Danish Saleheen, MBBS, PhD

Profile Headshot

Overview

Academic Appointments

  • Professor of Medical Sciences (in Medicine)

Administrative Titles

  • Director, Global Genomics, Department of Medicine

Gender

  • Male

Credentials & Experience

Education & Training

  • MBBS, Medicine, Aga Khan University
  • PhD, Cardiovascular Genomics, University of Cambridge (United Kingdom)

Research

Dr. Saleheen is the Principal Investigator of the Pakistan Genomic Resource (PGR), comprising of more than 150,000 participants in Pakistan on whom extensive genetic, biomarker and lifestyle information have been collected (www.cncd.org). PGR is being rapidly expanded to 1 Million participants. Whole-exome or whole-genome sequencing studies are already in progress in these participants. Of the first 65,000 participants who have undergone sequencing, roughly a fifth (> 12,000 participants) have been found to be homozygous null for predicted loss of function mutations (i.e., “Human Knockouts”) for > 6,000 unique genes. Many of these knockouts have never been reported previously. Once sequencing studies are completed, we anticipate to find > 300,000 human knockouts for > 15,000 unique genes. An experiment involving several million participants will be required in other outbred populations to get a similar yield of knockouts. These human knockouts are being systematically evaluated through deep phenotyping studies. Call-back involves recruiting family members who are also highly in-bred resulting into identification of more knockouts related to the primary proband (e.g., call back of one APOC3 knockout has led to the discovery of > 30 knockouts for APOC3). Knowledge gained from phenotyping studies in these knockouts and their family members is helping us understand: (i) the biology of genes; (ii) pharmaceutical inhibition of pathways; particularly dose-response relationships and safety profile; (iii) knowledge on essential genes; (iv) modifier genes that could inform about developing new therapies.

Selected Publications

Saleheen D, et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017 Apr 12;544(7649):235-239.

Zhao W, Rasheed A, Tikkanen E, ….., Saleheen D. Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nat Genet. 2017 Sep 4. doi: 10.1038/ng.3943. PMID: 28869590

Howson JMM, Zhao W, Barnes DR, …., Saleheen D. Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nat Genet. 2017 Jul;49(7):1113-1119. doi: 10.1038/ng.3874. Epub 2017 May 22. PMID: 28869590

Kooner JS*, Saleheen D* (joint first), Sim X, Sehmi J, Zhang W, Frossard P, et.al . Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet. 2011 Aug 28;43(10):984-9 PMID: 21874001

Peden JF*, Hopewell JC*, Saleheen D* (joint first), et.al. A genome-wide association study in Europeans and South Asians identifies five novel loci for coronary artery disease. Nat Genet. 2011 Mar 6;43(4):339-44 PMID: 21378988

Stitziel NO, Khera AV, Wang X, …, Saleheen D* (joint senior author), Musunuru K*, Kathiresan S*; PROMIS and Myocardial Infarction Genetics Consortium Investigators. ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J Am Coll Cardiol. 2017 Apr 25;69(16):2054-2063. PMID: 28385496

Saleheen D, Scott R, Javad S, Zhao W, Rodrigues A, Picataggi A, Lukmanova D, Mucksavage ML, Luben R, Billheimer J, Kastelein JJ, Boekholdt SM, Khaw KT, Wareham N, Rader DJ. Lancet Diabetes Endocrinol. 2015 May 26. PMID: 26025389

Saleheen D, Haycock PC, Zhao W, Rasheed A, Taleb A, Imran A, Abbas S, Majeed F, Akhtar S, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Mallick NH, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Frossard P, Tsimikas S, Witztum JL, Marcovina S, Sandhu M, Rader DJ, Danesh J. Lancet Diabetes Endocrinol. 2017 Jul;5(7):524-533. PMID: 28408323

Keenan T, Zhao W, Rasheed A,…, Saleheen D. Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study. J Am Coll Cardiol. 2016 Feb 2;67(4):407-16. PMID: 26821629

Saleheen D, Zaidi M, Rasheed A, et.al. The Pakistan Risk of Myocardial Infarction Study: a resource for the study of genetic, lifestyle and other determinants of myocardial infarction in South Asia. Eur J Epidemiol. 2009;24(6):329-38. PMID: 19404752