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).