33 results on '"Bugert P"'
Search Results
2. Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors.
- Author
-
Campa D, Capurso G, Pastore M, Talar-Wojnarowska R, Milanetto AC, Landoni L, Maiello E, Lawlor RT, Malecka-Panas E, Funel N, Gazouli M, De Bonis A, Klüter H, Rinzivillo M, Delle Fave G, Hackert T, Landi S, Bugert P, Bambi F, Archibugi L, Scarpa A, Katzke V, Dervenis C, Liço V, Furlanello S, Strobel O, Tavano F, Basso D, Kaaks R, Pasquali C, Gentiluomo M, Rizzato C, and Canzian F
- Subjects
- Aged, Alleles, Case-Control Studies, Computational Biology, Cyclin-Dependent Kinase Inhibitor p16, Female, Gene Silencing, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Homozygote, Humans, Linkage Disequilibrium, Male, Middle Aged, Models, Statistical, Neuroendocrine Tumors diagnosis, Odds Ratio, Pancreatic Neoplasms diagnosis, Risk, Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p18 genetics, Germ-Line Mutation, Neuroendocrine Tumors genetics, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide
- Abstract
Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (OR
hom = 2.08, 95% CI 1.05-4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs.- Published
- 2016
- Full Text
- View/download PDF
3. Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk.
- Author
-
Campa D, Pastore M, Gentiluomo M, Talar-Wojnarowska R, Kupcinskas J, Malecka-Panas E, Neoptolemos JP, Niesen W, Vodicka P, Delle Fave G, Bueno-de-Mesquita HB, Gazouli M, Pacetti P, Di Leo M, Ito H, Klüter H, Soucek P, Corbo V, Yamao K, Hosono S, Kaaks R, Vashist Y, Gioffreda D, Strobel O, Shimizu Y, Dijk F, Andriulli A, Ivanauskas A, Bugert P, Tavano F, Vodickova L, Zambon CF, Lovecek M, Landi S, Key TJ, Boggi U, Pezzilli R, Jamroziak K, Mohelnikova-Duchonova B, Mambrini A, Bambi F, Busch O, Pazienza V, Valente R, Theodoropoulos GE, Hackert T, Capurso G, Cavestro GM, Pasquali C, Basso D, Sperti C, Matsuo K, Büchler M, Khaw KT, Izbicki J, Costello E, Katzke V, Michalski C, Stepien A, Rizzato C, and Canzian F
- Subjects
- Alleles, Asian People, Binding Sites, Case-Control Studies, Cyclin-Dependent Kinase Inhibitor p16, DNA Methylation, Disease Progression, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Humans, International Cooperation, Japan, Odds Ratio, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms ethnology, Prognosis, Retrospective Studies, White People, Carcinoma, Pancreatic Ductal genetics, Cyclin-Dependent Kinase Inhibitor p15 genetics, Cyclin-Dependent Kinase Inhibitor p18 genetics, Pancreatic Neoplasms genetics, Polymorphism, Single Nucleotide
- Abstract
The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk., Competing Interests: John P. Neoptolemos has the following conflicts of interest. Payment for Lectures: Amgen, Mylan Research Grants: Taiho Pharma (Japan); KAEL GemVax (Korea); AstraZeneca; Clovis Oncology and Ventana; Pharma Nord. Consultancy: Boehringer Ingelheim Pharma GmbH & Co. KG; Novartis Pharma AG; KAEL GemVax; Astellas. Educational Travel Grants: NUCANA. The other authors do not have any conflict of interest to declare.
- Published
- 2016
- Full Text
- View/download PDF
4. PCR with sequence-specific primers for typing of diallelic blood groups.
- Author
-
Rink G, Scharberg EA, and Bugert P
- Subjects
- Alleles, Base Sequence, Electrophoresis, Agar Gel methods, Genotype, Humans, Blood Group Antigens genetics, DNA Primers genetics, Genotyping Techniques methods, Polymerase Chain Reaction methods, Polymorphism, Single Nucleotide
- Abstract
PCR with sequence-specific primers (PCR-SSP) is a cost-effective and robust method for the analysis of single nucleotide polymorphisms (SNPs). Many blood group antigens and the antithetic antigens are based on a diallelic SNP in the coding region of the corresponding blood group gene. Here, we describe PCR-SSP protocols for genotyping 24 blood group antigens based on 12 diallelic SNPs. We also provide protocols for molecular determination of the rare blood group phenotypes Yk(a-) and Vel-.
- Published
- 2015
- Full Text
- View/download PDF
5. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.
- Author
-
Milne RL, Burwinkel B, Michailidou K, Arias-Perez JI, Zamora MP, Menéndez-Rodríguez P, Hardisson D, Mendiola M, González-Neira A, Pita G, Alonso MR, Dennis J, Wang Q, Bolla MK, Swerdlow A, Ashworth A, Orr N, Schoemaker M, Ko YD, Brauch H, Hamann U, Andrulis IL, Knight JA, Glendon G, Tchatchou S, Matsuo K, Ito H, Iwata H, Tajima K, Li J, Brand JS, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Lambrechts D, Peuteman G, Christiaens MR, Smeets A, Jakubowska A, Lubinski J, Jaworska-Bieniek K, Durda K, Hartman M, Hui M, Yen Lim W, Wan Chan C, Marme F, Yang R, Bugert P, Lindblom A, Margolin S, García-Closas M, Chanock SJ, Lissowska J, Figueroa JD, Bojesen SE, Nordestgaard BG, Flyger H, Hooning MJ, Kriege M, van den Ouweland AM, Koppert LB, Fletcher O, Johnson N, dos-Santos-Silva I, Peto J, Zheng W, Deming-Halverson S, Shrubsole MJ, Long J, Chang-Claude J, Rudolph A, Seibold P, Flesch-Janys D, Winqvist R, Pylkäs K, Jukkola-Vuorinen A, Grip M, Cox A, Cross SS, Reed MW, Schmidt MK, Broeks A, Cornelissen S, Braaf L, Kang D, Choi JY, Park SK, Noh DY, Simard J, Dumont M, Goldberg MS, Labrèche F, Fasching PA, Hein A, Ekici AB, Beckmann MW, Radice P, Peterlongo P, Azzollini J, Barile M, Sawyer E, Tomlinson I, Kerin M, Miller N, Hopper JL, Schmidt DF, Makalic E, Southey MC, Hwang Teo S, Har Yip C, Sivanandan K, Tay WT, Shen CY, Hsiung CN, Yu JC, Hou MF, Guénel P, Truong T, Sanchez M, Mulot C, Blot W, Cai Q, Nevanlinna H, Muranen TA, Aittomäki K, Blomqvist C, Wu AH, Tseng CC, Van Den Berg D, Stram DO, Bogdanova N, Dörk T, Muir K, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Shu XO, Lu W, Gao YT, Zhang B, Couch FJ, Toland AE, Yannoukakos D, Sangrajrang S, McKay J, Wang X, Olson JE, Vachon C, Purrington K, Severi G, Baglietto L, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Devilee P, Tollenaar RA, Seynaeve C, Czene K, Eriksson M, Humphreys K, Darabi H, Ahmed S, Shah M, Pharoah PD, Hall P, Giles GG, Benítez J, Dunning AM, Chenevix-Trench G, and Easton DF
- Subjects
- A Kinase Anchor Proteins genetics, Adult, Alleles, Ataxin-7, Case-Control Studies, Cytoskeletal Proteins genetics, Female, Genome-Wide Association Study, Humans, Middle Aged, NIMA-Related Kinases, Nerve Tissue Proteins genetics, Protein Serine-Threonine Kinases genetics, Breast Neoplasms genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
- Abstract
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act., (© The Author 2014. Published by Oxford University Press.)
- Published
- 2014
- Full Text
- View/download PDF
6. Lack of replication of seven pancreatic cancer susceptibility loci identified in two Asian populations.
- Author
-
Campa D, Rizzato C, Bauer AS, Werner J, Capurso G, Costello E, Talar-Wojnarowska R, Jamroziak K, Pezzilli R, Gazouli M, Khaw KT, Key TJ, Bambi F, Mohelnikova-Duchonova B, Heller A, Landi S, Vodickova L, Theodoropoulos G, Bugert P, Vodicka P, Hoheisel JD, Delle Fave G, Neoptolemos JP, Soucek P, Büchler MW, Giese N, and Canzian F
- Subjects
- Adenocarcinoma etiology, Adenocarcinoma mortality, Adult, Aged, Asia epidemiology, Carcinoma, Pancreatic Ductal epidemiology, Carcinoma, Pancreatic Ductal mortality, Case-Control Studies, Europe epidemiology, Female, Follow-Up Studies, Genome-Wide Association Study, Humans, Male, Middle Aged, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms mortality, Prognosis, Risk Factors, Survival Rate, Biomarkers, Tumor genetics, Carcinoma, Pancreatic Ductal etiology, Genetic Predisposition to Disease, Pancreatic Neoplasms etiology, Polymorphism, Single Nucleotide genetics
- Abstract
Background: Two recent genome-wide association studies (GWAS) of pancreatic ductal adenocarcinoma (PDAC), conducted, respectively, in a Japanese and in a Chinese population, identified eight novel loci affecting PDAC risk., Methods: We attempted to replicate the novel loci in a series of PDACs and healthy controls of European ancestry in the context of the newly formed PANcreatic Disease ReseArch (PANDoRA) consortium. We genotyped seven single-nucleotide polymorphisms (SNP): rs12413624, rs1547374, rs372883, rs5768709, rs6464375, rs708224, rs9502893 (one SNP identified in the Chinese GWAS is not polymorphic in Caucasians) in 1,299 PDAC cases and 2,884 controls. We also attempted stratified analysis considering the different stages of the disease and addressed the possible involvement of the selected SNPs on the survival of patients., Results: None of the SNPs were significantly associated with PDAC risk if considering the overall population of the consortium. When stratifying for country of origin, we found that in the Polish subgroup, the G allele of rs372883 was statistically significantly associated with increased risk [OR, 6.40; 95% confidence interval (CI), 2.28-17.91]. However, the sample size of the subgroups was rather small; therefore, this result can be due to chance. None of the SNPs was associated with disease progression or survival., Conclusions: None of the SNPs associated with PDAC risk in two Asian populations were convincingly associated with PDAC risk in individuals of European descent., Impact: This study illustrates the importance of evaluation of PDAC risk markers across ethnic groups.
