Deep whole-genome sequencing reveals no evidence for heteroresistance influencing treatment outcomes among drug-susceptible tuberculosis patients

AbstractAchieving remission following initial antidepressant therapy in patients with major depressive disorder (MDD) is an important clinical result. Making predictions based on genetic markers holds promise for improving the remission rate. However, genetic variants found in previous genetic studies do not provide robust evidence to aid pharmacogenetic decision-making in clinical settings. Thus, the objective of this study was to perform whole-genome sequencing (WGS) using genomic DNA to identify genetic variants associated with the treatment outcomes of selective serotonin reuptake inhibitors (SSRIs). We performed WGS on 100 patients with MDD who were treated with escitalopram (discovery set: 36 remitted and 64 non-remitted). The findings were applied to an additional 553 patients with MDD who were treated with SSRIs (replication set: 185 remitted and 368 non-remitted). A novel loss-of-function variant (rs3213755) in keratin-associated protein 1–1 (KRTAP1-1) was identified in this study. This rs3213755 variant was significantly associated with remission following antidepressant treatment (p = 0.0184, OR 3.09, 95% confidence interval [CI] 1.22–7.80 in the discovery set; p = 0.00269, OR 1.75, 95% CI 1.22–2.53 in the replication set). Moreover, the expression level of KRTAP1-1 in surgically resected human temporal lobe samples was significantly associated with the rs3213755 genotype. WGS studies on a larger sample size in various ethnic groups are needed to investigate genetic markers useful in the pharmacogenetic prediction of remission following antidepressant treatment.

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Impact of Whole-Genome Sequencing of Mycobacterium Tuberculosis On Treatment Outcomes for MDR-TB/ XDR-TB: A Systematic Review Protocol

10.21203/rs.3.rs-1046897/v1 ◽

2021 ◽

Author(s):

Druti Hazra ◽

Connie Lam ◽

Vijay Shree Dhyani ◽

Bhumika T V ◽

Kiran Chawla ◽

...

Keyword(s):

Systematic Review ◽

Drug Resistance ◽

Mycobacterium Tuberculosis ◽

Whole Genome Sequencing ◽

Treatment Outcomes ◽

Genome Sequencing ◽

Meta Analysis ◽

Cochrane Library ◽

Whole Genome ◽

Mdr Tb

Abstract Background The emergence of drug-resistant tuberculosis (DR-TB) is a persistent threat to public health. The detection of DR-TB requires culture-based drug susceptibility testing (DST) or rapid molecular assays for targeted genes. The recent advances in Whole-genome sequencing (WGS) technology have offered a new capacity to identify resistance-conferring mutations in Mycobacterium tuberculosis (MTB). This study reviews and quantifies the emerging evidence on the association between genomic markers of drug resistance in MTB identified by WGS and treatment outcomes for DR-TB. Methods A literature search will be conducted in NCBI PubMed, Scopus, Cochrane Library, Web of Science, and CINAHL (Ebsco) to retrieve all the relevant original reports from 2000 onwards. Clinical trials and observational studies describing different applications of WGS to genotypic resistance testing for TB and detection of MDR-TB/ XDR-TB as well as treatment outcomes of the patients will be included. Two primary reviewers will separately screen and select papers for data extraction, risk of bias, and assess the quality. Any disagreement between the reviewers' will be clarified by a third reviewer. The I2 statistics will be used to assess the heterogeneity of the included studies and if the data are sufficiently homogenous, a meta-analysis will be performed. The Egger's test and visual representation of the funnel plot will be used to monitor for publication bias. Narrative data synthesis will be conducted for all the included studies if performing meta-analysis is not possible. Discussion This systematic review will examine the evidence on the feasibility and added value of WGS in improving treatment outcomes in DR-TB patients. The rapid detection of drug-resistance conferring mutations and selection of appropriate drug regimens is likely to improve the cure rates while minimizing adverse events and treatment costs. Hence, the outcome of this systematic review will inform policy-making and will guide clinical laboratory practice to improve drug resistance diagnostic capacity and treatment outcomes. Systematic review registration: PROSPERO CRD42020197099.

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Investigation of isoniazid and ethionamide cross-resistance by whole genome sequencing and association with poor treatment outcomes of multidrug-resistant tuberculosis patients in South Africa

International Journal of Mycobacteriology ◽

10.1016/j.ijmyco.2016.11.020 ◽

2016 ◽

Vol 5 ◽

pp. S36-S37 ◽

Cited By ~ 5

Author(s):

L. Malinga ◽

J. Brand ◽

C. Jansen van Rensburg ◽

G. Cassell ◽

M. van der Walt

Keyword(s):

South Africa ◽

Treatment Outcomes ◽

Genome Sequencing ◽

Multidrug Resistant ◽

Cross Resistance ◽

Whole Genome ◽

Tuberculosis Patients ◽

Resistant Tuberculosis ◽

Multidrug Resistant Tuberculosis ◽

Poor Treatment

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Whole Genome Sequencing of Drug Resistant and Drug Susceptible Mycobacterium tuberculosis Isolates From Tigray Region, Ethiopia

Frontiers in Microbiology ◽

10.3389/fmicb.2021.743198 ◽

2021 ◽

Vol 12 ◽

Author(s):

Letemichael Negash Welekidan ◽

Solomon Abebe Yimer ◽

Eystein Skjerve ◽

Tsehaye Asmelash Dejene ◽

Håvard Homberset ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Pulmonary Tuberculosis ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Significant Proportion ◽

Whole Genome ◽

Drug Resistant ◽

Tuberculosis Patients ◽

Tigray Region ◽

Transmission Index

Background: Tuberculosis, mainly caused by Mycobacterium tuberculosis (Mtb), is an ancient human disease that gravely affects millions of people annually. We wanted to explore the genetic diversity and lineage-specific association of Mtb with drug resistance among pulmonary tuberculosis patients.Methods: Sputum samples were collected from pulmonary tuberculosis patients at six different healthcare institutions in Tigray, Ethiopia, between July 2018 and August 2019. DNA was extracted from 74 Mtb complex isolates for whole-genome sequencing (WGS). All genomes were typed and screened for mutations with known associations with antimicrobial resistance using in silico methods, and results were cross-verified with wet lab methods.Results: Lineage (L) 4 (55.8%) was predominant, followed by L3 (41.2%); L1 (1.5%) and L2 (1.5%) occurred rarely. The most frequently detected sublineage was CAS (38.2%), followed by Ural (29.4%), and Haarlem (11.8%). The recent transmission index (RTI) was relatively low. L4 and Ural strains were more resistant than the other strains to any anti-TB drug (P < 0.05). The most frequent mutations to RIF, INH, EMB, SM, PZA, ETH, FLQs, and 2nd-line injectable drugs occurred at rpoB S450L, katG S315T, embB M306I/V, rpsL K43R, pncA V139A, ethA M1R, gyrA D94G, and rrs A1401G, respectively. Disputed rpoB mutations were also shown in four (16%) of RIF-resistant isolates.Conclusion: Our WGS analysis revealed the presence of diverse Mtb genotypes. The presence of a significant proportion of disputed rpoB mutations highlighted the need to establish a WGS facility at the regional level to monitor drug-resistant mutations. This will help control the transmission of DR-TB and ultimately contribute to the attainment of 100% DST coverage for TB patients as per the End TB strategy.

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