, Robertson, N., additional, Roderick, R.C., additional, Rodriquez, M., additional, Ruetten, H., additional, Rutters, F., additional, Sackett, W., additional, Scherer, N., additional, Schwenk, J.M., additional, Shah, N., additional, Sharma, S., additional, Sihinevich, I., additional, Sondertoft, N.B., additional, Staerfeldt, H., additional, Steckel-Hamann, B., additional, Teare, H., additional, Thomas, M.K., additional, Thomas, E.L., additional, Thomsen, H.S., additional, Thorand, B., additional, Thorne, C.E., additional, Tillner, J., additional, Troen Lundgaard, A.T.L., additional, Troll, M., additional, Tsirigos, K.D.T., additional, Tura, A., additional, Uhlen, M., additional, van Leeuwen, N., additional, van Oort, S., additional, Verkindt, H., additional, Vestergaard, H., additional, Viñuela, A., additional, Vogt, J.K, additional, Wad Sackett, P.W.S, additional, Wake, D., additional, Walker, M., additional, Wesolowska-Andersen, A., additional, Whitcher, B., additional, White, M.W., additional, and Wu, H., additional

Published
2023
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10. Genetically predicted glucose-dependent insulinotropic polypeptide (GIP) levels and cardiovascular disease risk are driven by distinct causal variants in the GIPR region

Author

Bowker, Nicholas, Hansford, Robert, Burgess, Stephen, Foley, Christopher N, Auyeung, Victoria PW, Erzurumluoglu, A Mesut, Stewart, Isobel D, Wheeler, Eleanor, Pietzner, Maik, Gribble, Fiona, Reimann, Frank, Bhatnagar, Pallav, Coghlan, Matthew P, Wareham, Nicholas J, Langenberg, Claudia, Gribble, Fiona [0000-0002-4232-2898], Langenberg, Claudia [0000-0002-5017-7344], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, Genotype, Genetic Variation, Gastric Inhibitory Polypeptide, Middle Aged, United Kingdom, Receptors, Gastrointestinal Hormone, Diabetes Mellitus, Type 2, Cardiovascular Diseases, Risk Factors, Humans, Female, Genetic Predisposition to Disease, Finland, Aged, Genome-Wide Association Study
Abstract

There is considerable interest in GIPR agonism to enhance the insulinotropic and extra-pancreatic effects of GIP, thereby improving glycaemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multi-trait colocalisation, we identified a GIPR missense variant rs1800437 (G allele; E354) as the putatively causal variant shared between fasting GIP levels, glycaemic traits and adiposity-related traits (posterior probability for colocalisation, PPcoloc>0.97; PP explained by the candidate variant; PPexplained=1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 ~770Kb; R2 with E354 = 0.004; PPcoloc>0.99; PPexplained=1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (OR per copy of E354 after adjustment 1.03; 95% CI, 1.02, 1.04; P=0.003). Instead, E354’s association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272, (R2 with E354=0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI, 0.99, 1.03; P=0.06). We demonstrate that associations with GIP, anthropometric and glycaemic traits are driven by distinct genetic signals from those driving CAD and lipid traits in the GIPR region, and higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP-1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect which has yet to be assessed in clinical trials.

Published
2021

11. Genetically predicted glucose-dependent insulinotropic polypeptide (GIP) levels and cardiovascular disease risk are driven by distinct causal variants in the GIPR region

Author

Bowker, Nicholas, primary, Hansford, Robert, primary, Burgess, Stephen, primary, Foley, Christopher N., primary, Auyeung, Victoria P.W., primary, Erzurumluoglu, A. Mesut, primary, Stewart, Isobel D., primary, Wheeler, Eleanor, primary, Pietzner, Maik, primary, Gribble, Fiona, primary, Reimann, Frank, primary, Bhatnagar, Pallav, primary, Coghlan, Matthew P., primary, Wareham, Nicholas J., primary, and Langenberg, Claudia, primary

Published
2021
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13. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Author

Teo, Kevin, Abeysekera, Kushala WM, Adams, Leon, Aigner, Elmar, Anstee, Quentin M, Banales, Jesus M, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Ida Chen, Yii-Der, Chowdhury, Abhijit, Daly, Ann K, Datz, Christian, de Gracia Hahn, Dana, DiStefano, Johanna K, Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S, GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K, Melton, Phillip E, Mori, Trevor A, Palmer, Nicholette D, Parisinos, Constantinos A, Pillai, Sreekumar G, Qayyum, Faiza, Reichert, Matthias C, Romeo, Stefano, Rotter, Jerome I, Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K, Stender, Stefan, Stickel, Felix, Still, Christopher D, Strnad, Pavel, Taylor, Kent D, Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E, Wareham, Nicholas J, Watanabe, Richard M, Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A, Mann, Jake P, Langenberg, Claudia [0000-0002-5017-7344], Wareham, Nicholas [0000-0003-1422-2993], Mann, Jake [0000-0002-4711-9215], and Apollo - University of Cambridge Repository