- Published
- 2013
- Full Text
- View/download PDF
7. The G534E-polymorphism of the gene encoding the factor VII-activating protease is a risk factor for venous thrombosis and recurrent events.
- Author
-
Ahmad-Nejad P, Dempfle CE, Weiss C, Bugert P, Borggrefe M, and Neumaier M
- Subjects
- Female, Genetic Markers genetics, Germany epidemiology, Humans, Incidence, Male, Middle Aged, Recurrence, Risk Factors, Venous Thrombosis enzymology, Genetic Predisposition to Disease epidemiology, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide genetics, Serine Endopeptidases genetics, Venous Thrombosis epidemiology, Venous Thrombosis genetics
- Abstract
Introduction: A single nucleotide polymorphism of the factor VII activating protease (FSAP), FSAP Marburg I (rs7080536) has been identified as a risk factor for venous thrombosis, but its clinical role has so far been controversial in part due to small cohort sizes. The aim of the present case-control study was to elucidate the impact of the FSAP Marburg I polymorphism (FSAP-MI) on the development of venous thromboembolic disease (VTE) with other known sequence variations, including Factor V Leiden (rs6025) and Factor II G20210A (rs1799963)., Materials and Methods: The study included 891 patients (312 male and 579 female) with a history of deep venous thrombosis (DVT) and/or pulmonary embolism (PE) and 1283 healthy blood donors with no history of venous thromboembolic disease., Results: We found that besides to the well-established aforementioned sequence variations of FV and Prothrombin, the FSAP Marburg I (FSAP-MI) polymorphism was significantly associated with the development of DVTs (1.65 (1.16-2.34) OR (95% CI)) and recurrent thromboembolic events (DVT and PE) (2.13 (1.35-3.36) OR (95% CI)). Comparing patients displaying one or more events FSAP-MI was still associated with the development of recurrent thromboembolic events (1.64 (1- 2.69) OR (95% CI))., Conclusions: We conclude that FSAP Marburg-I genotyping may be used to determine the risk for thromboembolic disorders in patients with suspected thrombophilia and known DVT or PE., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
8. The presence of functionally relevant toll-like receptor polymorphisms does not significantly correlate with development or outcome of sepsis.
- Author
-
Ahmad-Nejad P, Denz C, Zimmer W, Wacker J, Bugert P, Weiss C, Quintel M, and Neumaier M
- Subjects
- Adult, Aged, Case-Control Studies, Critical Care statistics & numerical data, Disease Progression, Emergency Service, Hospital statistics & numerical data, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Multiple Organ Failure epidemiology, Multiple Organ Failure etiology, Multiple Organ Failure genetics, Prognosis, Retrospective Studies, Sepsis complications, Sepsis epidemiology, Young Adult, Polymorphism, Single Nucleotide physiology, Sepsis diagnosis, Sepsis genetics, Toll-Like Receptor 2 genetics, Toll-Like Receptor 4 genetics, Toll-Like Receptor 5 genetics
- Abstract
Aims: Members of the toll-like receptor (TLR) family have been shown to play important roles in inflammatory responses. Single-nucleotide polymorphisms (SNPs) altering receptor activity may either have detectable effects or might be without results due to compensatory mechanisms. We determined the genotype frequencies of functionally relevant SNPs in TLR2, 4 and 5 in critically ill patients (n=150) from a multidisciplinary surgical intensive care unit (ICU). The inflammatory response (procalcitonin, C-reactive protein, white blood count) and clinical classification (Acute Physiology and Chronic Health Evaluation Score II, Simplified Acute Physiology Score II, Sepsis-related Organ Failure Assessment) were monitored daily., Results: The genetic polymorphisms correlate with neither development nor outcome of sepsis. No correlations were found between C-reactive protein or WBC and the investigated SNPs. In patients in the ICU with abdominal surgery and multiple trauma, the TLR2-R753Q SNP was associated with infection at ICU admission (p<0.01); and for carriers of the TLR4-D299G SNP, a trend was observed (p=0.0776). Patients with multiple trauma carrying the TLR4-D299G SNP displayed significantly higher levels of procalcitonin (p=0.0212)., Conclusions: None of the investigated SNPs clearly predicted outcome of sepsis-related multiorgan failure. TLR2-R753Q SNP may be a useful marker to identify patients with high risk to develop infections at ICU admission but should be validated in larger studies. Future SNP-arrays investigating predisposition for infection should include this SNP alone or in combination with other functionally relevant SNPs.
- Published
- 2011
- Full Text
- View/download PDF
9. No evidence for an association between the rs2824292 variant at chromosome 21q21 and ventricular fibrillation during acute myocardial infarction in a German population.
- Author
-
Bugert P, Elmas E, Stach K, Weiss C, Kälsch T, Dobrev D, and Borggrefe M
- Subjects
- Acute Disease, Cohort Studies, Female, Gene Frequency, Germany, Humans, Male, Middle Aged, Chromosomes, Human, Pair 21 genetics, Myocardial Infarction complications, Polymorphism, Single Nucleotide genetics, Ventricular Fibrillation complications, Ventricular Fibrillation genetics
- Abstract
Background: In a recently published genome-wide association study (GWAS), three single nucleotide polymorphisms (SNPs) (rs2824292, rs1353342, rs12090554) were significantly associated with increased susceptibility for ventricular fibrillation (VF) during acute myocardial infarction (AMI). The association of rs2824292 could be confirmed in a second cohort. Both cohorts were from the Netherlands. We aimed to replicate this association in a German cohort of AMI patients with or without VF., Methods: We included a German cohort of 90 individuals with AMI and VF (cases) and 167 AMI individuals without VF and used Taqman assays for SNP typing., Results: None of the loci showed evidence for a statistically significant association with VF. The observed genotype frequencies of the three loci were in Hardy-Weinberg equilibrium, which essentially excludes genotyping errors., Conclusions: In contrast to the data from the Netherlands, we could not detect a significant association of the rs2824292 locus and risk of VF during AMI in our German cohort. Differences in recruitment and clinical phenotypes between the Dutch and German cohorts may underlie different genotype associations.
- Published
- 2011
- Full Text
- View/download PDF
10. Genetic variants within miR-126 and miR-335 are not associated with breast cancer risk.
- Author
-
Yang R, Dick M, Marme F, Schneeweiss A, Langheinz A, Hemminki K, Sutter C, Bugert P, Wappenschmidt B, Varon R, Schott S, Weber BH, Niederacher D, Arnold N, Meindl A, Bartram CR, Schmutzler RK, Müller H, Arndt V, Brenner H, Sohn C, and Burwinkel B
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Models, Genetic, Young Adult, Breast Neoplasms genetics, Genetic Variation, MicroRNAs genetics, Polymorphism, Single Nucleotide genetics, Risk
- Abstract
MicroRNAs (miRNAs) are 20-22 nt non-coding RNAs which promote the degradation of target mRNAs or repression of the translation of mRNAs by sequence specific targeting. Many miRNAs are considered as oncogenes or tumor suppressors. MiR-126 and miR-335 play roles in the suppression of breast cancer metastasis by inhibiting tumor growth, proliferation, and cell invasion. The effects of SNPs within the two miRNAs are still unknown. In our study, we analyzed two SNPs, rs4636297 within miR-126 and rs41272366 within miR-335, in three study populations for a putative association with breast cancer risk. We compared the genotype and allele frequencies of rs4636297 and rs41272366 in 2854 cases versus 3188 controls of the three study populations independently and combined. None of the performed analyses showed statistically significant results. In conclusion, our data suggest that the two genetic variants within miR-126 and miR-335 are not associated with breast cancer risk.
- Published
- 2011
- Full Text
- View/download PDF
11. The P-selectin gene polymorphism Val168Met: a novel risk marker for the occurrence of primary ventricular fibrillation during acute myocardial infarction.
- Author
-
Elmas E, Bugert P, Popp T, Lang S, Weiss C, Behnes M, Borggrefe M, and Kälsch T
- Subjects
- Comorbidity, Female, Genetic Markers genetics, Germany epidemiology, Humans, Male, Middle Aged, Myocardial Infarction diagnosis, P-Selectin genetics, Prevalence, Risk Assessment, Risk Factors, Ventricular Fibrillation diagnosis, Genetic Predisposition to Disease epidemiology, Genetic Predisposition to Disease genetics, Myocardial Infarction epidemiology, Myocardial Infarction genetics, Polymorphism, Single Nucleotide genetics, Ventricular Fibrillation epidemiology, Ventricular Fibrillation genetics
- Abstract
Unlabelled: The P-Selectin Gene Polymorphism Val168Met., Aims: Ventricular fibrillation (VF) in the setting of acute myocardial infarction (AMI) is the leading cause of sudden cardiac death (SCD). Family history of SCD is described as risk factor for primary VF during acute AMI. Genetic factors may be associated with primary VF. We examined polymorphisms in genes related to the activation and adhesion of blood platelets in patients with and without VF in the setting of AMI and among healthy controls., Methods: Two hundred and forty patients with a history of AMI and 475 healthy controls were studied. Seventy-three patients (30%) had primary VF during AMI. By using PCR techniques with sequence-specific primers (PCR-SSP), we genotyped 5 single nucleotide polymorphisms (SNPs) in P-selectin (SELP) (V168M, S290N, N592D, V599L, T715P), 2 SNPs (M62I, S273F) in P-selectin glycoprotein ligand-1 (SELPLG), 5 SNPs in CD40LG (-3459A>G, -122A>C, -123A>C, 148T>C, intr4-13T>C), the H558R SNP in SCN5A, and rs2106261 in ZFHX3. In addition, length polymorphisms in SELPLG (36bp-tandem repeat) and CD40LG (CA-repeat) were genotyped by PCR methods. Results were evaluated by 2-sided t-tests, chi-square tests, and logistic regression analysis., Results: None of the gene polymorphisms showed significant differences between AMI patients and healthy controls. Among patients with a history of VF, however, the SELP 168M variant showed a significantly higher prevalence (14/73 patients; 19.2%) as compared with patients without VF (13/167 patients; 7.8%; P < 0.01). This association remained significant in a logistic regression analysis after adjustment for age and gender (P = 0.013; odds ratio 2.8; 95% confidence interval 1.2-6.3)., Conclusions: This is the first description of an association of the SELP gene variant 168M with primary VF during acute MI. This variant may be a candidate polymorphism for evaluating the susceptibility for VF in the setting of acute MI., (© 2010 Wiley Periodicals, Inc.)
