A population study of clinically actionable genetic variation affecting drug response from the Middle East

Clinical implementation of pharmacogenomics will help in personalizing drug prescriptions and alleviate the personal and financial burden due to inefficacy and adverse reactions to drugs. However, such implementation is lagging in many parts of the world, including the Middle East, mainly due to the lack of data on the distribution of actionable pharmacogenomic variation in these ethnicities. We analyzed 6,045 whole genomes from the Qatari population for the distribution of allele frequencies of 2,629 variants in 1,026 genes known to affect 559 drugs or classes of drugs. We also performed a focused analysis of genotypes or diplotypes of 15 genes affecting 46 drugs, which have guidelines for clinical implementation and predicted their phenotypic impact. The allele frequencies of 1,320 variants in 703 genes affecting 299 drugs or class of drugs were significantly different between the Qatari population and other world populations. On average, Qataris carry 3.6 actionable genotypes/diplotypes, affecting 13 drugs with guidelines for clinical implementation, and 99.5% of the individuals had at least one clinically actionable genotype/diplotype. Increased risk of simvastatin-induced myopathy could be predicted in ~32% of Qataris from the diplotypes of SLCO1B1, which is higher compared to many other populations, while fewer Qataris may need tacrolimus dosage adjustments for achieving immunosuppression based on the CYP3A5 diplotypes compared to other world populations. Distinct distribution of actionable pharmacogenomic variation was also observed among the Qatari subpopulations. Our comprehensive study of the distribution of actionable genetic variation affecting drugs in a Middle Eastern population has potential implications for preemptive pharmacogenomic implementation in the region and beyond

Characterisation and antimicrobial resistance of sepsis pathogens in neonates born in tertiary care centres in Delhi, India: A cohort study

Background: Sepsis is one of the most common causes of neonatal deaths globally. Most sepsis-related deaths occur in low-income and middle-income countries, where the epidemiology of neonatal sepsis remains poorly understood. Most of these countries lack proper surveillance networks, hampering accurate assessment of the burden of sepsis, implementation of preventive measures, and investment in research. We report results of neonates born in hospital from a multicentre collaboration on neonatal sepsis. Methods: In this cohort study, dedicated research teams prospectively followed up neonates born in one of three tertiary care centres in Delhi, India (Vardhaman Mahavir Medical College, Maulana Azad Medical College, and All India Institute of Medical Sciences [coordinating centre]) and subsequently admitted to the intensive care unit. Neonates were followed up daily until discharge or death. On clinical suspicion, neonates underwent sepsis work-up including blood cultures. The isolated organisms were identified and tested for antimicrobial susceptibility. We defined Gram-negative isolates resistant to any three of five antibiotic classes (extended-spectrum cephalosporins, carbapenems, aminoglycosides, fluoroquinolones, and piperacillin-tazobactam) as multidrug resistant. Findings: 13 530 neonates of 88 636 livebirths were enrolled between July 18, 2011, and Feb 28, 2014. The incidence of total sepsis was 14·3% (95% CI 13·8–14·9) and of culture-positive sepsis was 6·2% (5·8–6·6). Nearly two-thirds of total episodes occurred at or before 72 h of life (defined as early onset; 1351 [83%] of 1980). Two-thirds (645 [64%]) of 1005 isolates were Gram-negative including, Acinetobacter spp (22%), Klebsiella spp (17%), and Escherichia coli (14%). The pathogen mix in early-onset sepsis did not differ from that of late-onset sepsis (ie, after 72 h). High rates of multidrug resistance were observed in Acinetobacter spp (181/222, 82%), Klebsiella spp (91/169, 54%), and Escherichia coli (52/137, 38%) isolates. Meticillin resistance prevailed in 61% (85/140) of coagulase-negative staphylococci and 38% (43/114) of Staphylococcus aureus isolates. Nearly a quarter of the deaths were attributable to sepsis. The population-attributable risks of mortality were 8·6% in culture-negative sepsis, 15·7% in culture-positive sepsis by multidrug-resistant organisms, and 12·0% in culture-positive sepsis by non-multidrug-resistant organisms. Interpretation: The high incidence of sepsis and alarming degree of antimicrobial resistance among pathogens in neonates born in tertiary hospitals underscore the need to understand the pathogenesis of early-onset sepsis and to devise measures to prevent it in low-income and middle-income countries. Funding: Indian Council of Medical Researc