Analysis of possible genetic risk factors contributing to development of childhood acute lymphoblastic leukaemia in the Latvian population

Publisher Copyright: Copyright © 2016 Termedia & Banach.Introduction: Childhood acute lymphoblastic leukaemia (ALL) is a complex disease caused by a combination of genetic susceptibility and environmental exposure. Previous genome-wide association studies have reported several single nucleotide polymorphisms (SNPs) associated with the incidence of ALL. Several variations in genes encoding enzymes involved in carcinogenesis are suggested as being associated with an increased risk of ALL development. Material and methods: We enrolled 77 paediatric ALL patients and 122 healthy controls, and in addition parental DNA was also available for 45 probands. SNPs rs10821936 (ARID5B), rs4132601(IKZF1), rs2239633 (CEBPE), rs3731217 (CDKN2A) and rs1800566 (NQO1) and the presence of GSTT1 and GSTM1 null variants were detected. For statistical analysis the hybrid method of two designs 'Haplin' was used as well as linkage disequilibrium for family-based association studies. Results: We identified the SNP rs10821936 in the ARID5B gene as being statistically significantly associated with childhood ALL, especially if the C allele is in a homozygous state, relative risk (RR) 4.65, 95% CI: 2.03-10.6, p = 0.0006. Statistically significant differences were not found in other SNPs. We found risk combinations including all five variations, the strongest association being found in a combination where all five genetic variants are in a homozygous state, CCTTTTTTCC, p = 0.032. Conclusions: The identified SNP rs10821936 could serve as a potential risk marker for childhood ALL development. Further studies in an independent population are needed for verification.publishersversionPeer reviewe

A CASE REPORT : PKP2 GENE C.1592T>G VARIATION IN HOMOZYGOUS FORM IDENTIFIED IN ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA PATIENT

Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy. Early recognition and follow up of this disease can reduce sudden cardiac death burden. Arrhythmogenic right ventricular dysplasia is usually inherited as an autosomal dominant trait. We report a case of a young woman aged 26 years with a past history of chest pain and palpitations. During examination, abnormalities were found in results of an electrocardiogram and echocardiography. Genetic testing of the plakophilin 2 (PKP2) gene was done by direct sequencing and genetic variation "NG_009000.1: c.1592T>G" was found in a homozygote form. In family member screening in patients, parents' variation is found in a heterozygote form, where both are healthy. In all reports, "c.1592T>G" is reported only in a heterozygous state, with no known pathogenicity. We consider that this is possibly a pathogenic mutation, inherited as an autosomal recessive trait.publishersversionPeer reviewe

Association between inherited monogenic liver disorders and chronic hepatitis C

Aim: To determine the frequencies of mutations that cause inherited monogenic liver disorders in patients with chronic hepatitis C. Methods: This study included 86 patients with chronic hepatitis C (55 men, 31 women; mean age at diagnosis, 38.36 ± 14.52 years) who had undergone antiviral therapy comprising pegylated interferon and ribavirin. Viral load, biochemical parameter changes, and liver biopsy morphological data were evaluated in all patients. The control group comprised 271 unrelated individuals representing the general population of Latvia for mutation frequency calculations. The most frequent mutations that cause inherited liver disorders [gene (mutation): ATP7B (H1069Q), HFE (C282Y, H63D), UGT1A1 (TA)7, and SERPINA1 (PiZ)] were detected by polymerase chain reaction (PCR), bidirectional PCR allele-specific amplification, restriction fragment length polymorphism analysis, and sequencing. Results: The viral genotype was detected in 80 of the 86 patients. Viral genotypes 1, 2, and 3 were present in 61 (76%), 7 (9%), and 12 (15%) patients, respectively. Among all 86 patients, 50 (58%) reached an early viral response and 70 (81%) reached a sustained viral response. All 16 patients who did not reach a sustained viral response had viral genotype 1. Case-control analysis revealed a statistically significant difference in only the H1069Q mutation between patients and controls (patients, 0.057; controls, 0.012; odds ratio, 5.514; 95%CI: 1.119-29.827, P = 0.022). However, the H1069Q mutation was not associated with antiviral treatment outcomes or biochemical indices. The (TA) 7 mutation of the UGT1A1 gene was associated with decreased ferritin levels (beta regression coefficient = -295.7, P = 0.0087). Conclusion: Genetic mutations that cause inherited liver diseases in patients with hepatitis C should be studied in detail.publishersversionPeer reviewe

