Institution
Punjab Institute of Cardiology
Healthcare•Lahore, Pakistan•
About: Punjab Institute of Cardiology is a healthcare organization based out in Lahore, Pakistan. It is known for research contribution in the topics: Coronary artery disease & Population. The organization has 123 authors who have published 140 publications receiving 3763 citations.
Topics: Coronary artery disease, Population, Aortic valve replacement, Right coronary artery, Myocardial infarction
Papers published on a yearly basis
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TL;DR: This article conducted a meta-analysis of coronary artery disease (CAD) cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 millions low-frequency (0.005 < MAF < 0.5) variants.
Abstract: Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
1,839 citations
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TL;DR: Population-based long-term follow-up studies are urgently needed to demonstrate the association of risk factors with hypertension in Asia, and prevention programmes should be started based on cross-sectional surveys and case studies without waiting for the cohort studies.
Abstract: Reliable statistics related to the prevalence, incidence and mortality of hypertension and stroke are not available from Asia. The data may be in national or institutional reports or journals published in the local language only. The mortality rate for stroke has been on the decline since the mid 1960s in the developed countries of Asia, such as Australia, New Zealand, and Japan, with some improvement in Singapore, Taiwan and Hong Kong, some areas of China and Malaysia about 15 years later. In India, China, Phillippines, Thailand, Sri Lanka, Iran, Pakistan, Nepal, there has been a rapid increase in stroke mortality and prevalence of hypertension. The prevalence of hypertension according to new criteria (>140/90 mm Hg) varies between 15–35% in urban adult populations of Asia. In rural populations, the prevalence is two to three times lower than in urban subjects. Hypertension and stroke occur at a relatively younger age in Asians and the risk of hypertension increases at lower levels of body mass index of 23–25 kg/m2. Overweight, sedentary behaviour, alcohol, higher social class, salt intake, diabetes mellitus and smoking are risk factors for hypertension in most of the countries of Asia. In Australia, New Zealand and Japan, lower social class is a risk factor for hypertension and stroke. Population-based long-term follow-up studies are urgently needed to demonstrate the association of risk factors with hypertension in Asia. However prevention programmes should be started based on cross-sectional surveys and case studies without waiting for the cohort studies.
275 citations
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University of Pennsylvania1, Broad Institute2, Harvard University3, Samsung Medical Center4, Boston Children's Hospital5, Punjab Institute of Cardiology6, Karachi Institute of Heart Diseases7, Civil Hospital Karachi8, Liaquat National Hospital9, Icahn School of Medicine at Mount Sinai10, Children's Hospital Oakland Research Institute11, Wellcome Trust Sanger Institute12, University of Cambridge13
TL;DR: Overall, these observations provide a roadmap for a ‘human knockout project’, a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.
Abstract: A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.
268 citations
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Adam S. Butterworth1, Peter S. Braund2, Martin Farrall3, Robert J. Hardwick4 +352 more•Institutions (107)
TL;DR: This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.
Abstract: Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ~2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10; LPA:p<10; 1p13.3:p<10) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ~4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes. © 2011 Butterworth et al.
228 citations
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University of Pennsylvania1, University of Helsinki2, University of Cambridge3, Stanford University4, Lund University5, McMaster University6, University of Tokyo7, Imperial College London8, National University of Singapore9, University of Oklahoma Health Sciences Center10, Icahn School of Medicine at Mount Sinai11, Punjab Institute of Cardiology12, Karachi Institute of Heart Diseases13, Civil Hospital Karachi14, Liaquat National Hospital15, King Edward Medical University16, Lahore General Hospital17, All India Institute of Medical Sciences18, Los Angeles Biomedical Research Institute19, National Health Research Institutes20, National Taiwan University21, National Defense Medical Center22, International Centre for Diarrhoeal Disease Research, Bangladesh23, MedStar Washington Hospital Center24, Frederiksberg Hospital25, Copenhagen University Hospital26, Leiden University Medical Center27, University of Glasgow28, Columbia University29, National Institutes of Health30
TL;DR: A genome-wide, multi-ancestry study of genetic variation for type 2 diabetes and coronary heart disease finds variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.
Abstract: Danish Saleheen, Benjamin Voight and colleagues perform genome-wide analysis of multi-ancestry cohorts to identify genetic associations with type 2 diabetes (T2D) and coronary heart disease (CHD). They find novel loci and show that 24% of T2D loci are also associated with CHD and that greater genetic risk of T2D increases risk of CHD. To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D–CHD analysis identified eight variants—two of which are coding—where T2D and CHD associations appear to colocalize, including a new joint T2D–CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.
193 citations
Authors
Showing all 124 results
Name | H-index | Papers | Citations |
---|---|---|---|
Maqsood M. Elahi | 17 | 67 | 1544 |
Masood Sadiq | 14 | 41 | 539 |
Soheyl Sheikh | 13 | 53 | 744 |
Rana Muhammad Atif | 12 | 49 | 572 |
Nadeem Hayat Mallick | 9 | 24 | 1897 |
Khurram Shahzad | 9 | 40 | 286 |
Jawad Sajid Khan | 8 | 22 | 194 |
Ahmad Usaid Qureshi | 8 | 20 | 204 |
Abdul Rehman Abid | 7 | 12 | 119 |
Nadeem Hayyat Mallick | 7 | 7 | 1781 |
Raja Parvez Akhtar | 7 | 14 | 125 |
Muhammad Usman Khan | 5 | 8 | 94 |
Muhammad Azhar | 5 | 5 | 986 |
Mirrat Gul | 5 | 8 | 188 |
Imran Khan | 4 | 12 | 100 |