- Published
- 2010
- Full Text
- View/download PDF
12. A genetic variant in the pre-miR-27a oncogene is associated with a reduced familial breast cancer risk.
- Author
-
Yang R, Schlehe B, Hemminki K, Sutter C, Bugert P, Wappenschmidt B, Volkmann J, Varon R, Weber BH, Niederacher D, Arnold N, Meindl A, Bartram CR, Schmutzler RK, and Burwinkel B
- Subjects
- Adult, Age Distribution, Aged, Aged, 80 and over, Case-Control Studies, Family Health, Female, Genetic Predisposition to Disease genetics, Germany epidemiology, Humans, Middle Aged, Breast Neoplasms epidemiology, Breast Neoplasms genetics, MicroRNAs genetics, Polymorphism, Single Nucleotide
- Abstract
MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in breast cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with breast cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large familial breast cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced familial breast cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78-0.99, P = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group < 50 years of age ([G] vs. [A]: OR = 0.83, 95% CI 0.70-0.98, P = 0.0314), whereas no significant effect was observed in the age group >or= 50 years of age, indicating a possible hormone-related effect. It has been shown that artificial mutations in the terminal loop of miR-27a can block the maturation process of the miRNA. We hypothesize that the G-variant of rs895819 might impair the maturation of the oncogenic miR-27a and thus, is associated with familial breast cancer risk.
- Published
- 2010
- Full Text
- View/download PDF
13. Association of the single nucleotide polymorphism rs599839 in the vicinity of the sortilin 1 gene with LDL and triglyceride metabolism, coronary heart disease and myocardial infarction. The Ludwigshafen Risk and Cardiovascular Health Study.
- Author
-
Kleber ME, Renner W, Grammer TB, Linsel-Nitschke P, Boehm BO, Winkelmann BR, Bugert P, Hoffmann MM, and März W
- Subjects
- Adolescent, Adult, Aged, Coronary Disease blood, Coronary Disease genetics, Female, Humans, Male, Middle Aged, Adaptor Proteins, Vesicular Transport genetics, Cholesterol, LDL blood, Chromosomes, Human, Pair 1 genetics, Lipoproteins, LDL blood, Myocardial Infarction genetics, Polymorphism, Single Nucleotide, Triglycerides blood
- Abstract
Objective: The rs599839 polymorphism A/G in the vicinity of the sortilin 1 gene has been reported to be associated with low density lipoprotein cholesterol (LDL-C) and coronary artery disease (CAD). The objective of this study was to further characterize the protective effect of the minor allele by analyzing the association with a variety of quantitative traits., Methods: Association of rs599839 with plasma levels of different parameters of LDL and triglyceride (TRIG) metabolism as well as the risk of CAD was tested in the LURIC study cohort., Results: Compared to AA homozygotes, the levels of LDL-C, low density lipoprotein triglycerides (LDL-TRIG) and apolipoprotein B were decreased in carriers of at least one G-allele. The G-allele was also associated with an increasing radius of the LDL particles. Regarding TRIG metabolism we observed a significant decrease in the level of triglycerides for homozygous carriers of the G-allele as well as decreased levels of free fatty acids (FFA), free glycerol and free cholesterol. With each G-allele the prevalence of CAD (multivariate OR 0.806; 95% CI: 0.692-0.940, P=0.006) decreased significantly whereas we observed only a marginal decrease for MI which did not reach significance. For GG homozygotes, the OR for CAD was 0.588 (95% CI: 0.394-0.877; P=0.009) and the OR for previous myocardial infarction (MI) was 0.693 (95% CI: 0.490-0.980; P=0.038). These associations were independent of cardiovascular risk factors., Conclusion: In the LURIC Study the G-allele of rs599839 is associated with LDL and TRIG metabolism and the risk of coronary artery disease and myocardial infarction., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
14. Identification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity.
- Author
-
Tchatchou S, Riedel A, Lyer S, Schmutzhard J, Strobel-Freidekind O, Gronert-Sum S, Mietag C, D'Amato M, Schlehe B, Hemminki K, Sutter C, Ditsch N, Blackburn A, Hill LZ, Jerry DJ, Bugert P, Weber BH, Niederacher D, Arnold N, Varon-Mateeva R, Wappenschmidt B, Schmutzler RK, Engel C, Meindl A, Bartram CR, Mollenhauer J, and Burwinkel B
- Subjects
- Adult, Aged, Breast Neoplasms, Male genetics, Calcium-Binding Proteins, Case-Control Studies, DNA-Binding Proteins, Female, Humans, Male, Middle Aged, Promoter Regions, Genetic, Risk Factors, Tumor Suppressor Proteins, Breast Neoplasms genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics, Receptors, Cell Surface genetics
- Abstract
According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C>T, rs2981745, located in the DMBT1 promoter; and DMBT1 c.124A>C, p.Thr42Pro, rs11523871(odds ratio [OR]=1.66, 95% confidence interval [CI]=1.21-2.29, P=0.0017; and OR=1.66; 95% CI=1.21-2.28, P=0.0016, respectively), based on 1,195 BRCA1/2 mutation-negative German breast cancer families and 1,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5'-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk.
- Published
- 2010
- Full Text
- View/download PDF
15. Evaluation of SNPs in miR-146a, miR196a2 and miR-499 as low-penetrance alleles in German and Italian familial breast cancer cases.
- Author
-
Catucci I, Yang R, Verderio P, Pizzamiglio S, Heesen L, Hemminki K, Sutter C, Wappenschmidt B, Dick M, Arnold N, Bugert P, Niederacher D, Meindl A, Schmutzler RK, Bartram CC, Ficarazzi F, Tizzoni L, Zaffaroni D, Manoukian S, Barile M, Pierotti MA, Radice P, Burwinkel B, and Peterlongo P
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Genetic Predisposition to Disease, Germany, Humans, Italy, Middle Aged, Young Adult, Alleles, Breast Neoplasms genetics, MicroRNAs genetics, Penetrance, Polymorphism, Single Nucleotide genetics
- Abstract
Recently, the SNPs rs11614913 in hsa-mir-196a2 and rs3746444 in hsa-mir-499 were reported to be associated with increased breast cancer risk, and the SNP rs2910164 in hsa-mir-146a was shown to have an effect on age of breast cancer diagnosis. In order to further investigate the effect of these SNPs, we genotyped a total of 1894 breast cancer cases negative for disease-causing mutations or unclassified variants in BRCA1 and BRCA2, and 2760 controls from Germany and Italy. We compared the genotype and allele frequencies of rs2910164, rs11614913 and rs3746444 in cases versus controls of the German and Italian series, and of the two series combined; we also investigated the effect of the three SNPs on age at breast cancer diagnosis. None of the performed analyses showed statistically significant results. In conclusion, our data suggested lack of association between SNPs rs2910164, rs11614913 and rs3746444 and breast cancer risk, or age at breast cancer onset.
- Published
- 2010
- Full Text
- View/download PDF
16. Nuclear receptor coregulator SNP discovery and impact on breast cancer risk.
- Author
-
Hartmaier RJ, Tchatchou S, Richter AS, Wang J, McGuire SE, Skaar TC, Rae JM, Hemminki K, Sutter C, Ditsch N, Bugert P, Weber BH, Niederacher D, Arnold N, Varon-Mateeva R, Wappenschmidt B, Schmutzler RK, Meindl A, Bartram CR, Burwinkel B, and Oesterreich S
- Subjects
- Adolescent, Adult, Black or African American genetics, Aged, Aged, 80 and over, Female, Genotype, Humans, Male, Middle Aged, Risk Factors, White People genetics, Young Adult, Breast Neoplasms genetics, Nuclear Receptor Coactivators genetics, Polymorphism, Single Nucleotide
- Abstract
Background: Coregulator proteins are "master regulators", directing transcriptional and posttranscriptional regulation of many target genes, and are critical in many normal physiological processes, but also in hormone driven diseases, such as breast cancer. Little is known on how genetic changes in these genes impact disease development and progression. Thus, we set out to identify novel single nucleotide polymorphisms (SNPs) within SRC-1 (NCoA1), SRC-3 (NCoA3, AIB1), NCoR (NCoR1), and SMRT (NCoR2), and test the most promising SNPs for associations with breast cancer risk., Methods: The identification of novel SNPs was accomplished by sequencing the coding regions of these genes in 96 apparently normal individuals (48 Caucasian Americans, 48 African Americans). To assess their association with breast cancer risk, five SNPs were genotyped in 1218 familial BRCA1/2-mutation negative breast cancer cases and 1509 controls (rs1804645, rs6094752, rs2230782, rs2076546, rs2229840)., Results: Through our resequencing effort, we identified 74 novel SNPs (30 in NCoR, 32 in SMRT, 10 in SRC-3, and 2 in SRC-1). Of these, 8 were found with minor allele frequency (MAF) >5% illustrating the large amount of genetic diversity yet to be discovered. The previously shown protective effect of rs2230782 in SRC-3 was strengthened (OR = 0.45 [0.21-0.98], p = 0.04). No significant associations were found with the other SNPs genotyped., Conclusions: This data illustrates the importance of coregulators, especially SRC-3, in breast cancer development and suggests that more focused studies, including functional analyses, should be conducted.