Association of single nucleotide polymorphism in chromosome 11 with autism spectrum disorder

Funding Information: This study was supported by the European Social Foundation (ESF), Project No. 2009/0147/1DP/1.1.2.1.2/09/IPIA/ VIAA/009. We are grateful to all the parents and children for their participation in this study. Publisher Copyright: Copyright © 2011-2014 by Walter de Gruyter GmbH.Several genetic loci in chromosomes 11 and 15 have recently been associated with non-syndromic autism spectrum disorder (ASD) in populations from North America and Europe. The aim of the present study was to investigate whether such an association exists in a Latvian population. Ninety-five patients with ASD in the age range 3-20 years (mean age 8 years, SD 3.18) participated in the study. The control group consisted of 161 healthy, non-related individuals without ASD randomly selected from the Latvian Genome Database. Four single nucleotide polymorphisms (SNPs) - rs11212733, SNP rs1394119, rs2421826, rs1454985 - were genotyped by the TaqMan method. Allele frequency differences between ASD patients and control subjects were compared for each SNP using a standard chi-square test with Bonferroni correction. The level of statistical significance was set at 0.05 for nominal association. Only the genetic marker rs11212733, localised on the long arm of chromosome 11 in locus 22.3, was found to be strongly associated with the ASD patient group (X2 6.982, Padjusted 0.033, odds ratio 1.625). Our data demonstrating a significant relationship between the SNP rs11212733 and the development of ASD in a Latvian population suggest that it is not a population-specific relationship. Thus, future studies focusing on the DDX10 gene and related genetic loci are needed.publishersversionPeer reviewe

Higher CTX-M, TEM, and SHV extended-spectrum beta-lactamase plasmid gene combination frequency in ESBL producing Klebsiella pneumoniae compared with ESBL producing Escherichia coli

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Population Genetics of Latvians in the Context of Admixture between North-Eastern European Ethnic Groups

Publisher Copyright: © 2018 Astrida Krumiņa et al., published by Sciendo.This article presents a review on population genetics of Latvians, which alongside Lithuanians are the two extant Baltic speaking populations. The article provides a description of genome-wide single nucleotide polymorphism (SNP) data and contains a comparative analysis of the results of studies performed on classical autosomal genetic markers, mitochondrial DNA (mtDNA) and the non-recombining part of the Y chromosome (NRY), with data on neighbouring populations. The study also covers data of recently performed ancient DNA (aDNA) studies carried out on samples from the territory of today's Latvia. The results of population genetic studies have shown a mixture of eastern and western genetic traits in present-day Latvians with only small differences between Latvian subpopulations. Studies of the Baltic "tribal gene" LWb, as well as the gene's SERPINA1 allele PIZ have indicated the presence of a considerable Baltic admixture in the neighbouring Finno-Ugric and Slavic populations. Although mtDNA analyses have shown that Latvians genetically in general belong to the same common gene pool as most of the Europeans, the Y-chromosomal lineage composition suggests that they are most similar to Northern and Eastern European populations of Lithuanians, Estonians, and Eastern-Slavic populations, which are ethnogenetically closest to them. The analysis of aDNA from the Early and Middle Neolithic did not present any genomic evidence of gene-flow from Central European farmers or any mitochondrial or Y-chromosomal haplogroups that are typical for them in the hunter-gatherers from the territory of today's Latvia and Lithuania.publishersversionPeer reviewe

Risk Factors that Determine Less Favourable Hospitalisation Course and Outcome in Patients with ESBL Producing Enterobacteriaceae Infection : Preliminary Results