Subjects
Liver Cirrhosis, Diabetes, Membrane Proteins, Alanine Transaminase, ALSPAC, Fibrosis, Triglyceride, Polymorphism, Single Nucleotide, MBOAT7, Liver, Non-alcoholic Fatty Liver Disease, NAFLD, Drug Discovery, Humans, Genetic Predisposition to Disease, Acyltransferases
Abstract

BACKGROUND & AIMS: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. METHODS: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. RESULTS: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], pz = 4.8×10-5) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], pz = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], pz = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (pz = 0.002) and lower serum triglycerides (pz = 1.5×10-4). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. CONCLUSIONS: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. LAY SUMMARY: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes, but some genes are also thought to be important. We did this study to see whether one specific change ('variant') in one gene ('MBOAT7') was linked to fatty liver disease. We took data from over 40 published studies and found that this variant near MBOAT7 is linked to more severe fatty liver disease. This means that drugs designed to work on MBOAT7 could be useful for treating fatty liver disease.

Published
2021

14. rs641738C>T nearMBOAT7is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Author

Medicina, Medikuntza, Teo, Kevin, Abeysekera, Kushala W.M., Adams, Leon, Aigner, Elmar, Anstee, Quentin M., Bañales Asurmendi, Jesús María, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Chowdhury, Abhijit, Daly, Ann K., Datz, Christian, De Gracia Hahn, Dana, DiStefano, Johanna K., Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S., GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K., Melton, Phillip E., Mori, Trevor A., Palmer, Nicholette D., Parisinos, Constantinos A., Pillai, Sreekumar G., Qayyum, Faiza, Reichert, Matthias C., Romeo, Stefano, Rotter, Jerome I., Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K., Stender, Stefan, Stickel, Felix, Still, Christopher D., Strnad, Pavel, Taylor, Kent D., Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E., Wareham, Nicholas J., Watanabe, Richard M., Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A., Mann, Jake P., Medicina, Medikuntza, Teo, Kevin, Abeysekera, Kushala W.M., Adams, Leon, Aigner, Elmar, Anstee, Quentin M., Bañales Asurmendi, Jesús María, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Chowdhury, Abhijit, Daly, Ann K., Datz, Christian, De Gracia Hahn, Dana, DiStefano, Johanna K., Dong, Jiawen, Duret, Amedine, EU-PNAFLD Investigators, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S., GOLD Consortium, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Li, Lin, Lim, Hong Kai, Loomba, Rohit, Luukkonen, Panu K., Melton, Phillip E., Mori, Trevor A., Palmer, Nicholette D., Parisinos, Constantinos A., Pillai, Sreekumar G., Qayyum, Faiza, Reichert, Matthias C., Romeo, Stefano, Rotter, Jerome I., Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K., Stender, Stefan, Stickel, Felix, Still, Christopher D., Strnad, Pavel, Taylor, Kent D., Tybjærg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wagenknecht, Lynne E., Wareham, Nicholas J., Watanabe, Richard M., Wattacheril, Julia, Yaghootkar, Hanieh, Yki-Järvinen, Hannele, Young, Kendra A., and Mann, Jake P.

Abstract

Background & Aims: A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis. Methods: We performed a meta-analysis of studies with data on the association between rs641738C>T genotype and liver fat, NAFLD histology, and serum alanine aminotransferase (ALT), lipids or insulin. These included directly genotyped studies and population-level data from genome-wide association studies (GWAS). We performed a random effects meta-analysis using recessive, additive and dominant genetic models. Results: Data from 1,066,175 participants (9,688 with liver biopsies) across 42 studies were included in the meta-analysis. rs641738C>T was associated with higher liver fat on CT/MRI (+0.03 standard deviations [95% CI 0.02-0.05], p(z) = 4.8x10(-5)) and diagnosis of NAFLD (odds ratio [OR] 1.17 [95% CI 1.05-1.3], p(z) = 0.003) in Caucasian adults. The variant was also positively associated with presence of advanced fibrosis (OR 1.22 [95% CI 1.03-1.45], p(z) = 0.021) in Caucasian adults using a recessive model of inheritance (CC + CT vs. TT). Meta-analysis of data from previous GWAS found the variant to be associated with higher ALT (p(z) = 0.002) and lower serum triglycerides (p(z) = 1.5x10(-4)). rs641738C>T was not associated with fasting insulin and no effect was observed in children with NAFLD. Conclusions: Our study validates rs641738C>T near MBOAT7 as a risk factor for the presence and severity of NAFLD in individuals of European descent. Lay summary: Fatty liver disease is a common condition where fat builds up in the liver, which can cause liver inflammation and scarring (including 'cirrhosis'). It is closely linked to obesity and diabetes