- Published
- 2009
- Full Text
- View/download PDF
17. TIMP-2 gene polymorphism is associated with intracerebral hemorrhage.
- Author
-
Reuter B, Bugert P, Stroick M, Bukow S, Griebe M, Hennerici MG, and Fatar M
- Subjects
- Adult, Aged, Aged, 80 and over, Case-Control Studies, Female, Gene Frequency genetics, Genetic Predisposition to Disease genetics, Genotype, Heterozygote, Homozygote, Humans, Incidence, Male, Middle Aged, Cerebral Hemorrhage genetics, Polymorphism, Single Nucleotide genetics, Tissue Inhibitor of Metalloproteinase-2 genetics
- Abstract
Background: Both ischemic stroke and intracerebral hemorrhage are associated with altered expression and activation of matrix metalloproteinases (MMPs). Particularly relevant are MMP-2 and MMP-9. This proteolytic effect is dampened by tissue inhibitors of metalloproteinases (TIMPs). TIMP-2 is an important endogenous inhibitor of MMP-2. Alterations in the TIMP-2 gene expression may contribute to the incidence of ischemic stroke and intracerebral hemorrhage., Methods: TIMP-2 gene SNP -261G/A was genotyped from sequentially recruited stroke patients (n = 356, f/m 151/205, mean age 68.2 years, range 19-100 years) and gender and age matched controls (n = 253, f/m 114/139, mean age 68.5 years, range 32-92 years). The SNP -261G/A was detected after gene sequencing of 95 patients and controls. Furthermore, in a subgroup of 93 patients the serum levels of TIMP-2 were measured during the first 7 days after stroke onset and compared to the genotype., Results: SNP -261G/A in the TIMP-2 gene shows an allele frequency of approximately 39.14%. Homozygosity for allele A is associated significantly with the development of ICH (p = 0.025, OR = 2.020, CI = 1.115-3.661) as compared to heterozygosity and homozygosity for allele G (recessive genotypic model). Concordantly, the serum levels of TIMP-2 showed a nonsignificant decreases, depending on the genotype (p = 0.111)., Conclusion: We investigated a SNP 261 base pairs upstream of the start codon in exon 1 of TIMP-2. Our data suggest that carriers of homozygosity for allele A are at increased risk of developing intracerebral hemorrhage., (Copyright (c) 2009 S. Karger AG, Basel.)
- Published
- 2009
- Full Text
- View/download PDF
18. Association of a common AKAP9 variant with breast cancer risk: a collaborative analysis.
- Author
-
Frank B, Wiestler M, Kropp S, Hemminki K, Spurdle AB, Sutter C, Wappenschmidt B, Chen X, Beesley J, Hopper JL, Meindl A, Kiechle M, Slanger T, Bugert P, Schmutzler RK, Bartram CR, Flesch-Janys D, Mutschelknauss E, Ashton K, Salazar R, Webb E, Hamann U, Brauch H, Justenhoven C, Ko YD, Brüning T, Silva Idos S, Johnson N, Pharoah PP, Dunning AM, Pooley KA, Chang-Claude J, Easton DF, Peto J, Houlston R, Chenevix-Trench G, Fletcher O, and Burwinkel B
- Subjects
- Adult, Aged, Alleles, Australia epidemiology, Breast Neoplasms epidemiology, Case-Control Studies, Europe epidemiology, Female, Genetic Predisposition to Disease, Germany epidemiology, Humans, Isoleucine, Linkage Disequilibrium, Methionine, Middle Aged, Research Design, Risk Assessment, Risk Factors, White People genetics, A Kinase Anchor Proteins genetics, Breast Neoplasms genetics, Cytoskeletal Proteins genetics, Polymorphism, Single Nucleotide
- Abstract
Data from several studies have suggested that polymorphisms in A-kinase anchoring proteins (AKAPs), which are key components of signal transduction, contribute to carcinogenesis. To evaluate the impact of AKAP variants on breast cancer risk, we genotyped six nonsynonymous single-nucleotide polymorphisms that were predicted to be deleterious and found two (M463I, 1389G>T and N2792S, 8375A>G) to be associated with an allele dose-dependent increase in risk of familial breast cancer in a German population. We extended the analysis of AKAP9 M463I, which is in strong linkage disequilibrium with AKAP9 N2792S, to 9523 breast cancer patients and 13770 healthy control subjects from seven independent European and Australian breast cancer studies. All statistical tests were two-sided. The collaborative analysis confirmed the association of M463I with increased breast cancer risk. Among all breast cancer patients, the combined adjusted odds ratio (OR) of breast cancer for individuals homozygous for the rare allele TT (frequency = 0.19) compared with GG homozygotes was 1.17 (95% confidence interval [CI] = 1.08 to 1.27, P = .0003), and the OR for TT homozygotes plus GT heterozygotes compared with GG homozygotes was 1.10 (95% CI = 1.04 to 1.17, P = .001). Among the combined subset of 2795 familial breast cancer patients, the respective ORs were 1.27 (95% CI = 1.12 to 1.45, P = .0003) and 1.16 (95% CI = 1.06 to 1.27, P = .001).
- Published
- 2008
- Full Text
- View/download PDF
19. SNPs in ultraconserved elements and familial breast cancer risk.
- Author
-
Yang R, Frank B, Hemminki K, Bartram CR, Wappenschmidt B, Sutter C, Kiechle M, Bugert P, Schmutzler RK, Arnold N, Weber BH, Niederacher D, Meindl A, and Burwinkel B
- Subjects
- Adult, Case-Control Studies, Conserved Sequence, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Middle Aged, Odds Ratio, Risk, Breast Neoplasms genetics, Gene Expression Regulation, Neoplastic, Polymorphism, Single Nucleotide
- Abstract
Ultraconserved elements (UCEs) are segments of >200 bp length showing absolute sequence identity between orthologous regions of human, rat and mouse genomes. The selection factors acting on these UCEs are still unknown. Recent studies have shown that UCEs function as long-range enhancers of flanking genes or are involved in splicing when overlapping with exons. The depletion of UCEs among copy number variation as well as the significant under-representation of single-nucleotide polymorphisms (SNPs) within UCEs have also revealed their evolutional and functional importance indicating their potential impact on disease, such as cancer. In the present study, we investigated the influence of six SNPs within UCEs on familial breast cancer risk. Two out of six SNPs showed an association with familial breast cancer risk. Whereas rs9572903 showed only a borderline significant association, the frequency of the rare [G] allele of rs2056116 was higher in cases than in controls indicating an increased familial breast cancer risk ([G] versus [A]: odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06-1.30, P = 0.0020; [GG] versus [AA]: OR = 1.41, 95% CI 1.15-1.74, P = 0.0011). Interestingly, comparing with the older age group, the ORs were increased in woman younger than 50 years of age ([G] versus [A]: OR = 1.27, 95% CI 1.11-1.45, P = 0.0005; [GG] versus [AA]: OR = 1.60, 95% CI 1.22-2.10, P = 0.0007) pointing to an age- or hormone-related effect. This is the first study indicating that SNPs in UCEs might be associated with cancer risk.
- Published
- 2008
- Full Text
- View/download PDF
20. Single-nucleotide polymorphisms of MMP-2 gene in stroke subtypes.
- Author
-
Fatar M, Stroick M, Steffens M, Senn E, Reuter B, Bukow S, Griebe M, Alonso A, Lichtner P, Bugert P, Meitinger T, Wienker TF, and Hennerici MG
- Subjects
- Aged, Aged, 80 and over, Case-Control Studies, Female, Genetic Predisposition to Disease, Humans, Logistic Models, Male, Matrix Metalloproteinase 2 blood, Middle Aged, Phenotype, Risk Assessment, Risk Factors, Severity of Illness Index, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Stroke enzymology, Stroke pathology, Matrix Metalloproteinase 2 genetics, Polymorphism, Single Nucleotide, Stroke genetics
- Abstract
Background: Matrix metalloproteinases (MMP) are expressed after ischemic stroke. These proteases are responsible for a higher incidence of hemorrhages, are correlated to size of infarction and influence the effects of recombinant tissue plasminogen activator treatment. We therefore evaluated single nucleotide polymorphisms (SNP) of MMP-2 in different subtypes of stroke patients in an association study using a case-control design., Methods: 197 stroke patients were divided according to modified TOAST criteria (small vessel disease, large vessel disease, hemorrhagic stroke and asymptomatic carotid artery stenosis) and compared to 143 controls. Clinical data like age, sex, risk factors and diagnostic results including MRI or cranial CT scans and ultrasound evaluations of intra- and extracranial arteries were obtained. Genotypes of MMP-2 (12 SNP) were compared to controls and DNA samples were analyzed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) analysis. Logistic regression analysis was performed for small vessel disease to test for interactions between markers and defined clinical risk factors. Additionally, MMP-2 serum levels obtained in the first 24 h after stroke were measured., Results: From the MMP-2 gene, 5 markers (rs1030868, rs2241145, rs2287074, rs2287076, rs7201) showed a significant association with small vessel infarcts (p < 0.05) and rs7201:g.C was identified as an independent risk factor by multivariable logistic regression analysis. MMP-2 protein levels were significantly lower in this group (174 +/- 48 ng/dl) versus controls (214 +/- 56 ng/dl). For other stroke subtypes, no significant association with MMP-2 SNP could be found., Conclusion: Our study demonstrates an association of the MMP-2 gene with the development of lacunar stroke, and no association of MMP-2 with other stroke subtypes., ((c) 2008 S. Karger AG, Basel.)