Publisher Copyright: © 2016 by Vita Skuja. Copyright: Copyright 2016 Elsevier B.V., All rights reserved.Hospitalisation course and outcome for patients with extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae infection is less favourable due to extensive antibacterial resistance. This study was conducted to identify possible risk factors that could influence the hospitalisation course and outcome in these patients. The study protocol included demographic, clinical, hospitalisation, bacteriological and plasmid genetic data. The preliminary study results showed that hospitalisation course and outcome was less favourable for internal medicine profile patients with ESBL producing bacteria, TEM gene presence in the bacterial plasmid genome, patient age < 65 years and patients with infectious and musculoskeletal diseases. The study includes preliminary data only and further studies should be carried out to verify the suggested risk factors.publishersversionPeer reviewe

Endobiotiķu un ksenobiotiķu metabolismā iesaistīto enzīmu kodējošo gēnu polimorfismi hroniska C vīrushepatīta un akūta toksiska hepatīta gadījumā. Promocijas darba kopsavilkums

The study was conducted at: Scientific Laboratory of Molecular Genetics, Rīga Stradiņš University. Defence: on 2nd July, 2014 at 15.00 during Rīga Stradiņš University Medical Degree Committee open meeting in Lecture theatre Hippocrates, Rīga Stradiņš University, 16 Dzirciema Street, Riga.Endo– and xenobiotic metabolism pathways are not separated in the human body. Proteins involved in these pathways are including many proteins starting with the enzymes, which direct substrate are endo– or xenobiotic, followed by proteins, that regulates enzyme and their coding gene activity and proteins involved in the transport of these substances in the cell and the body (transport proteins receptors). The main detoxification processes in the human body are ongoing in the liver, and if they are changed, it can cause liver and other organ damage. The thesis are discussed two most common causes of liver injury and its consequences – alcohol induced liver toxicity and hepatitis C virus–induced chronic liver damage. Study subjects comprised 60 patients with acute alcohol induced hepatitis. Eight genetic markers of the genes UGT1A1, GSTA1, GSTP1, NAT2, GSTT1 and GSTM1 were genotyped. There were analysed biochemical markers and their association with clinical outcome of toxic hepatitis as well as with analysed genetic markers. In our study was proved that female gender is risk factor for alcohol toxic hepatitis. Prothrombin and alkaline phosphatise could be used as markers for severity of hepatitis. GSTT1 null genotype was identified as a risk allele for alcohol toxic hepatitis progression. GSTT1 null genotype was found to correlate negatively with the level of prothrombin and positively with hyaluronic acid. For patients who died of toxic liver damage more frequent slow acetylation encoding alleles (NAT2 gene) were found, that were associated also with higher levels of GGT and alkaline phosphatase. There were 233 patients included in the study with chronic viral hepatitis C, 162 of them received antiviral therapy. In the case group morphological, biochemical and genetic factors (polymorphisms in genes GSTT1, GSTM1, UGT1A1, CCR5, SERPINA1, ATP7B, HFE) were analysed. There was discovered that higher levels of hyaluronic acid and GGT, leukocyte count and more progressed fibrosis are associated with lower possibility to reach sustained viral response. Hyaluronic acid and cytokeratine–18 should be included in non–invasive tests in order to predict sustained viral response. From analysed genetic markers clinical outcome of chronic viral hepatitis C were influenced by GSTM1 null genotype and polymorphisms in the CCR5 and SERPINA1 genes.The thesis was co–funded by the ESF project “Support for Doctoral Students in Mastering the Study Programme and Acquisition of a Scientific Degree in Rīga Stradiņš University”, agreement No. 2009/0147/1DP/1.1.2.1.2/09/IPIA/VIAA/00

Impact of Polymorphisms in the Endobiotic and Xenobiotic Metabolism Involved Enzymes Coding Genes on Chronic Hepatitis C and Acute Toxic Hepatitis. Doctoral Thesis

