9 research outputs found
DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.
No full textSingle Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be
associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose
polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p,0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03– 1.16), p = 2.761023) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21,
p = 4.861023). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/ 2 mutation carriers and should be more comprehensively studied
AGER -429T/C is associated with an increased lung disease severity in cystic fibrosis.
No full textThe clinical course of cystic fibrosis (CF) varies between patients bearing identical CFTR mutations, suggesting the involvement of modifier genes. We assessed the association of lung disease severity with the variant AGER -429 T/C, coding for RAGE, a pro-inflammatory protein, in CF patients from the French CF Gene Modifier Study. We analyzed the lung function of 967 CF patients p.Phe508del homozygous. FEV(1) was analyzed as CF-specific percentile adjusted on age, height and mortality. AGER -429T/C polymorphism was genotyped and its function was evaluated in vitro by measurement of the luciferase activity. AGER -429 minor allele (C) was associated with poorer lung function (p = 0.03). In vitro, the promoter activity was higher in cells transfected with AGER -429C compared to cells transfected with the AGER -429T allele (p = 0.016 in BEAS-2B cells). AGER seems to be a modifier gene of lung disease severity in CF, and could be an interesting biomarker of CF airway inflammation. The functional promoter AGER -429C variant is associated with an increased RAGE expression that can lead to an increased lung inflammation and a more severe lung disease
Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function
No full textGenome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P-JMA = 5.00 x 10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P-JMA = 4.35 x 10(-9)), and KCNJ2 and SOX9 (smallest P-JMA = 1.28 x 10(-8)) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects
Estudi de les mutacions dels exons 2 i 4 del gen HFE en pacients amb porfiria cutània tarda esporàdica
No full text[cat] La Porfíria Cutània Tarda (PCT) és una malaltia metabòlica que afecta a la pell i al fetge i que és desencadenada per la interacció de múltiples factors que inclouen l´herència, l´alcohol, el VHC, els estrògens i alguns agents tòxics, entre d´altres encara en estudi. La sobrecàrrega fèrrica, de forma primària o secundària a d´altres factors de risc (com la infecció pel VHC), és un factor desencadenant de la PCT. En aquest contexte, considerem la hipòtesi de que la sobrecàrrega fèrrica observada en alguns pacients amb PCT pot estar associada amb les mutacions descrites en el gen de l´hemocromatosi (C282Y i H63D). Considerem d´interès també conèixer la interrelació entre la freqüència d'aquestes mutacions i els altres factors de risc, especialment el VHC, en el desencadenament de la malaltia en el nostre àmbit geogràfic.OBJECTIUS:1. Establir les prevalences de les mutacions C282Y i H63D del gen HFE en pacients amb PCT esporádica en el nostre ambient.2. Determinar la relació entre les mutacions del gen HFE en pacients amb PCT esporádica i la sobrecàrrega de ferro hepàtic. 3. Establir la relació entre la prevalença d'aquestes mutacions i la infecció pel VHC.MATERIAL I MÈTODES:S´han seleccionat de forma retrospectiva 99 pacients amb PCT i 126 controls (76 sans sense infecció per VHC i 50 individus amb infecció crònica per VHC). En els pacients amb PCT s´han recollit les següents variables: gènere, ingesta d´alcohol, presa d´anticonceptius, serologies per VHC, VHC i VIH. Els paràmetres se sobrecàrrega de ferro determinats en els pacients amb PCT han estat els següents: quantificació del ferro hepàtic (en 41 pacients) i la ferritina (en 71 pacients). S´ha estudiat la presència de les mutacions C282Y i H63D dels exons 4 i 2 respectivament del gen de l´hemocromatosi (HFE) mitjançant les següents tècniques:1-Extracció de l´ADN a partir de sang total i precipitació de l´ADN, 2-amplificació dels exons 2 i 4 i 3-digestió de l´ADN amb endonucleasses de restricció mitjançant tècnica de restriction fragment length polymorphism (RFLP). RESULTATS:Hem observat un augment de la prevalença de la mutació C282Y en els pacients amb PCT en el nostre àmbit geogràfic. Aquest augment és independent de la infecció pel VHC. A més, la mutació C282 s´associa amb un augment del ferro hepàtic i de la ferritina. Per altra banda, no hem observat un augment de la mutació H63D en els pacients amb PCT, excepte en el genotipus en homozigosi. Sí hem observat una associació significativa amb la PCT quan es comparen els pacients infectats per VHC i els controls amb aquesta infecció. Per tant, la mutació H63D pot actuar de forma sinèrgica amb la infecció per VHC en la inducció de PCT. No hem observat tampoc una associació entre la mutació H63D i la sobrecàrrega de ferro. Les mutacions del gen HFE, en especial la mutació C282Y, poden estar relacionades amb la sobrecàrrega de ferro i per tant en el possible desenvolupament d´hepatopatia crònica i de carcinoma hepatocelular. Per altra banda, el tractament amb flebotomies pot ser l´idoni en els pacients amb sobrecàrrega de ferro. Per tant, l´anàlisi de les mutacions del gen HFE s´ha d´incloure de forma sistemàtica en els protocols d´estudi dels pacients amb PCT.[eng] Title: STUDY ON EXONS 2 AND 4 HFE GENE MUTATIONS IN PATIENTS WITH SPORADIC PORPHYRIA CUTANEA TARDAHYPOTHESIS: the iron overload frequently observed in patients with Porphyria Cutanea Tarda (PCT) may be associated with the mutations that are usually found in the HFE gene in patients with hemochromatosis (C282Y and H63D mutations). These mutations may be independent of other risk factors of PCT, such as VHC infection and alcohol intake OBJECTIVES:1-To establish the prevalences of mutations C282Y and H63D of HFE gene in patients with sporadic PCT in our environment.2-To establish the relationship between the mutations in HFE gene in patients with sporadic PCT and iron overload.3-To establish the relationship between these mutations and VHC infectionDESIGN: Retrospective case-control study.SETTING: A large clinical and research institute for the study and treatment of cutaneous diseases in Barcelona, Spain.PATIENTS: Ninety-nine patients with PCT and one hundred and twenty six control patients (76 healthy subjects and 50 patients chronically infected with HCV), were included in the study. MAIN OUTCOME MEASURES: The frequency of the C282Y and H63D mutations in patients with PCT vs controls and the relationship of these mutations with HCV infection, and iron status, as judged by serum iron, liver iron and ferritin levels. RESULTS: C282Y mutation was significantly increased in PCT patients. This mutation was more frequent among non HCV-infected patients. Increased ferritin levels and hepatic iron overload were also observed in PCT patients with heterozygous C282Y state. H63D mutation was only significantly increased among PCT patients with chronic hepatitis C infection. No significant iron overload was observed in patients with H63D mutation.CONCLUSIONS: This study confirms the high frequency of C282Y mutation in patients with PCT and its relationship with iron overload. The C282Y mutation has a relevant role in Spanish patients with PCT non-associated with HCV chronic infection. On the other hand, the prevalence of the H63D mutation seems not to be increased in patients with PCT. The possibility of an association between HCV infection and H63D mutation in inducing PCT can be hypothesized
Immunoprophylaxie des cancers colorectaux par des glucides indigestibles fermentables : études chez la souris Min
No full textCertaines fibres alimentaires réduiraient l'apparition des cancers colorectaux mais l'hypothèse reste controversée. Un des mécanismes fait intervenir la production par fermentation de butyrate. Nous avons testé deux fibres butyrogènes chimiquement différentes (fructo-oligosaccharides à chaîne courte scFOS, et amidon résistant) versus une fibre faiblement productrice de butyrate (son de blé désamidonné) chez la souris Min, un modèle de carcinogenèse intestinale spontanée. Seul le régime scFOS réduisait le nombre de tumeurs coliques et stimulait l'immunité locale. La nature chimique de la fibre ou bien les propriétés prébiotiques des scFOS (ils favorisent la croissance de bactéries lactiques qui agiraient sur la réaction immunitaire) sont donc impliquées. Deux autres types d'amidons résistants réduisaient le nombre de petites tumeurs. L'addition de bifidobactéries à l'un de ces deux régimes réduisait le nombre de petites tumeurs, mais augmentait celui de grosses tumeurs illustrant le concept de modulation par l'immunogénicité de la dualité immunofacilitation surveillance. La déplétion en lymphocytes T associée au régime scFOS doublait le nombre de tumeurs par rapport aux
