Kohlhase S.,Hannover Medical School |
Bogdanova N.V.,Hannover Medical School |
Schurmann P.,Hannover Medical School |
Bermisheva M.,Hannover Medical School |
And 9 more authors.
PLoS ONE | Year: 2014
The ERCC4 protein forms a structure-specific endonuclease involved in the DNA damage response. Different cancer syndromes such as a subtype of Xeroderma pigmentosum, XPF, and recently a subtype of Fanconi Anemia, FA-Q, have been attributed to biallelic ERCC4 gene mutations. To investigate whether monoallelic ERCC4 gene defects play some role in the inherited component of breast cancer susceptibility, we sequenced the whole ERCC4 coding region and flanking untranslated portions in a series of 101 Byelorussian and German breast cancer patients selected for familial disease (set 1, n = 63) or for the presence of the rs1800067 risk haplotype (set 2, n = 38). This study confirmed six known and one novel exonic variants, including four missense substitutions but no truncating mutation. Missense substitution p.R415Q (rs1800067), a previously postulated breast cancer susceptibility allele, was subsequently screened for in a total of 3,698 breast cancer cases and 2,868 controls from Germany, Belarus or Russia. The Gln415 allele appeared protective against breast cancer in the German series, with the strongest effect for ductal histology (OR 0.67; 95%CI 0.49; 0.92; p = 0.003), but this association was not confirmed in the other two series, with the combined analysis yielding an overall Mantel-Haenszel OR of 0.94 (95% CI 0.81; 1.08). There was no significant effect of p.R415Q on breast cancer survival in the German patient series. The other three detected ERCC4 missense mutations included two known rare variants as well as a novel substitution, p.E17V, that we identified on a p.R415Q haplotype background. The p.E17V mutation is predicted to be probably damaging but was present in just one heterozygous patient. We conclude that the contribution of ERCC4/FANCQ coding mutations to hereditary breast cancer in Central and Eastern Europe is likely to be small. © 2014 Kohlhase et al.
Prokofyeva D.,Hannover Medical School |
Prokofyeva D.,Bashkir State University |
Bogdanova N.,Hannover Medical School |
Dubrowinskaja N.,Hannover Medical School |
And 13 more authors.
Breast Cancer Research and Treatment | Year: 2013
Bloom's syndrome is a rare autosomal recessive chromosomal instability disorder with a high incidence of various types of neoplasia, including breast cancer. Whether monoallelic BLM mutations predispose to breast cancer has been a long-standing question. A nonsense mutation, p.Q548X, has recently been associated with an increased risk for breast cancer in a Russian case-control study. In the present work, we have investigated the prevalence of this Slavic BLM founder mutation in a total of 3,188 breast cancer cases and 2,458 controls from Bashkortostan, Belarus, Ukraine, and Kazakhstan. The p.Q548X allele was most frequent in Russian patients (0.8 %) but was also prevalent in Byelorussian and Ukrainian patients (0.5 and 0.6 %, respectively), whereas it was absent in Altaic or other non-European subpopulations. In a combined analysis of our four case-control series, the p.Q548X mutation was significantly associated with breast cancer (Mantel-Haenszel OR 5.1, 95 % CI 1.2; 21.9, p = 0.03). A meta-analysis with the previous study from the St. Petersburg area corroborates the association (OR 5.7, 95 % CI 2.0; 15.9, p = 3.7 × 10-4). A meta-analysis for all published truncating mutations further supports the association of BLM with breast cancer, with an estimated two- to five-fold increase in risk (OR 3.3, 95 %CI 1.9; 5.6, p = 1.9 × 10-5). Altogether, these data indicate that BLM is not only a gene for Bloom's syndrome but also might represent a breast cancer susceptibility gene. © 2012 Springer Science+Business Media New York.