Published
2021

16. rs641738C>T near MBOAT7 promotes steatosis, NASH, fibrosis and hepatocellular carcinoma in non-alcoholic fatty liver disease: a meta-analysis

Author

Teo, Kevin, Abeysekera, Kushala WM, Adams, Leon, Aigner, Elmar, Banerjee, Rajarshi, Basu, Priyadarshi, Berg, Thomas, Bhatnagar, Pallav, Buch, Stephan, Canbay, Ali, Caprio, Sonia, Chatterjee, Ankita, Chen, Yii-Der Ida, Datz, Christian, de Gracia Hahn, Dana, DiStefano, Johanna K, Dong, Jiawen, Duret, Amedine, Emdin, Connor, Fairey, Madison, Gerhard, Glenn S, Guo, Xiuqing, Hampe, Jochen, Hickman, Matthew, Heintz, Lena, Hudert, Christian, Hunter, Harriet, Kelly, Matt, Kozlitina, Julia, Krawczyk, Marcin, Lammert, Frank, Langenberg, Claudia, Lavine, Joel, Lim, Hong Kai, Luukkonen, Panu, Melton, Philip E, Mori, Trevor A, Parisinos, Constantinos A, Pillai, Sreekumar G, Qayyum, Faiza, Reichert, Matthias C, Romeo, Stefano, Rotter, Jerome, Im, Yu Ri, Santoro, Nicola, Schafmayer, Clemens, Speliotes, Elizabeth K, Stender, Stefan, Stickel, Felix, Still, Christopher D, Strnad, Pavel, Taylor, Kent D, Tybjaerg-Hansen, Anne, Umano, Giuseppina Rosaria, Utukuri, Mrudula, Valenti, Luca, Wareham, Nicholas J, Wattacheril, Julia, Yki-Jarvinen, Hannele, and Mann, Jake P

Abstract

A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in non-alcoholic fatty liver disease (NAFLD), however, these findings have not been consistently replicated in the literature. Therefore, we aimed to establish whether rs641738 is a risk factor for NAFLD through meta-analysis. Data from 134,015 participants (7,692 with liver biopsies and 50,680 with imaging) was included in the meta-analysis. The minor T-allele of rs641738C>T was associated with higher liver fat on CT/MRI using an additive genetic model (+0.05 standard deviations [95% CI: 0.01 - 0.09], p=0.025), and with an increased risk of NAFLD (per-allele OR: 1.08 [95% CI: 1.01 - 1.15]), nonalcoholic steatohepatitis (OR: 1.11 [95% CI: 1.02 - 1.21]), advanced fibrosis (OR: 1.14 [95% CI: 1.05 - 1.23]), and hepatocellular carcinoma (OR: 1.43 [95% CI: 1.22 - 1.67]) in adults with NAFLD. Sub-group analysis did not demonstrate a difference in Caucasians and non-Caucasians. Rs641738C>T was not associated with markers of insulin resistance but was associated with higher risk of stroke in the UK Biobank. These data validate rs641738C>T near MBOAT7 as a risk factor for the development, activity, and stage of NAFLD including hepatocellular carcinoma.

Published
2019
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17. rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis

Author

Teo, Kevin, primary, Abeysekera, Kushala W.M., additional, Adams, Leon, additional, Aigner, Elmar, additional, Anstee, Quentin M., additional, Banales, Jesus M., additional, Banerjee, Rajarshi, additional, Basu, Priyadarshi, additional, Berg, Thomas, additional, Bhatnagar, Pallav, additional, Buch, Stephan, additional, Canbay, Ali, additional, Caprio, Sonia, additional, Chatterjee, Ankita, additional, Ida Chen, Yii-Der, additional, Chowdhury, Abhijit, additional, Daly, Ann K., additional, Datz, Christian, additional, de Gracia Hahn, Dana, additional, DiStefano, Johanna K., additional, Dong, Jiawen, additional, Duret, Amedine, additional, Emdin, Connor, additional, Fairey, Madison, additional, Gerhard, Glenn S., additional, Guo, Xiuqing, additional, Hampe, Jochen, additional, Hickman, Matthew, additional, Heintz, Lena, additional, Hudert, Christian, additional, Hunter, Harriet, additional, Kelly, Matt, additional, Kozlitina, Julia, additional, Krawczyk, Marcin, additional, Lammert, Frank, additional, Langenberg, Claudia, additional, Lavine, Joel, additional, Li, Lin, additional, Lim, Hong Kai, additional, Loomba, Rohit, additional, Luukkonen, Panu K., additional, Melton, Phillip E., additional, Mori, Trevor A., additional, Palmer, Nicholette D., additional, Parisinos, Constantinos A., additional, Pillai, Sreekumar G., additional, Qayyum, Faiza, additional, Reichert, Matthias C., additional, Romeo, Stefano, additional, Rotter, Jerome I., additional, Im, Yu Ri, additional, Santoro, Nicola, additional, Schafmayer, Clemens, additional, Speliotes, Elizabeth K., additional, Stender, Stefan, additional, Stickel, Felix, additional, Still, Christopher D., additional, Strnad, Pavel, additional, Taylor, Kent D., additional, Tybjærg-Hansen, Anne, additional, Umano, Giuseppina Rosaria, additional, Utukuri, Mrudula, additional, Valenti, Luca, additional, Wagenknecht, Lynne E., additional, Wareham, Nicholas J., additional, Watanabe, Richard M., additional, Wattacheril, Julia, additional, Yaghootkar, Hanieh, additional, Yki-Järvinen, Hannele, additional, Young, Kendra A., additional, Mann, Jake P., additional, Vreugdenhil, Anita, additional, Alisi, Anna, additional, Socha, Piotr, additional, Jańczyk, Wojciech, additional, Baumann, Ulrich, additional, Rajwal, Sanjay, additional, van Mourik, Indra, additional, Lacaille, Florence, additional, Dabbas, Myriam, additional, Kelly, Deirdre A., additional, Nobili, Valerio, additional, Eiriksdottir, Gudny, additional, Garcia, Melissa E., additional, Gudnason, Vilmundur, additional, Harris, Tamara B., additional, Kim, Lauren J., additional, Launer, Lenore J., additional, Nalls, Michael A., additional, Smith, Albert V., additional, Clark, Jeanne M., additional, Hernaez, Ruben, additional, Kao, W.H. Linda, additional, Mitchell, Braxton D., additional, Shuldiner, Alan R., additional, Yerges-Armstrong, Laura M., additional, Borecki, Ingrid B., additional, Carr, J. Jeffrey, additional, Feitosa, Mary F., additional, Wu, Jun, additional, Butler, Johannah L., additional, Fox, Caroline S., additional, Hirschhorn, Joel N., additional, Hoffmann, Udo, additional, Hwang, Shih-Jen, additional, Massaro, Joseph M., additional, O'Donnell, Christopher J., additional, Palmer, Cameron D., additional, and Sahani, Dushyant V., additional

Published
2021
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21. Genome-Wide Polygenic Score and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease

Author

Emdin, Connor A., primary, Bhatnagar, Pallav, additional, Wang, Minxian, additional, Pillai, Sreekumar G., additional, Li, Lin, additional, Qian, Hui-Rong, additional, Riesmeyer, Jeffrey S., additional, Lincoff, A. Michael, additional, Nicholls, Stephen J., additional, Nissen, Steven E., additional, Ruotolo, Giacomo, additional, Kathiresan, Sekar, additional, and Khera, Amit V., additional

Published
2020
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25. Genetically Predicted Glucose-Dependent Insulinotropic Polypeptide (GIP) Levels and Cardiovascular Disease Risk Are Driven by Distinct Causal Variants in the Region.

Author

Bowker, Nicholas, Hansford, Robert, Burgess, Stephen, Foley, Christopher N., Auyeung, Victoria P.W., Erzurumluoglu, A. Mesut, Stewart, Isobel D., Wheeler, Eleanor, Pietzner, Maik, Gribble, Fiona, Reimann, Frank, Bhatnagar, Pallav, Coghlan, Matthew P., Wareham, Nicholas J., and Langenberg, Claudia

Subjects
CARDIOVASCULAR diseases, CARDIOVASCULAR diseases risk factors, MISSENSE mutation, CORONARY artery disease, GLYCEMIC control, RESEARCH, SEQUENCE analysis, GENETICS, CELL receptors, EVALUATION research, TYPE 2 diabetes, COMPARATIVE studies, DISEASE susceptibility, GENOTYPES, RESEARCH funding
Abstract