- Published
- 2008
- Full Text
- View/download PDF
21. The risk for thromboembolic disease in lupus anticoagulant patients due to pathways involving P-selectin and CD154.
- Author
-
Bugert P, Pabinger I, Stamer K, Vormittag R, Skeate RC, Wahi MM, and Panzer S
- Subjects
- Adult, CD40 Ligand blood, Cohort Studies, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Logistic Models, Male, Membrane Glycoproteins genetics, Middle Aged, Odds Ratio, P-Selectin blood, Predictive Value of Tests, Proline, Risk Assessment, Risk Factors, Threonine, Thromboembolism diagnosis, Thromboembolism genetics, Thromboembolism immunology, Thrombosis etiology, Venous Thrombosis etiology, CD40 Ligand genetics, Lupus Coagulation Inhibitor blood, P-Selectin genetics, Polymorphism, Single Nucleotide, Thromboembolism etiology
- Abstract
Individuals with lupus anticoagulants (LA) are at risk for thromboembolism (TE). Chronic inflammation is an important characteristic in LA patients which may dispose for TE. Platelets play a key role in inflammation and TE. We therefore investigated gene polymorphisms as well as plasma levels of platelet receptors as predictors of TE in 107 LA patients. We compared 74 patients with a history of thromboembolic disease (TE+), 56 with venous thrombosis (VT), 12 with arterial thrombosis (AT), and six patients who had both, with 33 LA patients without previous thrombosis (TE-). The P-selectin Pro715 allele was slightly more frequent in VT (OR = 3.167,95% CI 0.955-10.503; p = 0.0594), but no patient with AT had this allele (OR = 0.099, 95 % CI 0.001-0.790; p = 0.0238) which therefore may protect from AT. Plasma levels of P-selectin, collected a median of 35 months (range 2-329 months) after the last thrombotic event, were higher in patients withVT (p = 0.0096) than in TE-, but not with AT (p = 0.4713). These high P-selectin levels were not explained by the P-selectin polymorphism. The CA repeat polymorphism in the 3'-noncoding region of CD154 was significantly associated with the development of AT (OR = 4.035,95 % CI 1.329-12.249; p = 0.0138). Plasma levels of CD154 were not significantly different among the subgroups. Thus, the Thr715Pro polymorphism of P-selectin and CA repeats of CD154 are differentiating between the risk for VT and AT. Further, soluble P-selectin is elevated in LA patients with previous VT, but its role to predict VT needs to be evaluated in prospective studies.
- Published
- 2007
22. The single nucleotide polymorphism IVS1+309 in mouse double minute 2 does not affect risk of familial breast cancer.
- Author
-
Wilkening S, Bermejo JL, Burwinkel B, Klaes R, Bartram CR, Meindl A, Bugert P, Schmutzler RK, Wappenschmidt B, Untch M, Hemminki K, and Försti A
- Subjects
- Adult, Age of Onset, Aged, Case-Control Studies, Cell Cycle, Cell Survival, DNA Mutational Analysis, Female, Genotype, Humans, Middle Aged, Pedigree, Tumor Suppressor Protein p53, Breast Neoplasms genetics, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-mdm2 genetics
- Abstract
The mouse double minute 2 (MDM2) oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. Further, MDM2 overexpression can inhibit DNA double-strand break repair in a p53-independent manner. Recently, it was shown that a single nucleotide polymorphism (SNP) in the MDM2 promoter was associated with an accelerated tumor formation in individuals with a p53 mutation. The present case-control study investigated the association of this SNP (IVS1+309) with the risk and the age of onset of familial breast cancer in patients with unknown p53 mutation status. Data from 549 women affected by familial breast cancer and 1,065 healthy controls were analyzed. The cases did not carry BRCA1/2 mutations. Cases and controls showed a similar genotype distribution and the SNP did not seem to modify the age of onset of familial breast cancer. The data were also examined taking into account the presence of any additional cancer after breast cancer and the family history of cases; however, no association was found. These results suggest that the SNP IVS1+309 alone affects neither the risk nor the age of onset of heritable breast cancer.
- Published
- 2006
- Full Text
- View/download PDF
23. Association of death receptor 4 haplotype 626C-683C with an increased breast cancer risk.
- Author
-
Frank B, Hemminki K, Shanmugam KS, Meindl A, Klaes R, Schmutzler RK, Wappenschmidt B, Untch M, Bugert P, Bartram CR, and Burwinkel B
- Subjects
- Adult, Aged, Aged, 80 and over, Alleles, Case-Control Studies, Female, Genetic Carrier Screening, Genotype, Humans, Middle Aged, Polymerase Chain Reaction, Receptors, TNF-Related Apoptosis-Inducing Ligand, Breast Neoplasms genetics, Genetic Predisposition to Disease, Haplotypes genetics, Polymorphism, Single Nucleotide genetics, Receptors, Tumor Necrosis Factor genetics
- Abstract
Dysregulation of apoptosis plays a crucial role in carcinogenesis. Tumour necrosis factor-related apoptosis-inducing ligand stimulates the extrinsic apoptotic pathway by binding to death receptor 4 (DR4). Thus, genetic alterations within the candidate tumour suppressor gene DR4 would be expected to provoke a deficient apoptotic signalling thereby facilitating the development of cancer. The DR4 variants Thr209Arg and Glu228Ala were genotyped in a series of 521 breast cancer cases and 1100 control subjects from Germany, determining their impact on breast cancer risk. Neither Thr209Arg (626C>G) nor Glu228Ala (683A>C) alone were significantly associated with breast cancer risk [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.65-1.08, P = 0.18 and OR = 0.89, 95% CI = 0.72-1.12, P = 0.30]. However, haplotype analysis revealed a 3.5-fold risk for carriers of the 626C-683C haplotype (OR = 3.52, 95% CI = 1.45-8.52, P = 0.003).
- Published
- 2005
- Full Text
- View/download PDF
24. Association of NCOA3 polymorphisms with breast cancer risk.
- Author
-
Burwinkel B, Wirtenberger M, Klaes R, Schmutzler RK, Grzybowska E, Försti A, Frank B, Bermejo JL, Bugert P, Wappenschmidt B, Butkiewicz D, Pamula J, Pekala W, Zientek H, Mielzynska D, Siwinska E, Bartram CR, and Hemminki K
- Subjects
- Acetyltransferases, Case-Control Studies, Female, Germany, Haplotypes genetics, Histone Acetyltransferases, Humans, Middle Aged, Nuclear Receptor Coactivator 3, Oncogene Proteins, Poland, Risk Factors, Breast Neoplasms genetics, Polymorphism, Single Nucleotide genetics, Trans-Activators genetics
- Abstract
The nuclear receptor coactivator 3 (NCOA3, also known as AIB1) is a coactivator of nuclear receptors like the estrogen receptor. NCOA3 is overexpressed in approximately 60% of primary human breast tumors, and high levels of NCOA3 expression are associated with tamoxifen resistance and worse survival rate. In contrast, NCOA3 deficiency suppresses v-Ha-ras-induced breast cancer initiation and progression in mice. Here, we analyzed the influence of NCOA3 coding single nucleotide polymorphisms on breast cancer risk by performing a case-control study using a German and a Polish study population and identified an association between NCOA3 polymorphisms and breast cancer. A joint analysis of the German and the Polish study population revealed a significant protective effect for the 1758G>C (Q586H) and 2880A>G (T960T) variants. In addition, haplotype analysis showed a protective effect of the 1758C-2880A and 1758G-2880G haplotypes (odds ratio 0.79; 95% confidence interval, 0.67-0.93; P = 0.004). Because of the impact of NCOA3 in antiestrogen therapy resistance, these polymorphisms might also influence therapy outcome in breast cancer.
- Published
- 2005
- Full Text
- View/download PDF
25. Polymorphisms in the P-selectin (CD62P) and P-selectin glycoprotein ligand-1 (PSGL-1) genes and coronary heart disease.
- Author
-
Bugert P, Vosberg M, Entelmann M, Jahn J, Katus HA, and Klüter H
- Subjects
- Adult, Aged, Case-Control Studies, Female, Genotype, Humans, Ligands, Male, Middle Aged, Mucins, Polymerase Chain Reaction, Recombinant Proteins, Coronary Artery Disease genetics, Membrane Glycoproteins genetics, P-Selectin genetics, Polymorphism, Single Nucleotide
- Abstract
P-selectin and its ligand, PSGL-1, are cell adhesion molecules that facilitate interaction of platelets, leukocytes and endothelial cells. Polymorphisms of these genes have been reported to be associated with coronary heart disease (CHD). In the present study, we characterized the entire coding regions of P-selectin and PSGL-1 genes in CHD patients and healthy controls. The 17 exons of the P-selectin gene and exon 2 of the PSGL-1 gene were screened for single nucleotide polymorphisms (SNPs) by exon re-sequencing in 88 CHD patients and 96 controls. For rapid genotyping of the SNPs we developed PCR techniques with sequence-specific primers (PCR-SSP). By using PCR-SSPs we genotyped 261 CHD patients and 214 controls for 5 SNPs in P-selectin and 2 SNPs in PSGL-1. In addition to the already described SNPs in P-selectin (S290N, N562D, V599L and T715P), we identified a novel SNP in exon 5 (V168M). The P-selectin 715P allele was more frequent among CHD patients with hypercholesterolemia compared to patients with normal cholesterol levels. A SNP (M621) in the PSGL-1 gene was found close to the P-selectin binding site and the 621 allele revealed a higher prevalence in the control group indicating a protective effect of the mutation. The molecular characterization of P-selectin and PSGL-1 in a case-control study including CHD patients and healthy controls revealed evidence for association of the genes with development of the disease. However, the functional role of the gene variants should be elucidated by further experimental data.
- Published
- 2004
- Full Text
- View/download PDF
26. Optimized sensitivity of allele-specific PCR for prenatal typing of human platelet alloantigen single nucleotide polymorphisms.