Agency: European Commission | Branch: FP7 | Program: CP-FP-SICA | Phase: HEALTH-2009-4.3.3-1 | Award Amount: 5.68M | Year: 2009
The subject of the proposal is the search and analysis of genomic variations underlying Alzheimers disease (AD), alcoholism and schizophrenia wide-spread diseases in human populations. Schizophrenia and alcoholism are common forms of behavior pathology and disability in adult life. AD is a most common form of dementia in human populations. Though the genomic variations presumably associated with AD, alcoholism and schizophrenia were described in preliminary studies for European populations, the significance of the putatively associated alleles, genetic background as well as the role of environmental factors is still poorly understood for them. Within the framework of this project we plan to extend the studies of genomic variations underlying these diseases by performing genome-wide association analysis in cohorts of patients and normal individuals from several ethnic populations of Europe and Russia.The genetic factors for cognition endophenotype will also be studied. Candidate regions, both newly found and reported previously for these diseases will be additionally analyzed by sequencing. Such large scale population studies combined with deep analysis of particular genes and genomic regions will allow us to reveal genetic reasons for susceptibility to these diseases. On the basis of this research we propose to contribute to development of a diagnostic instrument for the analysis of genetic risk factors for AD, alcoholism and schizophrenia. Comparison of several ethnic cohorts (different populations from Russia and Central/Western and Southern Europe) will also help to elucidate the influence of genetic background and environmental factors on the etiology of neuropsychiatric diseases. Consortium includes 6 groups from EU/AC and 7 groups from Russia. The participants are leading specialists in their fields and have joint publications on subjects related to this proposal.
Agency: European Commission | Branch: FP7 | Program: CP-FP-SICA | Phase: HEALTH.2011.2.4.3-4 | Award Amount: 4.32M | Year: 2012
MEDIGENE project will study genetic and environmental (G x E) determinants of the metabolic syndrome (MetS) in recent immigrants in Europe by a novel approach integrating ancestry of Mediterranean populations in epidemiology, locus refining and Genome Wide Association Studies (GWAS). West Mediterranean shores are place of pre-historical termini of population expansion from Southern Europe and North Africa. Archaeogenetic studies in Europe indicated that Y chromosome and mitochondrial DNA patterns or Ancestry Informative Markers (AIMs) revealed a close relationship between genetic and geographic distances able to locate an individual DNA within few hundred kilometers. The project will use this information in mapping the genetic basis of insulin resistance, cardiovascular and metabolic complications in immigrants (Albanians, Romanians, Turkish, Tunisians, Algerians and Morocco) in host countries France, Spain, Italy and Greece. Ancestry markers and studies on ancient DNA from Roman historical migration in Catalonia will help to give a better picture of the genetic landscape of Europe and North Africa. Genes for MetS will be studied in existing samples from host and home countries by GWAS, locus refining by next-generation sequencing and haplotype mapping. Informative filtered SNPs will be then used in epidemiology and novel DNA samples to reveal G x E interactions and specificities of the pathogenesis of MetS. Genetic findings will be replicated in home countries (Anatolia and North Africa) in the goal to develop markers ethnic specific and significant at a clinical scale. Major impact is expected from dissemination of our findings to prevent the occurrence of MetS and obesity in children and adolescents or in descendants of modern immigration, understanding variability clinical manifestations of MetS in the context of malnutrition and from the novel approach of GWAS strategies by ameliorating the association signal and bursting R&D activities of SMEs.
PubMed | Mashhad University of Medical Sciences, Hannover Medical School, Institute of Biochemistry and Genetics, Helmholtz Center for Infection Research and Nn Alexandrov Research Institute Of Oncology And Medical Radiology
Type: | Journal: Breast cancer research and treatment | Year: 2017
APOBEC3B belongs to the family of DNA-editing enzymes. A copy number variant targeting the genomic APOBEC3A-APOBEC3B locus has a significant impact on breast cancer risk, but the relative contribution of APOBEC3B is uncertain. In this study, we investigate a loss-of-function mutation that selectively targets APOBEC3B, for its association with breast cancer risk.We performed exome sequencing on genomic DNA samples of 6 Byelorussian patients with familial breast cancer. We then studied through mutation-specific genotyping four hospital-based breast cancer case-control series from Belarus, Russia, Germany, and Iran, respectively, comprising a total of 3070 breast cancer patients and 2878 healthy females. Results were evaluated using fixed-effects meta-analyses.Exome sequencing uncovered a frameshift mutation, APOBEC3B*c.783delG, that was recurrent in the study populations. Subsequent genotyping identified this mutation in 23 additional breast cancer cases and 9 healthy female controls, with an adjusted Odds Ratio 2.29 (95% CI 1.04; 5.03, P=0.04) in the combined analysis. There was an enrichment of the c.783delG mutation in patients with breast cancer diagnosed below 50years of age (OR 3.22, 95% CI 1.37; 7.56, P=0.007).APOBEC3B*c.783delG showed evidence of modest association with breast cancer and seemed to contribute to earlier onset of the disease. These results may need to be reconciled with proposals to consider APOBEC3B as a possible therapeutic target in breast cancer.