There is considerable interest in GIPR agonism to enhance the insulinotropic and extrapancreatic effects of GIP, thereby improving glycemic and weight control in type 2 diabetes (T2D) and obesity. Recent genetic epidemiological evidence has implicated higher GIPR-mediated GIP levels in raising coronary artery disease (CAD) risk, a potential safety concern for GIPR agonism. We therefore aimed to quantitatively assess whether the association between higher GIPR-mediated fasting GIP levels and CAD risk is mediated via GIPR or is instead the result of linkage disequilibrium (LD) confounding between variants at the GIPR locus. Using Bayesian multitrait colocalization, we identified a GIPR missense variant, rs1800437 (G allele; E354), as the putatively causal variant shared among fasting GIP levels, glycemic traits, and adiposity-related traits (posterior probability for colocalization [PPcoloc] > 0.97; PP explained by the candidate variant [PPexplained] = 1) that was independent from a cluster of CAD and lipid traits driven by a known missense variant in APOE (rs7412; distance to E354 ∼770 Kb; R2 with E354 = 0.004; PPcoloc > 0.99; PPexplained = 1). Further, conditioning the association between E354 and CAD on the residual LD with rs7412, we observed slight attenuation in association, but it remained significant (odds ratio [OR] per copy of E354 after adjustment 1.03; 95% CI 1.02, 1.04; P = 0.003). Instead, E354's association with CAD was completely attenuated when conditioning on an additional established CAD signal, rs1964272 (R2 with E354 = 0.27), an intronic variant in SNRPD2 (OR for E354 after adjustment for rs1964272: 1.01; 95% CI 0.99, 1.03; P = 0.06). We demonstrate that associations with GIP and anthropometric and glycemic traits are driven by genetic signals distinct from those driving CAD and lipid traits in the GIPR region and that higher E354-mediated fasting GIP levels are not associated with CAD risk. These findings provide evidence that the inclusion of GIPR agonism in dual GIPR/GLP1R agonists could potentiate the protective effect of GLP-1 agonists on diabetes without undue CAD risk, an aspect that has yet to be assessed in clinical trials. [ABSTRACT FROM AUTHOR]

Published
2021
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31. ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease

Author

Nissen, Steven E., primary, Pillai, Sreekumar G., additional, Nicholls, Stephen J., additional, Wolski, Kathy, additional, Riesmeyer, Jeffrey S., additional, Weerakkody, Govinda J., additional, Foster, Wendra M., additional, McErlean, Ellen, additional, Li, Lin, additional, Bhatnagar, Pallav, additional, Ruotolo, Giacomo, additional, and Lincoff, A. Michael, additional

Published
2018
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32. Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist

Author

Guzman, Cristina B., primary, Duvvuru, Suman, additional, Akkari, Anthony, additional, Bhatnagar, Pallav, additional, Battioui, Chakib, additional, Foster, Wendra, additional, Zhang, Xiaotian Michelle, additional, Shankar, Sudha S., additional, Deeg, Mark A., additional, Chalasani, Naga, additional, Hardy, Thomas A., additional, Kazda, Christof M., additional, and Pillai, Sreekumar G., additional

Published
2018
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33. Candidate Gene Associations with Vaso-Occlusive Crisis in Children with Sickle Cell Anemia Enrolled in the Multinational DOVE Trial

Author

Lori E. Heath, Carolyn Hoppe, Bhatnagar Pallav, Wendra M. Foster, Joseph A. Jakubowski, and Sreekumar G. Pillai

Subjects
medicine.medical_specialty, Prasugrel, Immunology, Population, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Clinical endpoint, 030212 general & internal medicine, education, Mean corpuscular volume, education.field_of_study, medicine.diagnostic_test, business.industry, Cell Biology, Hematology, medicine.disease, Sickle cell anemia, Clinical trial, Population study, business, Vaso-occlusive crisis, 030217 neurology & neurosurgery, medicine.drug
Abstract

