6 results on '"Siddiqui, Moneeza Kalhan"'
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2. Genetic factors in statin intolerance
- Author
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Siddiqui, Moneeza Kalhan and Palmer, Colin
- Subjects
615.7 ,Pharmacogenetics ,Adverse drug reactions ,Population genetics ,Statins - Abstract
Background: There are approximately 12 million statin users in the United Kingdom. Reports of statin intolerance occurs between 7 and 29% of users, manifesting as muscle ache, fatigue or more seriously, muscle breakdown leading to myopathy. Creatine phosphokinase (CK) levels are used as a biomarker of statin-induced muscle damage. Non-adherence or discontinuation of therapy is a common result of intolerance and can result in negative cardiovascular disease-related outcomes. Aim: This thesis attempts to identify trends in record-linked medical data in a Scottish Caucasian cohort (GoDARTS) that best represent statin intolerance in order to study associated genetic factors. Methods: Prescribing trends such as switching or discontinuation of statin therapy were examined, and thresholds created to select true cases of intolerance. Information on CK levels was gathered from medical records and appropriate test results were utilized. Genotypic data was gathered for the variants and genetic regions of interest using a variety of methods including chip-based genotyping followed by imputation, TAQMAN genotyping, and exome sequencing. Subsequently hypothesis-based association analyses were conducted, including linear and logistic regressions, followed by meta-analyses, regional GWAS followed by a regional meta –analysis. Results: The phenotypes of statin intolerance were validated both internally and externally. Previously reported missense variants in LILRB5 (Asp247Gly) and CKM (Glu83Gly) were replicated and shown to be associated with CK levels irrespective of statin usage in the GoDARTS cohort and the clinical trial setting (JUPITER). Further, the CKM variant was also associated with inducibility of CK at times of tissue injury. The Asp247 genotype in LILRB5 was associated with increased risk of statin intolerance, and was replicated in associations with non-compliance to statin therapy and the development of myalgia in the JUPITER trial. The association with myalgia showed a stratified effect based on therapy (statin or placebo), with those on placebo showing the genotype effect. Further, the variant was also associated with increased risk of statin-induced myositis, cases of which had been clinically adjudicated and exome sequenced for the PREDICTION-ADR consortium. Further exploration of the LILR gene region showed an association with variants in LILRB2 (His20Arg and Val235Met) which were in strong LD with each other but were not in linkage with the variant in LILRB5. Stratified analysis revealed that the risk for carriers of the LILRB2 variants was increased depending on the genotype carried at the LILRB5 variant. Conclusions: This study characterises novel genetic factors associated with statin intolerance impacting adherence. The findings point to the immunomodulatory effects of statins. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a possible role for the immune system in their development. The findings encourage further investigation into the immune-physiology of statin-induced muscle damage and identifies genetically susceptible groups who are more likely to be statin intolerant.
- Published
- 2016
3. Prescribing Patterns and Response to Antihyperglycemic Agents Among Novel Clusters of Type 2 Diabetes in Asian Indians.