souris immunocompétentes. Le régime scFOS diminuait l'expression du récepteur à l'IL2 à la surface des lymphocytes intra-épithéliaux (LIE) suggérant la mise en anergie temporaire du système immunitaire, mais pouvant aussi signifier l'implication d'une autre voie d'activation des LIE. Enfin, pour mettre en place une modélisation des intéractions lympho-épithéliales, nous avons croisé des
souris C57BL6 et Min avec la souris transgénique Immortomouse et isolé à partir de primo-cultures
de muqueuses des lignées cellulaires conditionnellement immortalisées saines et mutées sur Apc. Ce modèle permettra d'étudier en co-culture sur filtre, l'influence des glucides indigestibles et de leurs produits de fermentation sur les interactions lympho-épithéliales au cours de la carcinogenèse
Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.
No full textINTRODUCTION: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. METHODS: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. RESULTS: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. CONCLUSIONS: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified
The Transcriptomic and Genomic Analysis of Lamin A/C Expression in the Colon and in Colorectal Cancer
No full textLamins A and C, also known as A-type lamins, are type V nuclear intermediate filament proteins which form an interlacing meshwork of filaments subjacent to the inner nuclear membrane termed the nuclear lamina. A-type lamins have been implicated in DNA replication, gene transcription regulation, apoptosis, regulation of growth promoters and nuclear migration. Traditionally, expression of A-type lamins has been associated with differentiated cells. As such, mutations in A-type lamins have been associated with a diverse range of genetic diseases, including premature ageing syndromes and with increased proliferation, especially in tumours.
In colorectal cancer, expression of A-type lamins, have been shown to impart an adverse prognosis. In order to understand the underlying biological processes responsible for this adverse outcome in patients with colorectal cancer, I sought to clarify the expression profile of A-type lamins and their binding partners in normal colonic/rectal mucosa, prior to investigating the expression of A-type lamins in colorectal cancers. I used fresh tissue specimens obtained from patients with colorectal cancer for my experiments. A unique finding was the expression of lamin A in the putative stem cell niche of colonic / rectal mucosal crypts.
Further studies in the form of a microarray analysis, revealed a very complex picture of up regulation involving various signalling cascades in the cancer samples expressing A-type lamins. There was no evidence to suggest a direct involvement of A-type lamins influencing the Wnt signalling cascade, however, direct involvement of other signalling cascades, such as the IGF signalling cascade, Shh signalling cascade and TGF-β signalling cascades were noted. These signalling cascades were known to influence the Wnt signalling cascades and hence could play a crucial role in the pathogenesis of colorectal cancers expressing A-type lamins.
In addition to these important signalling cascades, other key genes involved in apoptosis, growth promoters, cell adhesion, stem cell regulation, oncogenes and tumour suppression, were noted to have a unique expression profile in the cancer sample expressing A-type lamins, not observed in the cancer sample lacking A-type lamin expression. These observations were suggestive of A-type lamins having a diverse range of actions via, as yet, undefined pathways. It would appear that A-type lamins were imparting a more motile, less adherent phenotype with stem cell like features in colorectal cancers expressing A-type lamins. This could explain the observed poor prognosis of patients with colorectal cancers expressing A-type lamins.