Promocijas darbs izstrādāts: Rīgas Stradiņa universitātes Molekulārās ģenētikas zinātniskajā laboratorijā. Aizstāvēšana: 2014. gada 2. jūlijā plkst. 15.00 Rīgas Stradiņa universitātes Medicīnas promocijas padomes atklātā sēdē Rīgā, Dzirciema ielā 16, Hipokrāta auditorijā.Cilvēka organismā neatdalīti viens no otra notiek endobiotiķu un ksenobiotiķu metabolisma ceļi. Olbaltumvielas, kas iesaistītas šajos ceļos, ir ļoti daudz, sākot ar fermentiem, kuriem tiešais substrāts ir endobiotiķis vai ksenobiotiķis, turpinot ar olbaltumvielām, kas regulē šos fermentus kodējošo gēnu darbību, un olbaltumvielām, kas iesaistītas šo vielu transportā šūnā un organismā (transporta olbaltumvielas, receptori). Galvenie atindēšanas procesi cilvēka organismā notiek aknās, un, ja tie ir izmainīti, tas var izraisīt aknu un citu orgānu bojājumu. Promocijas darbā tika apskatīti divi biežākie aknu bojājuma izraisītāji un to sekas – alkohola izraisīts aknu toksisks bojājums un C vīrushepatīta izraisīts hronisks aknu bojājums. Pētījumā tika iekļauti 60 pacienti ar akūtu toksisku alkohola izraisītu hepatītu un tika analizēti pacientu bioķīmiskie rādītāji, kā arī gēnu GSTM1, GSTT1, GSTA1, GSTP1, MTHFR, UGT1A1, NAT2 un ALDH2 funkcionālie polimorfismi un to saistība ar bioķīmiskajiem rādītājiem. Tika noskaidrots, ka sievietēm akūtam alkohola izraisītam hepatītam ir smagāka klīniskā norise. Akūta toksiska hepatīta smagumu var noteikt, izmantojot protrombīna laiku, un papildus tradicionālajiem rādītājiem būtu nepieciešams noteikt sārmaino fosfatāzi. Analizējot ģenētiskos marķierus, akūta toksiska hepatīta pacientiem biežāk bija sastopams GSTT1 nulles genotips, bet savukārt pacientiem, kuri mira no toksiska aknu bojājuma, biežāk bija lēnu acetilēšanu nosakošās alēles. Lēnā acetilēšana (nosaka gēna NAT2 kodētais enzīms) arī ir saistīta ar augstākiem aknu bojājumu raksturojošajiem bioķīmiskajiem rādītājiem (GGT un sārmainās fosfatāzes līmeni). Pētījumā tika iekļauti 233 pacienti ar hronisku C vīrushepatītu, 162 pacienti saņēma antivirālo terapiju. Pētījuma grupā tika analizēti morfoloģiskie, bioķīmiskie un ģenētiskie faktori (GSTT1, GSTM1, UGT1A1, CCR5, SERPINA1, ATP7B, HFE gēnos esošie polimorfismi). Tika noskaidrots, ka papildus esošajiem bioķīmiskajiem rādītājiem pacientiem terapijas efektivitāti palīdz prognozēt hialuronskābe un citokeratīna–18 līmenis. No ģenētiskajiem marķieriem vīrushepatīta C klīnisko gaitu ietekmē GSTM1 gēna nulles genotips, CCR5 gēna un SERPINA1 polimorfismi.Promocijas darbs izstrādāts ar Eiropas sociālā fonda projekta “Atbalsts doktorantiem studiju programmas apguvei un zinātniskā grāda ieguvei Rīgas Stradiņa universitātē” atbalstu, vienošanās Nr. 2009/0147/1DP/1.1.2.1.2/09/IPIA/VIAA/009

Lack of association between polymorphisms in genes MTHFR and MDR1 with risk of childhood acute lymphoblastic leukemia

Background: Acute lymphoblastic leukemia (ALL) is a complex disease caused by interactions between hazardous exogenous or/and endogenous agents and many mild effect inherited susceptibility mutations. Some of them are known, but their functional roles still requireinvestigation. Age is a recognized risk factor; children with disease onset after the age of ten have worse prognosis, presumably also triggered by inherited factors. Materials and Methods: The MDR1 gene polymorphisms rs1045642, rs2032582 and MTHFR gene polymorphisms rs1801131 and rs1801133 were genotyped in 68 ALL patients in remission and 102 age and gender matched controls; parental DNA samples were also available for 42 probands. Results: No case control association was found between analyzed polymorphisms and a risk of childhood ALL development. Linkage disequilibrium was not observed in a family-based association study either. Only marginal association was observed between genetic marker rs2032582A and later disease onset (p=0.04). Conclusions: Our data suggest that late age of ALL onset could be triggered by mild effect common alleles.publishersversionPeer reviewe