Introduction: Sickle cell disease (SCD) is complex, with marked inter-individual variability in disease severity. The clinical heterogeneity of SCD is largely influenced by genetic factors, including several well-established modifiers of fetal hemoglobin (HbF) levels within the beta globin locus, BCL11A, and HBS1L-MYB genes. However, little is known about genetic factors that may influence variability in treatment response, particularly in clinical trials assessing potential therapeutic agents for SCD. The DOVE (Determining Effects of Platelet Inhibition on Vaso-Occlusive Events) study was a multinational, phase 3, randomized, double-blinded, placebo-controlled trial evaluating the efficacy and safety of the antiplatelet agent prasugrel for the reduction of vaso-occlusive crisis (VOC) in children with sickle cell anemia (NCT01794000). Although the primary endpoint of reduction of rate of VOC did not reach statistical significance in the DOVE trial in the ITT population, a treatment effect of prasugrel was suggested in certain subgroups. The objective of this study was to evaluate candidate genetic variants with SCD severity and to assess impact of these variants on response to prasugrel, as measured by the frequency of VOC (composite of painful crisis and acute chest syndrome events) during the study period of up to 24 months. Methods: De-identified dried blood spot samples were collected for genetic analyses as per informed consent and study protocol. Genomic DNA was extracted from a 3 mm Whatman FTA card punch using Qiagen QIAamp DNA kit. A total of 313 (92%) DOVE patients (Hb SS or Hb S/β0 thalassemia) were genotyped using the TaqMan assay. After quality control, 253 patients and 28 variants were considered for genetic evaluation. These variants have been reported to be associated with SCD and/or its related comorbidities. All variants were analyzed for VOC in the prasugrel and placebo groups separately and for treatment by variant interactions in the overall study population. Variants were also assessed in the overall study population for associations with a hemolytic score, derived from 5 biomarkers of hemolysis and baseline hematologic markers including leukocyte, neutrophil, and platelet counts, and red cell mean corpuscular volume. All analyses were conducted using additive multivariate regression framework as the main model and were adjusted for age, race, geographic region, and hydroxyurea (HU) use at baseline. In addition, genotypic, dominant, and recessive models were evaluated as supportive analyses. Results: Two variants, rs7482144, located in the 5'- HBG2 gene promoter (-158 Xmn1) on chr 11 and rs1427407, located in the BCL11A gene on chr 2, were associated with VOC and a treatment interaction effect of prasugrel. HBG2 rs7482144, was associated with a significant decrease in frequency of VOC in prasugrel-treated patients relative to placebo (adjusted p=0.0065). The BCL11A rs1427407 variant was associated with an increase in VOC in prasugrel-treated patients relative to placebo (adjusted p=0.0205). No genetic associations were found with baseline composite hemolytic score in the overall population. However, significant associations with KLF-1, HBG2, and HBE variants were observed with individual hematologic markers. The KLF-1 variant (rs112631212) was associated with lower leukocyte (p Conclusions: Given the study sample size, this study highlights the significance of HBG2 and BCL11A variants for the frequency of VOC in prasugrel-treated patients versus placebo. These variants have been reported in association with HbF/F-cells, an ameliorating factor for VOC that is only partly explained by endogenous levels of HbF. Our findings suggest that these variants may have contributed to the treatment-related effects of prasugrel on VOC outcomes in the DOVE trial. Identifying such genetic variants that are associated with differential response to treatment may help guide selection of patients for clinical trials based on predicted risk of VOC. Disclosures Hoppe: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jakubowski: Eli Lilly and Company: Employment, Equity Ownership, Other: Former employee and minor shareholder of Eli Lilly and Company. Foster: Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company. Heath: Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company. Pillai: Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company. Pallav: Eli Lilly and Company: Employment, Equity Ownership, Other: Employee and minor shareholder of Eli Lilly and Company.

Published
2017

34. Stress-Dependent Association Between Polygenic Risk for Schizophrenia and Schizotypal Traits in Young Army Recruits

Author

Hatzimanolis, Alex, primary, Avramopoulos, Dimitrios, additional, Arking, Dan E, additional, Moes, Anna, additional, Bhatnagar, Pallav, additional, Lencz, Todd, additional, Malhotra, Anil K, additional, Giakoumaki, Stella G, additional, Roussos, Panos, additional, Smyrnis, Nikolaos, additional, Bitsios, Panos, additional, and Stefanis, Nicholas C, additional

Published
2017
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35. Salmonella spinal osteomyelitis: A case report and review of literature

Author

Acharya, Shankar and Bhatnagar, Pallav

Subjects
Kyphosis -- Diagnosis -- Care and treatment, Salmonella -- Diagnosis -- Care and treatment, Health, Diagnosis, Care and treatment
Abstract

Byline: Shankar. Acharya, Pallav. Bhatnagar A case of vertebral osteomyelitis is presented where initial presumptive diagnosis of tuberculous infection was made on clinico-radiological grounds but eventually turned out to be [...]

Published
2004

36. Common genetic variation and schizophrenia polygenic risk influence neurocognitive performance in young adulthood

Author

Hatzimanolis, Alex Bhatnagar, Pallav Moes, Anna Wang, Ruihua and Roussos, Panos Bitsios, Panos Stefanis, Costas N. and Pulver, Ann E. Arking, Dan E. Smyrnis, Nikolaos Stefanis, Nicholas C. Avramopoulos, Dimitrios

