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Variation and association to diabetes in 2000 full mtDNA sequences mined from an exome study in a Danish population.

ABSTRACT: In this paper, we mine full mtDNA sequences from an exome capture data set of 2000 Danes, showing that it is possible to get high-quality full-genome sequences of the mitochondrion from this resource. The sample includes 1000 individuals with type 2 diabetes and 1000 controls. We characterise the variation found in the mtDNA sequence in Danes and relate the variation to diabetes risk as well as to several blood phenotypes of the controls but find no significant associations. We report 2025 polymorphisms, of which 393 have not been reported previously. These 393 mutations are both very rare and estimated to be caused by very recent mutations but individuals with type 2 diabetes do not possess more of these variants. Population genetics analysis using Bayesian skyline plot shows a recent history of rapid population growth in the Danish population in accordance with the fact that >40% of variable sites are observed as singletons.

SUBMITTER: Li S

PROVIDER: S-EPMC4350597 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Variation and association to diabetes in 2000 full mtDNA sequences mined from an exome study in a Danish population.

Li Shengting S Besenbacher Soren S Li Yingrui Y Kristiansen Karsten K Grarup Niels N Albrechtsen Anders A Sparsø Thomas T Korneliussen Thorfinn T Hansen Torben T Wang Jun J Wang Jun J Nielsen Rasmus R Pedersen Oluf O Bolund Lars L Schierup Mikkel H MH

European journal of human genetics : EJHG 20140122 8

In this paper, we mine full mtDNA sequences from an exome capture data set of 2000 Danes, showing that it is possible to get high-quality full-genome sequences of the mitochondrion from this resource. The sample includes 1000 individuals with type 2 diabetes and 1000 controls. We characterise the variation found in the mtDNA sequence in Danes and relate the variation to diabetes risk as well as to several blood phenotypes of the controls but find no significant associations. We report 2025 polym ...[more]

PMID: 24448545

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Project description:In genes related to drug pharmacokinetics, molecular variations determine interindividual variability in the therapeutic efficacy and adverse drug reactions. The assessment of single-nucleotide variants (SNVs) is used with growing frequency in pharmacogenetic practice, and recently, high-throughput genomic analyses obtained through next-generation sequencing (NGS) have been recognized as powerful tools to identify common, rare and novel variants. These genetic profiles remain underexplored in Latin-American populations, including Colombia. In this study, we investigated the variability of 35 genes included in the ADME core panel (absorption, distribution, metabolism, and excretion) by whole-exome sequencing (WES) of 509 unrelated Colombian individuals with no previous reports of adverse drug reactions. Rare variants were filtered according to the minor allele frequencies (MAF) <1% and potential deleterious consequences. The functional impact of novel and rare missense variants was assessed using an optimized framework for pharmacogenetic variants. Bioinformatic analyses included the identification of clinically validated variants described in PharmGKB and ClinVar databases. Ancestry from WES data was inferred using the R package EthSEQ v2.1.4. Allelic frequencies were compared to other populations reported in the public gnomAD database. Our analysis revealed that rare missense pharmacogenetic variants were 2.1 times more frequent than common variants with 121 variants predicted as potentially deleterious. Rare loss of function (LoF) variants were identified in 65.7% of evaluated genes. Regarding variants with clinical pharmacogenetic effect, our study revealed 89 sequence variations in 28 genes represented by missense (62%), synonymous (22.5%), splice site (11.2%), and indels (3.4%). In this group, ABCB1, ABCC2, CY2B6, CYP2D6, DPYD, NAT2, SLC22A1, and UGTB2B7, are the most polymorphic genes. NAT2, CYP2B6 and DPYD metabolizer phenotypes demonstrated the highest variability. Ancestry analysis indicated admixture in 73% of the population. Allelic frequencies exhibit significant differences with other Latin-American populations, highlighting the importance of pharmacogenomic studies in populations of different ethnicities. Altogether, our data revealed that rare variants are an important source of variability in pharmacogenes involved in the pharmacokinetics of drugs and likely account for the unexplained interindividual variability in drug response. These findings provide evidence of the utility of WES for pharmacogenomic testing and into clinical practice.

Project description:IntroductionSarcoma is a rare type of cancer. The incidence increases with age and elderly patients may have comorbidity that affects the prognosis. The aim of this study was to describe the type and prevalence of comorbidity in a nationwide population-based study in Denmark from 2000-2013 and to analyse the impact of the different comorbidities on mortality.Material and methodsThe Danish Sarcoma Registry is a national clinical database containing all patients with sarcoma in the extremities or trunk wall from 2000 and onwards. By linking data to other registries, we were able to get patient information on an individual level including date and cause of death as well as the comorbidity type up to 10 years prior to the sarcoma diagnosis. Based on diseases in the Charlson Comorbidity Index, we pooled the patients into six categories: no comorbidity, cardiopulmonary disease, gastrointestinal disease, neurovascular disease, malignant neoplasms, and miscellaneous (diabetes, renal and connective tissue diseases). 2167 patients were included.ResultsThe prevalence of comorbidity was 20%. For patients with localized disease, comorbidity increased the disease-specific mortality significantly (HR 1.70 (95% CI 1.36-2.13)). For patients with metastatic disease at the time of diagnosis, comorbidity did not affect the disease-specific mortality (HR 1.05 (95% CI 0.78-1.42)). The presence of another cancer diagnosis within 10 years prior to the sarcoma diagnosis was the only significant independent prognostic factor of disease-specific mortality with an increase of 66% in mortality rate compared to patients with no comorbidity (HR 1,66 (95% CI 1.22-2.25)).ConclusionComorbidity is a strong independent prognostic factor of mortality in patients with localized disease. This study emphasizes the need for optimizing the general health of comorbid patients in order to achieve a survival benefit from treatment of patients with localized disease, as this is potentially modifiable.

Dataset Information

Variation and association to diabetes in 2000 full mtDNA sequences mined from an exome study in a Danish population.

Publications

Variation and association to diabetes in 2000 full mtDNA sequences mined from an exome study in a Danish population.

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