- Author
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Anjana, Ranjit Mohan, Siddiqui, Moneeza Kalhan, Jebarani, Saravanan, Vignesh, Mani Arun, Kamal Raj, Nithyanantham, Unnikrishnan, Ranjit, Pradeepa, Rajendra, Panikar, Vijay K., Kesavadev, Jothydev, Saboo, Banshi, Gupta, Sunil, Sosale, Aravind R., Seshadri, Krishna G., Deshpande, Neeta, Chawla, Manoj, Chawla, Purvi, Das, Sidhartha, Behera, Manoranjan, Chawla, Rajeev, and Nigam, Anant
- Subjects
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TYPE 2 diabetes , *INDIANS (Asians) , *GLYCOSYLATED hemoglobin , *CD26 antigen , *CLINICAL trials , *K-means clustering , *THERAPEUTIC use of protease inhibitors , *RESEARCH , *RESEARCH methodology , *HYPOGLYCEMIC agents , *EVALUATION research , *COMPARATIVE studies , *RESEARCH funding , *METFORMIN - Abstract
Aim: To assess the prescribing patterns and response to different classes of antihyperglycemic agents in novel clusters of type 2 diabetes (T2D) described in India. Materials and Methods: We attempted to replicate the earlier described clusters of T2D, in 32,867 individuals with new-onset T2D (within 2 years of diagnosis) registered between October 2013 and December 2020 at 15 diabetes clinics located across India, by means of k-means clustering utilizing 6 clinically relevant variables. Individuals who had follow-up glycated hemoglobin (HbA1c) up to 2 years were included for the drug response analysis (n = 13,247). Results: Among the 32,867 participants included in the study, 20,779 (63.2%) were males. The average age at diagnosis was 45 years and mean HbA1c at baseline was 8.9%. The same four clusters described in India earlier were replicated. Forty percent of the study participants belonged to the mild age-related diabetes cluster, followed by insulin-resistant obese diabetes (27%), severe insulin-deficient diabetes (21%), and combined insulin-resistant and insulin-deficient diabetes (12%) clusters. The most frequently used antihyperglycemic agents were sulfonylureas, metformin, and dipeptidyl peptidase-4 inhibitors apart from insulin. While there were significant differences in HbA1c reduction between drugs across clusters, these were largely driven by differences in the baseline (pretreatment) HbA1c. Conclusions: In this new cohort, we were able to reliably replicate the four subtypes of T2D earlier described in Asian Indians. Prescribing patterns show limited usage of newer antihyperglycemic agents across all clusters. Randomized clinical trials are required to establish differential drug responses between clusters. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
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4. Exome Sequencing Reveals Common and Rare Variants in F5 Associated With ACE Inhibitor and Angiotensin Receptor Blocker–Induced Angioedema.
- Author
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Maroteau, Cyrielle, Siddiqui, Moneeza Kalhan, Veluchamy, Abirami, Carr, Fiona, White, Myra, Cassidy, Andrew J., Baranova, Ekaterina V., Rasmussen, Eva R., Eriksson, Niclas, Bloch, Katarzyna M., Brown, Nancy J., Bygum, Anette, Hallberg, Par, Karawajczyk, Malgorzata, Magnusson, Patrik K. E., Yue, Qun‐Ying, Syvänen, Ann‐Christine, Buchwald, Christian, Alfirevic, Ana, and Maitland‐van der Zee, Anke H.
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ANGIOTENSIN receptors ,EXOMES ,ANGIONEUROTIC edema ,ACTIVATED protein C resistance ,ASIANS ,ACE inhibitors ,ANGIOTENSIN-receptor blockers - Abstract
Angioedema occurring in the head and neck region is a rare and sometimes life‐threatening adverse reaction to angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Few studies have investigated the association of common variants with this extreme reaction, but none have explored the combined influence of rare variants yet. Adjudicated cases of ACEI‐induced angioedema (ACEI‐AE) or ARB‐induced angioedema (ARB‐AE) and controls were recruited at five different centers. Sequencing of 1,066 samples (408 ACEI‐AE, ARB‐AE, and 658 controls) was performed using exome‐enriched sequence data. A common variant of the F5 gene that causes an increase in blood clotting (rs6025, p.Arg506Gln, also called factor V Leiden), was significantly associated with both ACEI‐AE and ARB‐AE (odds ratio: 2.85, 95% confidence interval (CI), 1.89–4.25). A burden test analysis of five rare missense variants in F5 was also found to be associated with ACEI‐AE or ARB‐AE, P = 2.09 × 10−3. A combined gene risk score of these variants, and the common variants rs6025 and rs6020, showed that individuals carrying at least one variant had 2.21 (95% CI, 1.49–3.27, P = 6.30 × 10−9) times the odds of having ACEI‐AE or ARB‐AE. The increased risk due to the common Leiden allele was confirmed in a genome‐wide association study from the United States. A high risk of angioedema was also observed for the rs6020 variant that is the main coagulation defect‐causing variant in black African and Asian populations. We found that deleterious missense variants in F5 are associated with an increased risk of ACEI‐AE or ARB‐AE. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
5. CKM Glu83Gly Is Associated With Blunted Creatine Kinase Variation, but Not With Myalgia.
- Author
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Siddiqui, Moneeza Kalhan, Veluchamy, Abirami, Maroteau, Cyrielle, Tavendale, Roger, Carr, Fiona, Pearson, Ewan, Colhoun, Helen, Morris, Andrew D., George, Jacob, Doney, Alexander, Pirmohamed, Munir, Alfirevic, Ana, Wadelius, Mia, Maitland van der Zee, Anke H., Ridker, Paul M., Chasman, Daniel I., and Palmer, Colin N. A.
