Danish Saleheen, MBBS, PhD

faculty photo
Associate Professor of Epidemiology in Biostatistics and Epidemiology
Department: Biostatistics and Epidemiology

Contact information
11-134, Perleman Research Center
3400 Civic Center Blvd
Philadelphia, PA 19104-5127
Fax: 215-573-8606
Aga Khan University, Karachi, Pakistan, 2005.
Epidemiology, University of Cambridge, 2007.
Epidemiology, University of Cambridge (“Genetic determinants of myocardial infarction and lipids in Pakistan”), 2010.
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Description of Research Expertise

Dr. Saleheen’s research program on population genetics has been focused to: (i) identify genetic risk factors predisposing to diseases like coronary heart disease (CHD) and type-2 diabetes (T2D); (ii) assess therapeutic relevance of drug targets by conducting gene-biomarker studies; and (iii) conduct deep phenotyping studies in human knockouts.
In this respect, his group has established the Pakistan Genomic Resource, comprising of more than 100,000 participants in Pakistan on whom extensive lifestyle information and biological samples have been collected. This biological resource includes approximately 45,000 participants with myocardial infarction (included in the PROMIS study), 6,000 patients with imaging confirmed stroke, 15,000 patients with type-2 diabetes, 8,000 patients with heart failure, 8,000 patients with chronic kidney disease and 45,000 healthy participants. This research program is being rapidly expanded to include 200,000 participants. A number of state-of-the art measurements have already been conducted in a large majority of these participants, including evaluation of millions of genetic markers and more than 200 blood-based factors. All of the 100,000 participants in this resource are funded for whole-exome / whole-genome sequencing studies.
A distinguishing feature of this population is the high prevalence of intermarriages; for instance, close to 40% of the participants in this resource are born of unions who are cousins. Dr. Saleheen’s group is particularly leveraging the high levels of consanguinity in Pakistan. Through WES studies in this highly inbred population, his group has identified a number of null homozygotes (i.e., human knockouts). These human knockouts are being systematically evaluated through deep phenotyping studies. For instance, whole-exome sequencing analyses of 10,503 Pakistanis led to the identification of > 1800 knockouts for > 1300 unique genes. On average, every fifth participant in the Pakistan Genomic Resource was found to be a knockout. Ongoing whole-exome sequencing studies in this resource continue to find a similar yield of knockouts. Hence, the number of knockouts is likely to grow as sequencing studies further continue in this resource. Many of these knockouts have been identified for the first time. For instance, his group has identified the world's first humans who are completely deficient of APOC3. Dr. Saleheen’s group is conducting deep phenotyping studies which would help validate APOC3 inhibition as a safe therapeutic target for cardiovascular disease protection.
Dr. Saleheen has also been instrumental in the discovery of several dozen genetic loci through multiethnic meta-analyses, including discovery of 35 novel genes for CHD (Peden J et al., 2011; Deloukas P et al., 2013; Nikpay M et al., 2015 - role: joint first author in all three; Howson J et al, 2017 – role: senior author); discovery of 21 novel genes for T2D (Kooner J et al., 2011- role: joint first author; Zhao W et al., 2017 – role: senior author; Mahajan A et al., 2018 – role: joint senior author); and discovery of 42 novel genes for blood pressure (Kato N et al., 2015; Surendran et al., 2016 – role: joint first or senior author). His group has also investigated the causal relevance of a number of biomarkers in CHD, including identification of cholesterol efflux capacity as an independent risk factor of CHD (Saleheen et al., 2015); deprioritized a causal role for uric acid in cardiometabolic diseases (Keenan et al., 2016 – role: senior author); and found causal relevance of Lp(a) and its associated apo(a) isoform size in CHD (Saleheen et al., 2017). Finally, his group has also conducted gene-environment interaction studies and identified genetic variation associated with differences in BMI among smokers (Ahmad et al., 2016 – role: senior author) and genetic variation conferring increased CHD risk among smokers compared to non-smokers (Saleheen et al., 2017).

Selected Publications

Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, Won HH, Karczewski KJ, O’Donnell-Luria AH, Samocha KE, Weisburd B, Gupta N, Zaidi M, Samuel M, Imran A, Abbas S, Majeed F, Ishaq M, Akhtar S, Trindade K, Mucksavage M, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SN, Memon A, Hayyat Mallick N, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Do R, Krauss RM, MacArthur DG, Gabriel S, Lander ES, Daly MJ, Frossard P, Danesh J, Rader DJ, Kathiresan S: Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature 544(7649): 235-39, April 2017.