- Author
-
Bugert P, Lese A, Meckies J, Zieger W, Eichler H, and Klüter H
- Subjects
- Amniocentesis, Antigens, Human Platelet classification, Gene Frequency, Genotype, Humans, Prenatal Care methods, Prenatal Diagnosis methods, Quality Control, Sequence Analysis, Protein, Antigens, Human Platelet analysis, Antigens, Human Platelet genetics, Gene Expression Profiling methods, Gene Expression Regulation, Developmental genetics, Genetic Testing methods, Polymerase Chain Reaction methods, Polymorphism, Single Nucleotide, Sequence Alignment methods
- Abstract
PCR using sequence-specific primers (PCR-SSP) is widely employed for the genotyping of single nucleotide polymorphisms (SNPs) in both routine diagnosis and medical research. The human platelet alloantigens (HPAs) represent SNPs in platelet-specific glycoproteins, and HPA-1, -2, -3, and -5 are the most relevant in immunohematology. In most protocols, the respective HPA-SNPs are analyzed in allele-specific reactions, each with at least 100 ng DNA. In many cases, prenatal HPA typing in the diagnosis of neonatal alloimmune thrombocytopenia is often limited by the restricted amounts of fetal DNA that are obtainable. We developed a novel PCR-SSP technique to achieve accurate HPA genotypes using only 1 ng DNA per reaction. The concentration of HPA-specific primers was increased to 1 microM each and exhibited a higher sensitivity compared to a commercial PCR-SSP kit. The modified PCR-SSP technique enabled the identification of fetal HPA genotypes using only 0.5 mL amniotic fluid (from week 16 of gestation) and from a maternal plasma sample (from week 38 of gestation). The principle of the modified PCR-SSP technique may also be applied for the genotyping of other SNPs from limited amounts of DNA.
- Published
- 2003
- Full Text
- View/download PDF
27. Common variants in glyoxalase I do not inease chronic pancreatitis risk
- Author
-
Kaune T., Hollenbach M., Keil B., Chen J. -M., Masson E., Becker C., Damm M., Ruffert C., Grutzmann R., Hoffmeister A., Te Morsche R. H. M., Cavestro G. M., Zuppardo R. A., Saftoiu A., Malecka-Panas E., Gluszek S., Bugert P., Lerch M. M., Weiss F. U., Zou W. -B., Liao Z., Hegyi P., Drenth J. P. H., Riedel J., Ferec C., Scholz M., Kirsten H., Toth A., Ewers M., Witt H., Griesmann H., Michl P., Rosendahl J., Kaune, T., Hollenbach, M., Keil, B., Chen, J. -M., Masson, E., Becker, C., Damm, M., Ruffert, C., Grutzmann, R., Hoffmeister, A., Te Morsche, R. H. M., Cavestro, G. M., Zuppardo, R. A., Saftoiu, A., Malecka-Panas, E., Gluszek, S., Bugert, P., Lerch, M. M., Weiss, F. U., Zou, W. -B., Liao, Z., Hegyi, P., Drenth, J. P. H., Riedel, J., Ferec, C., Scholz, M., Kirsten, H., Toth, A., Ewers, M., Witt, H., Griesmann, H., Michl, P., and Rosendahl, J.
- Subjects
Glycation End Products, Advanced ,Male ,Genotype ,Pancreatitis, Alcoholic ,Lactoylglutathione Lyase ,Middle Aged ,Pyruvaldehyde ,Polymorphism, Single Nucleotide ,Oxidative Stress ,Risk Factors ,Pancreatitis, Chronic ,Humans ,Female ,Genetic Predisposition to Disease ,Reactive Oxygen Species ,Genetic Association Studies - Abstract
Introduction Chronic pancreatitis (CP) may be caused by oxidative stress. An important source of reactive oxygen species (ROS) is the methylglyoxal-derived formation of advanced glycation endproducts (AGE). Methylglyoxal is detoxified by Glyoxalase I (GLO1). A reduction in GLO1 activity results in increased ROS. Single nucleotide polymorphisms (SNPs) of GLO1 have been linked to various inflammatory diseases. Here, we analyzed whether common GLO1 variants are associated with alcoholic (ACP) and non-alcoholic CP (NACP). Methods Using melting curve analysis, we genotyped a screening cohort of 223 ACP, 218 NACP patients, and 328 controls for 11 tagging SNPs defined by the SNPinfo LD TAG SNP Selection tool and the functionally relevant variant rs4746. For selected variants the cohorts were extended to up to 1,441 patient samples. Results In the ACP cohort, comparison of genotypes for rs1937780 between patients and controls displayed an ambiguous result in the screening cohort (p = 0.08). However, in the extended cohort of 1,441 patients no statistically significant association was found for the comparison of genotypes (p = 0.11), nor in logistic regression analysis (p = 0.214, OR 1.072, 95% CI 0.961-1.196). In the NACP screening cohort SNPs rs937662, rs1699012, and rs4746 displayed an ambiguous result when patients were compared to controls in the recessive or dominant model (p = 0.08, 0.08, and 0.07, respectively). Again, these associations were not confirmed in the extended cohorts (rs937662, dominant model: P = 0.07, logistic regression: P = 0.07, OR 1.207, 95% CI 0.985-1.480) or in the replication cohorts for rs4746 (Germany, p = 0.42, OR 1.080, 95% CI 0.673-1.124; France, p = 0.19, OR 0.90, 95% CI 0.76-1.06; China, p = 0.24, OR 1.18, 95% CI 0.90-1.54) and rs1699012 (Germany, Munich; p = 0.279, OR 0.903, 95% CI 0.750-1.087). Conclusions Common GLO1 variants do not increase chronic pancreatitis risk.
- Published
- 2019
28. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade
- Author
-
Purrington, K.S., Slettedahl, S., Bolla, M.K., Michailidou, K., Czene, K., Nevanlinna, H., Bojesen, S.E., Andrulis, I.L., Cox, A., Hall, P., Carpenter, J., Yannoukakos, D., Haiman, C.A., Fasching, P.A., Mannermaa, A., Winqvist, R., Brenner, H., Lindblom, A., Chenevix-Trench, G., Benitez, J., Swerdlow, A., Kristensen, V., Guenel, P., Meindl, A., Darabi, H., Eriksson, M., Fagerholm, R., Aittomaki, K., Blomqvist, C., Nordestgaard, B.G., Nielsen, S.F., Flyger, H., Wang, X.S., Olswold, C., Olson, J.E., Mulligan, A.M., Knight, J.A., Tchatchou, S., Reed, M.W.R., Cross, S.S., Liu, J.J., Li, J.M., Humphreys, K., Clarke, C., Scott, R., Fostira, F., Fountzilas, G., Konstantopoulou, I., Henderson, B.E., Schumacher, F., Marchand, L. le, Ekici, A.B., Hartmann, A., Beckmann, M.W., Hartikainen, J.M., Kosma, V.M., Kataja, V., Jukkola-Vuorinen, A., Pylkas, K., Kauppila, S., Dieffenbach, A.K., Stegmaier, C., Arndt, V., Margolin, S., Balleine, R., Perez, J.I.A., Zamora, M.P., Menendez, P., Ashworth, A., Jones, M., Orr, N., Arveux, P., Kerbrat, P., Truong, T., Bugert, P., Toland, A.E., Ambrosone, C.B., Labreche, F., Goldberg, M.S., Dumont, M., Ziogas, A., Lee, E., Dite, G.S., Apicella, C., Southey, M.C., Long, J.R., Shrubsole, M., Deming-Halverson, S., Ficarazzi, F., Barile, M., Peterlongo, P., Durda, K., Jaworska-Bieniek, K., Tollenaar, R.A.E.M., Seynaeve, C., Bruning, T., Ko, Y.D., Deurzen, C.H.M. van, Martens, J.W.M., Kriege, M., Figueroa, J.D., Chanock, S.J., Lissowska, J., Tomlinson, I., Kerin, M.J., Miller, N., Schneeweiss, A., Tapper, W.J., Gerty, S.M., Durcan, L., Mclean, C., Milne, R.L., Baglietto, L., Silva, I.D., Fletcher, O., Johnson, N., Van'T Veer, L.J., Cornelissen, S., Forsti, A., Torres, D., Rudiger, T., Rudolph, A., Flesch-Janys, D., Nickels, S., Weltens, C., Floris, G., Moisse, M., Dennis, J., Wang, Q., Dunning, A.M., Shah, M., Brown, J., Simard, J., Anton-Culver, H., Neuhausen, S.L., Hopper, J.L., Bogdanova, N., Dork, T., Zheng, W., Radice, P., Jakubowska, A., Lubinski, J., Devillee, P., Brauch, H., Hooning, M., Garcia-Closas, M., Sawyer, E., Burwinkel, B., Marmee, F., Eccles, D.M., Giles, G.G., Peto, J., Schmidt, M., Broeks, A., Hamann, U., Chang-Claude, J., Lambrechts, D., Pharoah, P.D.P., Easton, D., Pankratz, V.S., Slager, S., Vachon, C.M., Couch, F.J., ABCTB Investigators, Australian Ovarian Canc Study Grp, kConFab Investigators, GENICA Network, Medical Oncology, Pathology, and Clinical Genetics
- Subjects