- Abstract
Background--To test the association of a recently reported variant in the creatine kinase (CK) muscle gene, CKM Glu83Gly (rs11559024) with constitutive creatine phosphokinase (CK) levels, CK variation, and inducibility. Given the diagnostic importance of CK in determining muscle damage, we tested the association of the variant with myalgia. Methods and Results--Meta-analysis between longitudinal cohort GoDARTS (Genetics of Diabetes Audit and Research, Tayside Scotland), minor allele frequency (=0.02), and randomized clinical trial (JUPITER [Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin], minor allele frequency=0.018) was used to replicate the association with baseline CK measures. GoDARTS was used to study the relationship with CK variability. Myalgia was studied in JUPITER trial participants. Baseline and SDs of CK were on average 18% (P value=6x10
-63 ) and 24% (P value=2x10-5 ) lower for carriers of the variant, respectively. The variant was not associated with myalgia (odds ratio, 0.84; 95% confidence interval, 0.52-1.38). Conclusions--This study highlights that a genetic factor known to be associated with constitutive CK levels is also associated with CK variability and inducibility. This is discussed in the context of evidence to suggest that the variant has an impact on inducibility of CK by trauma through a previously reported case of a homozygous carrier. However, the lack of association between the variant and myalgia suggests that it cannot reliably be used as a biomarker for muscle symptoms. [ABSTRACT FROM AUTHOR]- Published
- 2017
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6. Novel subgroups of type 2 diabetes and their association with microvascular outcomes in an Asian Indian population: a data-driven cluster analysis: the INSPIRED study.
- Author
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Anjana RM, Baskar V, Nair ATN, Jebarani S, Siddiqui MK, Pradeepa R, Unnikrishnan R, Palmer C, Pearson E, and Mohan V
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- Humans, India epidemiology, Insulin, Risk Factors, Diabetes Mellitus, Type 2 epidemiology, Insulin Resistance
- Abstract
Introduction: Type 2 diabetes is characterized by considerable heterogeneity in its etiopathogenesis and clinical presentation. We aimed to identify clusters of type 2 diabetes in Asian Indians and to look at the clinical implications and outcomes of this clustering., Research Design and Methods: From a network of 50 diabetes centers across nine states of India, we selected 19 084 individuals with type 2 diabetes (aged 10-97 years) with diabetes duration of less than 5 years at the time of first clinic visit and performed k-means clustering using the following variables: age at diagnosis, body mass index, waist circumference, glycated hemoglobin, serum triglycerides, serum high-density lipoprotein cholesterol and C peptide (fasting and stimulated). This was then validated in a national epidemiological data set of representative individuals from 15 states across India., Results: We identified four clusters of patients, differing in phenotypic characteristics as well as disease outcomes: cluster 1 (Severe Insulin Deficient Diabetes, SIDD), cluster 2 (Insulin Resistant Obese Diabetes, IROD), cluster 3 (Combined Insulin Resistant and Deficient Diabetes, CIRDD) and cluster 4 (Mild Age-Related Diabetes, MARD). While SIDD and MARD are similar to clusters reported in other populations, IROD and CIRDD are novel clusters. Cox proportional hazards showed that SIDD had the highest hazards for developing retinopathy, followed by CIRDD, while CIRDD had the highest hazards for kidney disease., Conclusions: Compared with previously reported clustering, we show two novel subgroups of type 2 diabetes in the Asian Indian population with important implications for prognosis and management. The coexistence of insulin deficiency and insulin resistance seems to be peculiar to the Asian Indian population and is associated with an increased risk of microvascular complications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2020
- Full Text
- View/download PDF
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