Genome Database of the Latvian Population (LGDB): Design, Goals, and Primary Results

Rovīte, Vita; Wolff-Sagi, Yael; Zaharenko, Linda; Ņikitina-Zaķe, Liene; Grens, Elmars; Kloviņš, Jānis

doi:10.2188/jea.je20170079

Cited by 69 publications

(73 citation statements)

References 32 publications

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“…The study involved two longitudinal cohorts of participants: OPTIMED cohort of newly-diagnosed T2D patients (N = 50) recruited within the framework of Genome Database of Latvian population [ 13 ], and a cohort of healthy individuals (N = 35). A full list of inclusion/exclusion criteria for both cohorts can be found in the S1 Text .…”

Section: Methodsmentioning

confidence: 99%

Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients

et al. 2020

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Background The study was conducted to investigate the effects of metformin treatment on the human gut microbiome’s taxonomic and functional profile in the Latvian population, and to evaluate the correlation of these changes with therapeutic efficacy and tolerance. Methods In this longitudinal observational study, stool samples for shotgun metagenomic sequencing-based analysis were collected in two cohorts. The first cohort included 35 healthy nondiabetic individuals (metformin dose 2x850mg/day) at three time-points during metformin administration. The second cohort was composed of 50 newly-diagnosed type 2 diabetes patients (metformin dose–determined by an endocrinologist) at two concordant times. Patients were defined as Responders if their HbA1c levels during three months of metformin therapy had decreased by ≥12.6 mmol/mol (1%), while in Non-responders HbA1c were decreased by <12.6 mmol/mol (1%). Results Metformin reduced the alpha diversity of microbiota in healthy controls (p = 0.02) but not in T2D patients. At the species level, reduction in the abundance of Clostridium bartlettii and Barnesiella intestinihominis , as well as an increase in the abundance of Parabacteroides distasonis and Oscillibacter unclassified overlapped between both study groups. A large number of group-specific changes in taxonomic and functional profiles was observed. We identified an increased abundance of Prevotella copri (FDR = 0.01) in the Non-Responders subgroup, and enrichment of Enterococcus faecium , Lactococcus lactis , Odoribacter , and Dialister at baseline in the Responders group. Various taxonomic units were associated with the observed incidence of side effects in both cohorts. Conclusions Metformin effects are different in T2D patients and healthy individuals. Therapy induced changes in the composition of gut microbiome revealed possible mediators of observed short-term therapeutic effects. The baseline composition of the gut microbiome may influence metformin therapy efficacy and tolerance in T2D patients and could be used as a powerful prediction tool.

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Section: Methodsmentioning

confidence: 99%

Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients

et al. 2020

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“…Eighteen healthy volunteers of Caucasian origin were included in this exploratory study through the Genome Database of Latvian Population [ 22 ] as a part of an ongoing clinical trial (50 individuals to be included in total), by assessing the 25 individuals available at the time. Baseline characteristics and registered clinical parameters are shown in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Association of metformin administration with gut microbiome dysbiosis in healthy volunteers

et al. 2018

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BackgroundMetformin is a widely used first-line drug for treatment of type 2 diabetes. Despite its advantages, metformin has variable therapeutic effects, contraindications, and side effects. Here, for the very first time, we investigate the short-term effect of metformin on the composition of healthy human gut microbiota.MethodsWe used an exploratory longitudinal study design in which the first sample from an individual was the control for further samples. Eighteen healthy individuals were treated with metformin (2 × 850 mg) for 7 days. Stool samples were collected at three time points: prior to administration, 24 hours and 7 days after metformin administration. Taxonomic composition of the gut microbiome was analyzed by massive parallel sequencing of 16S rRNA gene (V3 region).ResultsThere was a significant reduction of inner diversity of gut microbiota observed already 24 hours after metformin administration. We observed an association between the severity of gastrointestinal side effects and the increase in relative abundance of common gut opportunistic pathogen Escherichia-Shigella spp. One week long treatment with metformin was associated with a significant decrease in the families Peptostreptococcaceae and Clostridiaceae_1 and four genera within these families.ConclusionsOur results are in line with previous findings on the capability of metformin to influence gut microbiota. However, for the first time we provide evidence that metformin has an immediate effect on the gut microbiome in humans. It is likely that this effect results from the increase in abundance of opportunistic pathogens and further triggers the occurrence of side effects associated with the observed dysbiosis. An additional randomized controlled trial would be required in order to reach definitive conclusions, as this is an exploratory study without a placebo control arm. Our findings may be further used to create approaches that improve the tolerability of metformin.

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“…LGDB is a central institution for human genetic material biobanking for research needs in Latvia [23]. Two written informed consents were obtained from the patient, broad consent for LGDB for use of biological material and medical data for human health and hereditary research, and project-specific consent with approval of the use of biological material and clinical data in research related to pituitary tumours that included all procedures and analyses described in this manuscript.…”

Section: Discussionmentioning

confidence: 99%

“…In August 2010, the patient underwent surgery via craniotomy, and partial resection of the suprasellar part of the pituitary adenoma was performed. Before the surgery, the patient was enrolled in national government-funded biobank -the Genome Database of the Latvian population (LGDB) [23]. During recruitment patient has signed two written informed consents (1) broad consent for LGDB for the use of the samples and data for health-related studies, and (2) project-specific consent for pituitary tumour studies.…”

Section: Case Presentationmentioning

confidence: 99%

Case report: recurrent pituitary adenoma has increased load of somatic variants

et al. 2020

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Background: Pituitary adenomas (PA) have an increased potential for relapse in one to 5 years after resection. In this study, we investigated the genetic differences in genomic DNA of primary and rapidly recurrent tumours in the same patient to explain the causality mechanisms of PA recurrence. Case presentation: The patient was a 69-year-old female with non-functional pituitary macroadenoma with extension into the left cavernous sinus (Knosp grade 2) who underwent craniotomy and partial resection in August 2010. Two years later, the patient had prolonged tumour growth with an essential suprasellar extension (Knosp grade 2), and a second craniotomy with partial tumour resection was performed in September 2012. In both tumours, the KI-67 level was below 1.5%. Exome sequencing via semiconductor sequencing of patient germline DNA and somatic DNA from both tumours was performed. Tmap alignment and Platypus variant calling were performed followed by variant filtering and manual review with IGV software. We observed an increased load of missense variants in the recurrent PA tumour when compared to the original tumour. The number of detected variants increased from ten to 26 and potential clonal expansion of four variants was observed. Additionally, targeted SNP analysis revealed five rare missense SNPs with a potential impact on the function of the encoded proteins. Conclusions: In this case study, an SNP located in HRAS is the most likely candidate inducing rapid PA progression. The relapsed PA tumour had a higher variation load and fast tumour recurrence in this patient could be caused by clonal expansion of the leftover tumour tissue.

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Genome Database of the Latvian Population (LGDB): Design, Goals, and Primary Results

Cited by 69 publications

References 32 publications

Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients

Baseline gut microbiome composition predicts metformin therapy short-term efficacy in newly diagnosed type 2 diabetes patients

Association of metformin administration with gut microbiome dysbiosis in healthy volunteers

Case report: recurrent pituitary adenoma has increased load of somatic variants

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