Kuramshina Z.M.,Bashkir State University |
Smirnova Y.V.,Institute of Biochemistry and Genetics |
Khairullin R.M.,Institute of Biochemistry and Genetics
Russian Journal of Plant Physiology | Year: 2016
Impact of inoculation of wheat seeds with endophytic strains of B. subtilis bacterium on revealing cadmium phytotoxicity of the plants was investigated. It was shown that, in the presence of Cd in the plants whose seeds were inoculated with the above bacteria, the activities of catalase and peroxidase and the content of nonprotein thiols were increased, while an intensity of lipid peroxidation decreased. Moreover, inoculation of plant seeds with the bacteria contributed to lowering the metal content in plant shoots. © 2016, Pleiades Publishing, Ltd.
Korytina G.,Institute of Biochemistry and Genetics |
Kochetova O.,Institute of Biochemistry and Genetics |
Akhmadishina L.,Institute of Biochemistry and Genetics |
Viktorova E.,University of Gottingen |
Victorova T.,Institute of Biochemistry and Genetics
Balkan Medical Journal | Year: 2012
Objective: To determine the prevalence of the most common allelic variants of CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2E1, CYP2F1, CYP2J2 and CYP2S1 in a representative sample of the three ethnic groups (Russians, Tatars and Bashkirs) from Republic of Bashkortostan (Russia), and compare the results with existing data published for other populations. Material and Methods: CYPs genotypes were determined in 742 DNA samples of healthy unrelated individuals representative of three ethnic groups. The CYPs gene polymorphisms were examined using the PCR-RLFP method. Results: Analysis of the CYP1A1 (rs1048943, rs4646903), CYP1A2 (rs762551), CYP2E1 (rs2031920) allele, genotype and haplotype frequencies revealed significant differences among healthy residents of the Republic of Bashkortostan of different ethnicities. Distribution of allele and genotype frequencies of CYP1A2 (rs35694136), CYP1B1 (rs1056836), CYP2C9 (rs1799853, rs1057910), CYP2F1 (rs11399890), CYP2J2 (rs890293), CYP2S1 (rs34971233, rs338583) genes were similar in Russians, Tatars, and Bashkirs. Analysis of the CYPs genes allele frequency distribution patterns among the ethnic groups from the Republic of Bashkortostan in comparison with the different populations worldwide was conducted. Conclusion: The peculiarities of the allele frequency distribution of CYPs genes in the ethnic groups of the Republic of Bashkortostan should be taken into consideration in association and pharmacogenetic studies. The results of the present investigation will be of great help in elucidating the genetic background of drug response, susceptibility to cancer and complex diseases, as well as in determining the toxic potentials of environmental pollutants in our region. © Trakya University Faculty of Medicine.
Korytina G.F.,Institute of Biochemistry and Genetics |
Akhmadishina L.Z.,Institute of Biochemistry and Genetics |
Viktorova E.V.,University of Gottingen |
Tselousova O.S.,Institute of Biochemistry and Genetics |
And 3 more authors.
