In a clinical setting, DNA sequencing can uncover findings unrelated to the purpose of genetic evaluation. The American College of Medical Genetics and Genomics (ACMG) recommends the evaluation and reporting of 59 genes from clinic genomic sequencing. While the prevalence of secondary findings is available from large population studies, these data lack Arab and other Middle Eastern populations. The Qatar Genome Program (QGP) generates whole-genome sequencing (WGS) data and combines it with phenotypic information to create a comprehensive database for studying the Qatari and wider Arab and Middle Eastern populations at the molecular level. This study identified and analyzed medically actionable variants in the 59 ACMG genes using WGS data from 6045 QGP participants. Our results identified a total of 60 pathogenic and likely pathogenic variants in 25 ACMG genes in 141 unique individuals. Overall, 2.3% of the QGP sequenced participants carried a pathogenic or likely pathogenic variant in one of the 59 ACMG genes. We evaluated the QGP phenotype-genotype association of additional nonpathogenic ACMG variants. These variants were found in patients from the Hamad Medical Corporation or reported incidental findings data in Qatar. We found a significant phenotype association for two variants, c.313+3A>C in LDLR, and c.58C>T (p.Gln20*) in the TPM1.
Arab populations are largely understudied, notably their genetic structure and history. Here we present an in-depth analysis of 6,218 whole genomes from Qatar, revealing extensive diversity as well as genetic ancestries representing the main founding Arab genealogical lineages of Qahtanite (Peninsular Arabs) and Adnanite (General Arabs and West Eurasian Arabs). We find that Peninsular Arabs are the closest relatives of ancient hunter-gatherers and Neolithic farmers from the Levant, and that founder Arab populations experienced multiple splitting events 12–20 kya, consistent with the aridification of Arabia and farming in the Levant, giving rise to settler and nomadic communities. In terms of recent genetic flow, we show that these ancestries contributed significantly to European, South Asian as well as South American populations, likely as a result of Islamic expansion over the past 1400 years. Notably, we characterize a large cohort of men with the ChrY J1a2b haplogroup (n = 1,491), identifying 29 unique sub-haplogroups. Finally, we leverage genotype novelty to build a reference panel of 12,432 haplotypes, demonstrating improved genotype imputation for both rare and common alleles in Arabs and the wider Middle East.
The protective effect of N-acetylcysteine (NAC) and genistein (GEN) on an experimental model of indomethacin (IND)-induced gastric injury was investigated. A total of 50 male rats were divided into 5 groups: (1) control, (2) IND, (3) NAC pretreated, (4) GEN pretreated, and (5) NAC+GEN pretreated. Rats in groups 3-5 were orally administered NAC (500 mg/kg), GEN (10 mg/kg), or both, respectively, once daily for 7 days before the induction of gastric injury by IND (50 mg/kg). The stomach was removed for biochemical analysis and histopathological examination. Pretreatment with NAC, GEN, or both significantly improved ulcer indices and increased nitric oxide level and superoxide dismutase activity. They also significantly decreased malondialdehyde, tumour necrosis factor α levels, and myeloperoxidase activity, and downregulated matrix metalloproteinase 9 (MMP-9) gene expression compared to the IND group. NAC alone ameliorated IND-induced apoptosis, whereas GEN only significantly increased prostaglandin E level. Further, coadministration of both resulted in a significantly better gastroprotective effect versus solo administration. Coadministration of NAC and GEN has an additive gastroprotective effect in IND-induced gastric injury, which may be through interaction of their potential cytoprotective, antioxidant, anti-inflammatory, and antiapoptotic mechanisms together with regulation of MMP-9 expression.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.