Zhao W, Rasheed A, Tikkanen E, Lee JJ, Butterworth AS, Howson JMM, Assimes TL, Chowdhury R, Orho-Melander M, Damrauer S, Small A, Asma S, Imamura M, Yamauch T, Chambers JC, Chen P, Sapkota BR, Shah N, Jabeen S, Surendran P, Lu Y, Zhang W, Imran A, Abbas S, Majeed F, Trindade K, Qamar N, Mallick NH, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Rasheed SZ, Memon FU, Mehmood K, Ahmed N, Qureshi IH, Tanveer-Us-Salam, Iqbal W, Malik U, Mehra N, Kuo JZ, Sheu WH, Guo X, Hsiung CA, Juang JJ, Taylor KD, Hung YJ, Lee WJ, Quertermous T, Lee IT, Hsu CC, Bottinger EP, Ralhan S, Teo YY, Wang TD, Alam DS, Di Angelantonio E, Epstein S, Nielsen SF, Nordestgaard BG, Tybjaerg-Hansen A, Young R; CHD Exome+ Consortium, Benn M, Frikke-Schmidt R, Kamstrup PR; EPIC-CVD Consortium; EPIC-Interact Consortium; Michigan Biobank, Jukema JW, Sattar N, Smit R, Chung RH, Liang KW, Anand S, Sanghera DK, Ripatti S, Loos RJF, Kooner JS, Tai ES, Rotter JI, Chen YI, Frossard P, Maeda S, Kadowaki T, Reilly M, Pare G, Melander O, Salomaa V6, Rader DJ, Danesh J, Voight BF, Saleheen D: Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nat Genet. Sept 2017 Notes: doi: 10.1038/ng.3943. [Epub ahead of print]

Howson JMM, Zhao W, Barnes DR, Ho WK, Young R, Paul DS, Waite LL, Freitag DF, Fauman EB, Salfati EL, Sun BB, Eicher JD9, Johnson AD, Sheu WHH, Nielsen SF, Lin WY, Surendran P, Malarstig A, Wilk JB, Tybjærg-Hansen A, Rasmussen KL, Kamstrup PR, Deloukas P, Erdmann J, Kathiresan S, Samani NJ, Schunkert H, Watkins H, CARDIoGRAMplusCD, Do R, Rader DJ, Johnson JA, Hazen SL, Quyyumi AA, Spertus JA, Pepine CJ, Franceschini N, Justice A, Reiner AP, Buyske S, Hindorff LA, Carty CL, North KE, Kooperberg C, Boerwinkle E, Young K, Graff M, Peters U, Absher D, Hsiung CA, Lee WJ, Taylor KD, Chen YH, Lee IT, Guo X, Chung RH, Hung YJ, Rotter JI, Juang JJ, Quertermous T, Wang TD, Rasheed A, Frossard P, Alam DS, Majumder AAS, Di Angelantonio E, Chowdhury R; EPIC-CVD, Chen YI, Nordestgaard BG, Assimes TL7, Danesh J, Butterworth AS, Saleheen D: Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms. Nature Genetics May 2017 Notes: doi: 10.1038/ng.3874. [Epub ahead of print]

Saleheen D, Zhao W, Young R, Nelson CP, Ho W, Ferguson JF, Rasheed A, Ou K, Nurnberg ST, Bauer RC, Goel A, Do R, Stewart AFR, Hartiala J, Zhang W, Thorleifsson G, Strawbridge RJ, Sinisalo J, Kanoni S, Sedaghat S, Marouli E, Kristiansson K, Hua Zhao J, Scott R, Gauguier D, Shah SH, Smith AV, van Zuydam N, Cox AJ, Willenborg C, Kessler T, Zeng L, Province MA, Ganna A, Lind L, Pedersen NL, White CC, Joensuu A, Edi Kleber M, Hall AS, März W, Salomaa V, O'Donnell C, Ingelsson E, Feitosa MF, Erdmann J, Bowden DW, Palmer CNA, Gudnason V, Faire U, Zalloua P, Wareham N, Thompson JR, Kuulasmaa K, Dedoussis G, Perola M, Dehghan A, Chambers JC, Kooner J, Allayee H, Deloukas P, McPherson R, Stefansson K, Schunkert H, Kathiresan S, Farrall M, Marcel Frossard P, Rader DJ, Samani NJ, Reilly MP: Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions. Circulation 135(24): 2336-53, Jun 2017.