Abstract

Neurocognitive abilities constitute complex traits with considerable heritability. Impaired neurocognition is typically observed in schizophrenia (SZ), whereas convergent evidence has shown shared genetic determinants between neurocognition and SZ. Here, we report a genome-wide association study (GWAS) on neuropsychological and oculomotor traits, linked to SZ, in a general population sample of healthy young males (n=1079). Follow-up genotyping was performed in an identically phenotyped internal sample (n=738) and an independent cohort of young males with comparable neuropsychological measures (n=825). Heritability estimates were determined based on genome-wide single-nucleotide polymorphisms (SNPs) and potential regulatory effects on gene expression were assessed in human brain. Correlations with general cognitive ability and SZ risk polygenic scores were tested utilizing meta-analysis GWAS results by the Cognitive Genomics Consortium (COGENT) and the Psychiatric Genomics Consortium (PGC-SZ). The GWAS results implicated biologically relevant genetic loci encoding protein targets involved in synaptic neurotransmission, although no robust individual replication was detected and thus additional validation is required. Secondary permutation-based analysis revealed an excess of strongly associated loci among GWAS top-ranked signals for verbal working memory (WM) and antisaccade intra-subject reaction time variability (empirical P

Published
2015

40. Meta-analysis of 2040 sickle cell anemia patients: BCL11A and HBS1L-MYB are the major modifiers of HbF in African Americans

Author

Bae, Harold T., primary, Baldwin, Clinton T., additional, Sebastiani, Paola, additional, Telen, Marilyn J., additional, Ashley-Koch, Allison, additional, Garrett, Melanie, additional, Hooper, W. Craig, additional, Bean, Christopher J., additional, DeBaun, Michael R., additional, Arking, Dan E., additional, Bhatnagar, Pallav, additional, Casella, James F., additional, Keefer, Jeffrey Renn, additional, Barron-Casella, Emily, additional, Gordeuk, Victor, additional, Kato, Gregory J., additional, Minniti, Caterina, additional, Taylor, James, additional, Campbell, Andrew, additional, Luchtman-Jones, Lori, additional, Hoppe, Carolyn, additional, Gladwin, Mark T., additional, Zhang, Yingze, additional, and Steinberg, Martin H., additional

Published
2012
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42. A Genome-Wide Association Study of Total Bilirubin and Cholelithiasis Risk in Sickle Cell Anemia

Author

Milton, Jacqueline N., primary, Sebastiani, Paola, additional, Solovieff, Nadia, additional, Hartley, Stephen W., additional, Bhatnagar, Pallav, additional, Arking, Dan E., additional, Dworkis, Daniel A., additional, Casella, James F., additional, Barron-Casella, Emily, additional, Bean, Christopher J., additional, Hooper, W. Craig, additional, DeBaun, Michael R., additional, Garrett, Melanie E., additional, Soldano, Karen, additional, Telen, Marilyn J., additional, Ashley-Koch, Allison, additional, Gladwin, Mark T., additional, Baldwin, Clinton T., additional, Steinberg, Martin H., additional, and Klings, Elizabeth S., additional

Published
2012
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43. Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Author

Arking, Dan E., primary, Junttila, M. Juhani, additional, Goyette, Philippe, additional, Huertas-Vazquez, Adriana, additional, Eijgelsheim, Mark, additional, Blom, Marieke T., additional, Newton-Cheh, Christopher, additional, Reinier, Kyndaron, additional, Teodorescu, Carmen, additional, Uy-Evanado, Audrey, additional, Carter-Monroe, Naima, additional, Kaikkonen, Kari S., additional, Kortelainen, Marja-Leena, additional, Boucher, Gabrielle, additional, Lagacé, Caroline, additional, Moes, Anna, additional, Zhao, XiaoQing, additional, Kolodgie, Frank, additional, Rivadeneira, Fernando, additional, Hofman, Albert, additional, Witteman, Jacqueline C. M., additional, Uitterlinden, André G., additional, Marsman, Roos F., additional, Pazoki, Raha, additional, Bardai, Abdennasser, additional, Koster, Rudolph W., additional, Dehghan, Abbas, additional, Hwang, Shih-Jen, additional, Bhatnagar, Pallav, additional, Post, Wendy, additional, Hilton, Gina, additional, Prineas, Ronald J., additional, Li, Man, additional, Köttgen, Anna, additional, Ehret, Georg, additional, Boerwinkle, Eric, additional, Coresh, Josef, additional, Kao, W. H. Linda, additional, Psaty, Bruce M., additional, Tomaselli, Gordon F., additional, Sotoodehnia, Nona, additional, Siscovick, David S., additional, Burke, Greg L., additional, Marbán, Eduardo, additional, Spooner, Peter M., additional, Cupples, L. Adrienne, additional, Jui, Jonathan, additional, Gunson, Karen, additional, Kesäniemi, Y. Antero, additional, Wilde, Arthur A. M., additional, Tardif, Jean-Claude, additional, O'Donnell, Christopher J., additional, Bezzina, Connie R., additional, Virmani, Renu, additional, Stricker, Bruno H. C. h., additional, Tan, Hanno L., additional, Albert, Christine M., additional, Chakravarti, Aravinda, additional, Rioux, John D., additional, Huikuri, Heikki V., additional, and Chugh, Sumeet S., additional