Oncology ,Candidate gene ,Fibroblast Growth Factor ,amplification ,cancer susceptibility loci ,Bioinformatics ,medicine.disease_cause ,Medical and Health Sciences ,prostate-cancer ,Prostate cancer ,Risk Factors ,Medizinische Fakultät ,Genetics (clinical) ,Genetics & Heredity ,tacc2 ,Association Studies Articles ,Single Nucleotide ,General Medicine ,Biological Sciences ,ddc ,risk loci ,cell-division ,kConFab Investigators ,Female ,GENICA Network ,Type 2 ,Receptor ,Australian Ovarian Cancer Study Group ,Breast Neoplasms ,Carrier Proteins ,Case-Control Studies ,Haplotypes ,Humans ,Neoplasm Staging ,Polymorphism, Single Nucleotide ,Receptor, Fibroblast Growth Factor, Type 2 ,Tumor Suppressor Proteins ,Genetic Variation ,Molecular Biology ,Genetics ,medicine.medical_specialty ,Mitotic index ,ABCTB Investigators ,Single-nucleotide polymorphism ,Biology ,Breast cancer ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,ddc:610 ,Polymorphism ,Lung cancer ,Odds ratio ,medicine.disease ,genome-wide association ,lung-cancer ,progression ,Carcinogenesis - Abstract
Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
- Published
- 2014
29. Large-scale gene-centric analysis identifies novel variants for coronary artery disease
- Author
-
Butterworth, As, Braund, Ps, Farrall, M, Hardwick, Rj, Saleheen, D, Peden, Jf, Soranzo, N, Chambers, Jc, Sivapalaratnam, S, Kleber, Me, Keating, B, Qasim, A, Klopp, N, Erdmann, J, Assimes, Tl, Ball, Sg, Balmforth, Aj, Barnes, Ta, Basart, H, Baumert, J, Bezzina, Cr, Boerwinkle, E, Boehm, Bo, Brocheton, J, Bugert, P, Cambien, F, Clarke, R, Codd, V, Collins, R, Couper, D, Cupples, La, de Jong JS, Diemert, P, Ejebe, K, Elbers, Cc, Elliott, P, Fornage, M, Franzosi, Mg, Frossard, P, Garner, S, Goel, A, Goodall, Ah, Hengstenberg, C, Hunt, Se, Kastelein, Jj, Klungel, Oh, Klüter, H, Koch, K, König, Ir, Kooner, As, Laaksonen, R, Lathrop, M, Li, M, Liu, K, Mcpherson, R, Musameh, Md, Musani, S, Nelson, Cp, O'Donnell, Cj, Ongen, H, Papanicolaou, G, Peters, A, Peters, Bj, Potter, S, Psaty, Bm, Qu, L, Rader, Dj, Rasheed, A, Rice, C, Scott, J, Seedorf, U, Sehmi, Js, Sotoodehnia, N, Stark, K, Stephens, J, van der Schoot CE, van der Schouw YT, Thorsteinsdottir, U, Tomaszewski, M, van der Harst, P, Vasan, Rs, Wilde, Aa, Willenborg, C, Winkelmann, Br, Zaidi, M, Zhang, W, Ziegler, A, de Bakker PI, Koenig, W, Mätz, W, Trip, Md, Reilly, Mp, Kathiresan, S, Schunkert, H, Hamsten, A, Hall, As, Kooner, Js, Thompson, Sg, Thompson, Jr, Deloukas, P, Ouwehand, Wh, Watkins, H, Danesh, J, Samani, Nj, Barnes, T, Rafelt, S, Bruinsma, N, Dekker, Lr, Henriques, Jp, Koch, Kt, de Winter RJ, Alings, M, Allaart, Cf, Gorgels, Ap, Verheugt, Fw, Mueller, M, Meisinger, C, Derohannessian, S, Mehta, Nn, Ferguson, J, Hakonarson, H, Matthai, W, Wilensky, R, Hopewell, Jc, Parish, S, Linksted, P, Notman, J, Gonzalez, H, Young, A, Ostley, T, Munday, A, Goodwin, N, Verdon, V, Shah, S, Cobb, L, Edwards, C, Mathews, C, Gunter, R, Benham, J, Davies, C, Cobb, M, Crowther, J, Richards, A, Silver, M, Tochlin, S, Mozley, S, Clark, S, Radley, M, Kourellias, K, Silveira, A, Söderholm, B, Olsson, P, Barlera, S, Tognoni, G, Rust, S, Assmann, G, Heath, S, Zelenika, D, Gut, I, Green, F, Peden, J, Aly, A, Anner, K, Björklund, K, Blomgren, G, Cederschiöld, B, Danell Toverud, K, Eriksson, P, Grundstedt, U, Heinonen, M, Hellénius, Ml, van't Hooft, F, Husman, K, Lagercrantz, J, Larsson, A, Larsson, M, Mossfeldt, M, Mälarstig, A, Olsson, G, Sabater Lleal, M, Sennblad, B, Strawbridge, R, Öhrvik, J, Zaman, Ks, Mallick, Nh, Azhar, M, Samad, A, Ishaq, M, Shah, N, Samuel, M, Reilly, M, Holm, H, Preuss, M, Stewart, Af, Barbalic, M, Gieger, C, Absher, D, Aherrahrou, Z, Allayee, H, Altshuler, D, Anand, S, Andersen, K, Anderson, Jl, Ardissino, D, Becker, Lc, Becker, Dm, Berger, K, Bis, Jc, Boekholdt, Sm, Brown, Mj, Burnett, Ms, Buysschaert, I, Carlquist, Jf, Chen, L, Davies, Rw, Dedoussis, G, Dehghan, A, Demissie, S, Devaney, J, Do, R, Doering, A, El Mokhtari NE, Ellis, Sg, Elosua, R, Engert, Jc, Epstein, S, de Faire, U, Fischer, M, Folsom, Ar, Freyer, J, Gigante, B, Girelli, D, Gretarsdottir, S, Gudnason, V, Gulcher, Jr, Tennstedt, S, Halperin, E, Hammond, N, Hazen, Sl, Hofman, A, Horne, Bd, Illig, T, Iribarren, C, Jones, Gt, Jukema, Jw, Kaiser, Ma, Kaplan, Lm, Khaw, Kt, Knowles, Jw, Kolovou, G, Kong, A, Lambrechts, D, Leander, K, Lieb, W, Lettre, G, Loley, C, Lotery, Aj, Mannucci, Pm, Maouche, S, Martinelli, Nicola, Mckeown, Pp, Meitinger, T, Melander, O, Merlini, Pa, Mooser, V, Morgan, T, Mühleisen, Tw, Muhlestein, Jb, Musunuru, K, Nahrstaedt, J, Nöthen, Mm, Olivieri, Oliviero, Peyvandi, F, Patel, Rs, Patterson, Cc, Quyyumi, Aa, Rallidis, Ls, Roosendaal, Fr, Rubin, D, Salomaa, V, Sampietro, Ml, Sandhu, Ms, Schadt, E, Schäfer, A, Schillert, A, Schreiber, S, Schrezenmeir, J, Schwartz, Sm, Siscovick, Ds, Sivananthan, M, Smith, Av, Smith, Tb, Snoep, Jd, Spertus, Ja, Stefansson, K, Stirrups, K, Stoll, M, Tang, Wh, Thorgeirsson, G, Thorleifsson, G, Uitterlinden, Ag, van Rij AM, Voight, Bf, Wareham, Nj, Awells, G, Wichmann, He, Witteman, Jc, Wright, Bj, Ye, S, Quertermous, T, März, W, Blankenberg, S, Roberts, R, Onland Moret NC, van Setten, J, Verschuren, Wm, Boer, Jm, Wijmenga, C, Hofker, Mh, Maitland van der Zee AH, de Boer, A, Grobbee, De, Attwood, T, Belz, S, Braund, P, Cooper, J, Crisp Hihn, A, Foad, N, Gracey, J, Gray, E, Gwilliams, R, Heimerl, S, Jolley, J, Krishnan, U, Lloyd Jones, H, Lugauer, I, Lundmark, P, Moore, Js, Muir, D, Murray, E, Neudert, J, Niblett, D, O'Leary, K, Pollard, H, Rankin, A, Rice, Cm, Sager, H, Sambrook, J, Schmitz, G, Scholz, M, Schroeder, L, Syvannen, Ac, Wallace, C., Cardiologie, RS: CAPHRI School for Public Health and Primary Care, Vascular Medicine, Other departments, ACS - Amsterdam Cardiovascular Sciences, Cardiology, Landsteiner Laboratory, Clinical Haematology, Pulmonology, and Medical Research Council (MRC)
- Subjects
Male ,Cancer Research ,Candidate gene ,Epidemiology ,Genome-wide association study ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Cardiovascular ,0302 clinical medicine ,GENETICS & HEREDITY ,Genetics (clinical) ,Genetics ,0303 health sciences ,Cardiovascular diseases [NCEBP 14] ,Middle Aged ,3. Good health ,CYP17A1 ,Genetic Epidemiology ,Genome-wide association ,Myocardial-infarction ,Susceptibility loci ,Risk ,Atherosclerosis ,Metanalysis ,Lipoprotein ,Medicine ,Female ,Life Sciences & Biomedicine ,Research Article ,Asian Continental Ancestry Group ,Adult ,SUSCEPTIBILITY LOCI ,lcsh:QH426-470 ,European Continental Ancestry Group ,Biology ,Polymorphism, Single Nucleotide ,coronary artery disease ,genetics ,White People ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Asian People ,Genetic variation ,Humans ,Genetic Predisposition to Disease ,GENOME-WIDE ASSOCIATION ,Allele ,Molecular Biology ,Gene ,METAANALYSIS ,Ecology, Evolution, Behavior and Systematics ,Genetic Association Studies ,Cardiovascular Disease Epidemiology ,Alleles ,030304 developmental biology ,Aged ,0604 Genetics ,Science & Technology ,Case-control study ,Genetic Variation ,Human Genetics ,Odds ratio ,large-scale gene analysis ,lcsh:Genetics ,LIPOPROTEIN ,MYOCARDIAL-INFARCTION ,ATHEROSCLEROSIS ,Case-Control Studies ,Genetics of Disease ,IBC 50K CAD Consortium ,Developmental Biology ,Genome-Wide Association Study - Abstract
Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p, Author Summary Coronary artery disease (CAD) has a strong genetic basis that remains poorly characterised. Using a custom-designed array, we tested the association with CAD of almost 50,000 common and low frequency variants in ∼2,000 genes of known or suspected cardiovascular relevance. We genotyped the array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin) and attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. We report the novel association of variants in or near four genes with CAD and in additional studies identify potential mechanisms by which some of these novel variants affect CAD risk. Interestingly, we found that these variants, as well as the majority of previously reported CAD variants, have similar associations in Europeans and South Asians. Contrary to prior expectations, many previously suggested candidate genes did not show evidence of any effect on CAD risk, and neither did we identify any novel low frequency alleles with strong effects amongst the genes tested. Discovery of novel genes associated with heart disease may help to further understand the aetiology of cardiovascular disease and identify new targets for therapeutic interventions.