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 SN, Memon A, Mahmood K, Ahmed N, Frossard P, Tsimikas S, Witztum JL, Marcovina S, Sandhu M, Rader DJ, Danesh J: Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. The Lancet Diabetes & Endocrinology April 2017 Notes: In Press http://dx.doi.org/10.1016/S2213-8587(17)30088-8.

Keenan T, Zhao W, Rasheed A, Ho WK, Malik R, Felix JF, Young R, Shah N, Samuel M, Sheikh N, Mucksavage ML, Shah O, Li J, Morley M, Laser A, Mallick NH, Zaman KS, Ishaq M, Rasheed SZ, Memon FU, Ahmed F, Hanif B, Lakhani MS, Fahim M, Ishaq M, Shardha NK, Ahmed N, Mahmood K, Iqbal W, Akhtar S, Raheel R, O'Donnell CJ, Hengstenberg C, März W, Kathiresan S, Samani N, Goel A, Hopewell JC, Chambers J, Cheng YC, Sharma P, Yang Q, Rosand J, Boncoraglio GB, Kazmi SU, Hakonarson H, Köttgen A, Kalogeropoulos A, Frossard P, Kamal A, Dichgans M, Cappola T, Reilly MP, Danesh J, Rader DJ, Voight BF, Saleheen D: Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study. Journal of the American College of Cardiology 67(4): 407-16, Feb 2016.

Döring Y, Noels H1, van der Vorst EPC, Neideck C, Egea V, Drechsler M, Mandl M, Pawig L, Jansen Y, Schröder K, Bidzhekov K, Megens RTA, Theelen W, Klinkhammer BM, Boor P, Schurgers L, van Gorp R, Ries C, Kusters PJH, van der Wal A, Hackeng TM, Gäbel G, Brandes RP, Soehnlein O, Lutgens E, Vestweber D, Teupser D, Holdt LM, Rader DJ, Saleheen D, Weber C.: Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity: Evidence From Mouse and Human Studies. Circulation 136(4): 388-403, July 2017.

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: Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. Lancet Diabetes Endocrinol. 3(7): 507-13, Jul 2015.

Kooner JS, Saleheen D (joint first), Sim X, Sehmi J, Zhang W, Frossard P, Been LF, Chia KS, Dimas AS, Hassanali N, Jafar T, Jowett JB, Li X, Radha V, Rees SD, Takeuchi F, Young R, Aung T, Basit A, Chidambaram M, Das D, Grundberg E, Hedman AK, Hydrie ZI, Islam M, Khor CC, Kowlessur S, Kristensen MM, Liju S, Lim WY, Matthews DR, Liu J, Morris AP, Nica AC, Pinidiyapathirage JM, Prokopenko I, Rasheed A, Samuel M, Shah N, Shera AS, Small KS, Suo C, Wickremasinghe AR, Wong TY, Yang M, Zhang F; DIAGRAM; MuTHER, Abecasis GR, Barnett AH, Caulfield M, Deloukas P, Frayling TM, Froguel P, Kato N, Katulanda P, Kelly MA, Liang J, Mohan V, Sanghera DK, Scott J, Seielstad M, Zimmet PZ, Elliott P, Teo YY, McCarthy MI, Danesh J, Tai ES, Chambers JC.: Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet. 43(10): 984-9, Aug 2011.

Saleheen D, Zaidi M, Rasheed A, Ahmad U, Hakeem A, Murtaza M, Kayani W, Faruqui A, Kundi A, Zaman KS, Yaqoob Z, Cheema LA, Samad A, Rasheed SZ, Mallick NH, Azhar M, Jooma R, Gardezi AR, Memon N, Ghaffar A, Fazal-ur-Rehman, Khan N, Shah N, Ali Shah A, Samuel M, Hanif F, Yameen M, Naz S, Sultana A, Nazir A, Raza S, Shazad M, Nasim S, Javed MA, Ali SS, Jafree M, Nisar MI, Daood MS, Hussain A, Sarwar N, Kamal A, Deloukas P, Ishaq M, Frossard P, Danesh J.: 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 24(6): 329-88, June 2009.

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Last updated: 05/17/2018
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