Creatine kinase brain (CKB), was also identified as an additional, potential, prognostic indicator in the Duke’s B group of patients with colorectal cancer expressing A-type lamins. This potential marker, in conjunction with A-type lamin expression could be used to identify a sub group of Duke’s B patients at high risk. Whether adjuvant therapy in this group would help improve their long term survival is unknown since no study has been done to assess this
An investigation of genetic risk factors in primary open-angle glaucoma
No full textPrimary open-angle glaucoma (POAG) is a multifactorial disease with a strong genetic
component. Notably however, few genes have been robustly associated with POAG in
the general population. Genes in which mutation causes anterior segment angle
anomalies, including LMX1B and FOXC1 are associated with a high incidence of
glaucoma to about 33-75% and are strong candidates for glaucoma susceptibility. In
addition, growth factors including TGFβ2 and BMP4 act in concert to maintain a
balance between extracellular matrix (ECM) deposition and degradation and may play a
role in glaucoma pathogenesis through misregulation of ECM synthesis of the
trabecular meshwork (TM). Furthermore, OPTN E50K mutation, a known genetic locus
for POAG, has been shown to account for a high percentage of 13.5% of familial
normal-tension glaucoma (NTG) in individuals of white British origin. In this study, the
contribution of variation at the LMX1B, FOXC1, TGFβ2 and BMP4 loci to risk of
glaucoma was investigated in a case-control genetic association study in a cohort of
white British descent recruited in the North-East of England comprised of 272 patients
with high-tension glaucoma (HTG), 37 patients with NTG, 58 patients with ocular
hypertension (OHT), and 276 normal controls. The role of OPTN E50K mutation in
these unrelated white British individuals with POAG was also examined. No significant
associations were identified for FOXC1, TGFβ2 and BMP4. The OPTN E50K mutation
was also absent in this cohort. The study identified a significant under representation of
two LMX1B haplotypes [ATG; P = 5.0E-4 (permutation P = 0.01), GCAGAC; P =
5.0E-4 (permutation P = 0.0150)] among the POAG individuals compared to the control
population, consistent with a 0.3 fold decreased risk of developing POAG. A replication
study involving a second cohort of 222 NTGs and 108 HTGs recruited in London
showed a similar distribution of the ATG haplotype (P = 0.0047) but did not withstand
permutation testing.
In conclusion, LMX1B haplotypes may influence susceptibility to develop POAG in the
white British population, suggesting altered LMX1B function predisposes to
glaucomatous damage
НОВЫЕ ГЕНЫ-КАНДИДАТЫ ПОДВЕРЖЕННОСТИ ТУБЕРКУЛЕЗУ, УСТАНОВЛЕННЫЕ С ПОМОЩЬЮ ПОСТРОЕНИЯ И АНАЛИЗА АССОЦИАТИВНЫХ СЕТЕЙ
No full textTuberculosis (TB) is a common disease caused by infection of Mycobacterium tuberculosis and influenced by host hereditary and environmental factors. Accumulated genomic data obtained through the use of new methodological approaches, including analysis of associative networks, contribute to the understanding of the hereditary basis of the disease. In the current study, we carried out the reconstruction and analysis of associative network representing molecular genetic links between proteins/genes involved in the development of TB. In the associative network, well studied proteins and genes with a decisive importance in the efficiency of the human immune response against a pathogen predominated. However, this approach identified 12 new genes encoding for the respective proteins in the associative network polymorphismsof which has not been studied regarding the development of TB.Туберкулез (ТБ) является распространенным заболеванием, развитие которого вызвано инфекцией Mycobacterium tuberculosis при модифицирующем влиянии наследственных и средовых факторов. Накопленные к настоящему времени геномные данные способствуют пониманию наследственных основ развития заболевания с использованием новых методологических подходов, в том числе анализа ассоциативных сетей. В настоящем исследовании выполнены реконструкция и анализ ассоциативной сети, представляющей собой молекулярно-генетические взаимосвязи между белками и генами, участвующими в развитии ТБ. Преимущественно в ассоциативной сети находятся хорошо изученные белки и гены, способные оказывать решающее значение в повышении эффективности иммунного ответа организ-ма человека против патогена. Однако, благодаря данному подходу, выявлено 12 новых генов, кодирующих соответствующие белки в ассоциативной сети, полиморфизм которых не изучен в связи с развитием ТБ