Published
2011
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47. Association of DRD2 gene variant with schizophrenia

Author

Kukreti, Ritushree, primary, Tripathi, Sudipta, additional, Bhatnagar, Pallav, additional, Gupta, Simone, additional, Chauhan, Chitra, additional, Kubendran, Shobhana, additional, Janardhan Reddy, Y.C., additional, Jain, Sanjeev, additional, and Brahmachari, Samir K., additional

Published
2006
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49. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin.

Author

Daly, Ann K., Donaldson, Peter T., Bhatnagar, Pallav, Shen, Yufeng, Pe'er, Itsik, Floratos, Aris, Daly, Mark J., Goldstein, David B., John, Sally, Nelson, Matthew R., Graham, Julia, Park, B. Kevin, Dillon, John F., Bernal, William, Cordell, Heather J., Pirmohamed, Munir, Aithal, Guruprasad P., and Day, Christopher P.

Subjects
HLA histocompatibility antigens, LIVER diseases, ANTI-infective agents, MAJOR histocompatibility complex, GENETICS, HISTOCOMPATIBILITY antigens
Abstract

Drug-induced liver injury (DILI) is an important cause of serious liver disease. The antimicrobial agent flucloxacillin is a common cause of DILI, but the genetic basis for susceptibility remains unclear. We conducted a genome-wide association (GWA) study using 866,399 markers in 51 cases of flucloxacillin DILI and 282 controls matched for sex and ancestry. The GWA showed an association peak in the major histocompatibility complex (MHC) region with the strongest association (P = 8.7 × 10−33) seen for rs2395029[G], a marker in complete linkage disequilibrium (LD) with HLA-B*5701. Further MHC genotyping, which included 64 flucloxacillin-tolerant controls, confirmed the association with HLA-B*5701 (OR = 80.6, P = 9.0 × 10−19). The association was replicated in a second cohort of 23 cases. In HLA-B*5701 carrier cases, rs10937275 in ST6GAL1 on chromosome 3 also showed genome-wide significance (OR = 4.1, P = 1.4 × 10−8). These findings provide new insights into the mechanism of flucloxacillin DILI and have the potential to substantially improve diagnosis of this serious disease. [ABSTRACT FROM AUTHOR]

Published
2009
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50. Pharmacogenomics of β2-agonist: key focus on signaling pathways.

Author

Bhatnagar, Pallav, Guleria, Randeep, and Kukreti, Ritushree

Subjects
PHARMACOGENOMICS, BRONCHODILATOR agents, ANTIASTHMATIC agents, ADRENERGIC receptors, DRUG receptors
Abstract

Asthma is one of the most common respiratory diseases, where inhalation and exhalation are obstructed due to narrowing of the airways by broncho-constriction or by inflammation. Among all the available anti-asthma therapies, β2-agonists are the most effective bronchodilators available, and give rapid relief of asthma symptoms. Evidence suggests that the degree of β2-agonist response varies greatly between patients and genetic factors have a major role in it. Despite several studies on the β2-agonist pharmacogenetics, significant gaps in knowledge still remain and need to be resolved before the pharmacotyping of β2-agonist responsiveness comes to clinical practice. As we know, β2-agonists show their influence by targeting β2-adrenergic receptors, leading to the activation of β2-adrenergic receptors and its downstream cascade. Signaling through β2-adrenergic receptors mediates numerous airway functions by regulating broncho-constriction and dilation pathways. Therefore, it is an important prerequisite to understand these pathways, which will assist in defining the variability in therapeutic responses for β2-agonists. Owing to the complexity of the action of a β2-agonist and its therapeutic response, a broader genomics approach will help in optimizing therapy for the individual patient. This might be achieved by considering and focusing on receptor/s at which the drug binds directly, signal transduction cascades or downstream proteins and proteins involved in the relaxation and constriction of the airway smooth muscle. Considering that a drug response may involve a large number of proteins, it seems unlikely that a single polymorphism or haplotype in a single gene would explain a high degree of drug response variability in a consistent fashion. Thus, it shows that a polygenic approach will be more appropriate. In order to follow this, the mode of action of the β2-agonist and its downstream signaling cascade should essentially be assessed to resolve the β2-agonist enigma. [ABSTRACT FROM AUTHOR]

Published
2006
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