Journal of Human Genetics | Year: 2013
We investigated the association of matrix metalloproteinases, the disintegrin and metalloprotease 33 and the tissue and serum inhibitors of proteinase gene polymorphisms with severe chronic respiratory diseases in Tatar children. We analyzed the case-control data sample from a total of 592 Tatar individuals, consisting of 119 children with chronic bronchitis, 138 with recurrent pneumonia and 335 control children residing in Ufa (Russia). The percentage of heterozygous genotype for the MMP9 (2660A>G) was higher among healthy children (52.54% vs 36.13% in chronic bronchitis patients, P adj =0.0033, P cor =0.033, odds ratio (OR)=0.51; and 36.96% in recurrent pneumonia group, P adj =0.0034, P cor =0.034, OR=0.53). The MMP12 (-82A>G) locus was associated with chronic bronchitis in the additive model (P adj =0.0091, P cor =0.09, OR=0.45, β=-0.798). The relationship between the 6A6A genotype of MMP3 (-1171 5A>6A) (P adj =0.0013, P cor =0.013, OR=3.91) and the 6A-A haplotype of MMP3 (-1171 5A>6A) and MMP12 (-82A>G) and recurrent pneumonia were unraveled (P adj =0.001, P cor =0.01, OR=2.07). This haplotype was also associated with a higher risk of chronic bronchitis (P adj =0.0012, P cor =0.012, OR=2.15). The TIMP3 (-1296T>C) was associated with recurrent pneumonia in the dominant model (P adj =0.0031, P cor =0.031, OR=1.91). The MMP9, MMP3 and TIMP3 (tissue inhibitors of matrix metalloproteinases) polymorphisms and MMP3 and MMP12 haplotypes may play a substantial role in susceptibility to severe airway and lung injury in children with chronic bronchitis and recurrent pneumonia. © 2013 The Japan Society of Human Genetics All rights reserved.
Noskowicz M.,Hannover Medical School |
Bogdanova N.,Hannover Medical School |
Bogdanova N.,N N Alexandrov Research Institute Of Oncology And Medical Radiology |
Bermisheva M.,Hannover Medical School |
And 10 more authors.
Familial Cancer | Year: 2014
Inherited mutations in PALB2 are known to be associated with increased breast cancer risk. We aimed to investigate the prevalence and risk association of a recurrent PALB2 mutation, c.509-510delGA, among 3,924 unselected breast cancer patients from Belarus, Russia or Germany. High-resolution melting analyses and direct sequencing identified the c.509-510delGA allele in 3/1,008 (0.3 %) German breast cancer patients, 2/994 (0.2 %) Russian breast cancer patients and 5/1,922 (0.3 %) Byelorussian breast cancer patients. Breast tumours were mainly estrogen receptor positive and included both ductal and lobular histology. Only one of the ten patients had a first-degree family history of breast cancer. The mutation was not detected in 2,827 healthy females from the same populations, confirming the association of PALB2*c.509-510delGA with breast cancer risk (p = 0.007). These data indicate that the PALB2*c.509-510delGA mutation is prevalent in about 1 in 400 breast cancer patients from Central and Eastern Europe, and the low occurrence of familial clustering is consistent with a moderate penetrance of this mutation. © 2013 Springer Science+Business Media.
Baygildina A.A.,Bashkir State Medical University |
Islamgulov D.V.,Institute of Biochemistry and Genetics |
Minniakhmetov I.R.,Institute of Biochemistry and Genetics
Bulletin of Experimental Biology and Medicine | Year: 2012
The dynamics of plasma level of plasminogen-1 activator inhibitor (PAI-1) and frequency distribution of PAI-1 gene polymorphic locus 4G/5G genotypes and alleles were studied in male and female patients of different age with hemorrhagic fever complicated by renal syndrome of different severity. A significant elevation of PAI-1 level was recorded during fever in adult patients of mature age groups I and II with medium severe and severe uncomplicated disease, the elevation being followed by a significant reduction, except the oliguric and polyuric periods of medium severe form. In complicated disease, the concentration of PAI-1 was low during fever in patients of mature age group I, after which it increased significantly until the period of diuresis recovery; in patients of mature age group II it remained low, except the polyuria period. No appreciable age- or gender-related differences in frequency distributions of PAI-1 gene polymorphic locus 4G/5G genotypes and alleles in patients with disease of different severity were found; no differences from the control group by these parameters were revealed. The dynamics of PAI-1 plasma level in different forms of hemorrhagic fever with renal syndrome were not genetically determined and represented an adequate metabolic response to endotheliotropic virus. © 2012 Springer Science+Business Media, Inc.