- Published
- 2016
30. Large scale association analysis of novel genetic loci for coronary artery disease
- Author
-
Amouyel, P., Arveiler, D., Boekholdt, S. M., Braund, P., Bruse, P., Bumpstead, S. J., Bugert, P., Cambien, F., Danesh, J., Deloukas, P., Doering, A., Ducimetiere, P., Dunn, R. M., El Mokhtari, N. E., Erdmann, J., Evans, A., Ewels, P., Ferrieres, J., Fischer, Matthias, Frossard, P., Garner, S., Gieger, C., Gohri, M. J. R., Goodall, A. H., Grosshennig, A., Hall, A., Hardwick, R., Haukijarvi, A., Hengstenberg, C., Illig, T., Karvanen, J., Kastelein, J., Kee, F., Khaw, K. T., Kluter, H., Konig, I. R., Kuulasmaa, K., Laiho, P., Luc, G., Marz, W., McGinnis, R., McLaren, W., Meisinger, C., Morrison, C., Ou, X., Ouwehand, W. H., Preuss, M., Proust, C., Ravindrarajah, R., Renner, W., Rice, K., Ruidavets, J. B., Saleheen, D., Salomaa, V., Samani, N. J., Sandhu, M. S., Schafer, A. S., Scholz, M., Schreiber, Stefan, Schunkert, H., Silander, K., Singh, R., Soranzo, N., Stark, K., Stegmayr, B., Stephens, J., Thompson, J., Tiret, L., Trip, M. D., van der Schoot, E., Virtamo, J., Wareham, N. J., Wichmann, H. E., Wiklund, P. G., Wright, B., Ziegler, A., Zwaginga, J. J., Amsterdam Cardiovascular Sciences, and Cardiology
- Subjects
Male ,Risk ,Single-nucleotide polymorphism ,Locus (genetics) ,Genome-wide association study ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Polymorphism, Single Nucleotide ,White People ,Article ,Coronary artery disease ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Odds Ratio ,medicine ,Humans ,Genetic Predisposition to Disease ,Family history ,Aged ,030304 developmental biology ,Genetic association ,Genetics ,0303 health sciences ,business.industry ,Case-control study ,Odds ratio ,Middle Aged ,medicine.disease ,Case-Control Studies ,Female ,business ,Cardiology and Cardiovascular Medicine ,Genome-Wide Association Study - Abstract
Background— Combined analysis of 2 genome-wide association studies in cases enriched for family history recently identified 7 loci (on 1p13.3, 1q41, 2q36.3, 6q25.1, 9p21, 10q11.21, and 15q22.33) that may affect risk of coronary artery disease (CAD). Apart from the 9p21 locus, the other loci await substantive replication. Furthermore, the effect of these loci on CAD risk in a broader range of individuals remains to be determined. Methods and Results— We undertook association analysis of single nucleotide polymorphisms at each locus with CAD risk in 11 550 cases and 11 205 controls from 9 European studies. The 9p21.3 locus showed unequivocal association (rs1333049, combined odds ratio [OR]=1.20, 95% CI [1.16 to 1.25], probability value=2.81×10 −21 ). We also confirmed association signals at 1p13.3 (rs599839, OR=1.13 [1.08 to 1.19], P =1.44×10 −7 ), 1q41 (rs3008621, OR=1.10 [1.04 to 1.17], P =1.02×10 −3 ), and 10q11.21 (rs501120, OR=1.11 [1.05 to 1.18], P =4.34×10 −4 ). The associations with 6q25.1 (rs6922269, P =0.020) and 2q36.3 (rs2943634, P =0.032) were borderline and not statistically significant after correction for multiple testing. The 15q22.33 locus did not replicate. The 10q11.21 locus showed a possible sex interaction ( P =0.015), with a significant effect in women (OR=1.29 [1.15 to 1.45], P =1.86×10 −5 ) but not men (OR=1.03 [0.96 to 1.11], P =0.387). There were no other strong interactions of any of the loci with other traditional risk factors. The loci at 9p21, 1p13.3, 2q36.3, and 10q11.21 acted independently and cumulatively increased CAD risk by 15% (12% to 18%), per additional risk allele. Conclusions The findings provide strong evidence for association between at least 4 genetic loci and CAD risk. Cumulatively, these novel loci have a significant impact on risk of CAD at least in European populations.
- Published
- 2009
31. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium
- Author
-
Milne, R.L., Burwinkel, B., Michailidou, K., Arias-Perez, J.I., Zamora, M.P., Menendez-Rodriguez, P., Hardisson, D., Mendiola, M., Gonzalez-Neira, A., Pita, G., Alonso, M.R., Dennis, J., Wang, Q., Bolla, M.K., Swerdlow, A., Ashworth, A., Orr, N., Schoemaker, M., Ko, Y.D., Brauch, H., Hamann, U., Andrulis, I.L., Knight, J.A., Glendon, G., Tchatchou, S., Matsuo, K., Ito, H., Iwata, H., Tajima, K., Li, J.M., Brand, J.S., Brenner, H., Dieffenbach, A.K., Arndt, V., Stegmaier, C., Lambrechts, D., Peuteman, G., Christiaens, M.R., Smeets, A., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Hartman, M., Hui, M., Lim, W.Y., Chan, C.W., Marme, F., Yang, R.X., Bugert, P., Lindblom, A., Margolin, S., Garcia-Closas, M., Chanock, S.J., Lissowska, J., Figueroa, J.D., Bojesen, S.E., Nordestgaard, B.G., Flyger, H., Hooning, M.J., Kriege, M., Ouweland, A.M.W. van den, Koppert, L.B., Fletcher, O., Johnson, N., Dos-Santos-Silva, I., Peto, J., Zheng, W., Deming-Halverson, S., Shrubsole, M.J., Long, J.R., Chang-Claude, J., Rudolph, A., Seibold, P., Flesch-Janys, D., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Cox, A., Cross, S.S., Reed, M.W.R., Schmidt, M.K., Broeks, A., Cornelissen, S., Braaf, L., Kang, D., Choi, J.Y., Park, S.K., Noh, D.Y., Simard, J., Dumont, M., Goldberg, M.S., Labreche, F., Fasching, P.A., Hein, A., Ekici, A.B., Beckmann, M.W., Radice, P., Peterlongo, P., Azzollini, J., Barile, M., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Hopper, J.L., Schmidt, D.F., Makalic, E., Southey, M.C., Teo, S.H., Yip, C.H., Sivanandan, K., Tay, W.T., Shen, C.Y., Hsiung, C.N., Yu, J.C., Hou, M.F., Guenel, P., Truong, T., Sanchez, M., Mulot, C., Blot, W., Cai, Q.Y., Nevanlinna, H., Muranen, T.A., Aittomaki, K., Blomqvist, C., Wu, A.H., Tseng, C.C., Berg, D. van den, Stram, D.O., Bogdanova, N., Dork, T., Muir, K., Lophatananon, A., Stewart-Brown, S., Siriwanarangsan, P., Mannermaa, A., Kataja, V., Kosma, V.M., Hartikainen, J.M., Shu, X.O., Lu, W., Gao, Y.T., Zhang, B., Couch, F.J., Toland, A.E., Yannoukakos, D., Sangrajrang, S., McKay, J., Wang, X.S., Olson, J.E., Vachon, C., Purrington, K., Severi, G., Baglietto, L., Haiman, C.A., Henderson, B.E., Schumacher, F., Marchand, L. le, Devilee, P., Tollenaar, R.A.E.M., Seynaeve, C., Czene, K., Eriksson, M., Humphreys, K., Darabi, H., Ahmed, S., Shah, M., Pharoah, P.D.P., Hall, P., Giles, G.G., Benitez, J., Dunning, A.M., Chenevix-Trench, G., Easton, D.F., GENICA Network, kConFab Investigators, Australian Ovarian Canc Study Grp, TNBCC, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
- Subjects
Adult ,Ataxin-7 ,A Kinase Anchor Proteins ,Breast Neoplasms ,Nerve Tissue Proteins ,Middle Aged ,Protein Serine-Threonine Kinases ,Polymorphism, Single Nucleotide ,Cytoskeletal Proteins ,Case-Control Studies ,Humans ,NIMA-Related Kinases ,Female ,Genetic Predisposition to Disease ,health care economics and organizations ,Alleles ,Genome-Wide Association Study - Abstract
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility\ud variants, although most studies have been underpowered to detect associations of a realistic magnitude.\ud We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which\ud evidence of association with breast cancer risk had been previously reported. Case-control data were combined\ud from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional\ud logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21\ud [rs1053338, per allele OR 5 1.07, 95% confidence interval (CI) 5 1.04–1.10, P 5 2.9 3 1026\ud ], AKAP9-M463I at\ud 7q21 (rs6964587, OR 5 1.05, 95% CI 5 1.03–1.07, P 5 1.7 3 1026\ud ) and NEK10-L513S at 3p24 (rs10510592,\ud OR 5 1.10, 95% CI 5 1.07 –1.12, P 5 5.1 3 10217). The first two associations reached genome-wide statistical\ud significance in a combined analysis of available data, including independent data from nine genome-wide association\ud studies (GWASs): for ATXN7-K264R, OR 5 1.07 (95% CI 5 1.05–1.10, P 5 1.0 3 1028\ud ); for AKAP9-M463I,\ud OR 5 1.05 (95% CI 5 1.04–1.07, P 5 2.0 3 10210). Further analysis of other common variants in these two\ud regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified\ud a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is\ud associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility\ud region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of\ud the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast\ud cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying\ud variants and the genes through which they act.
- Published
- 2014
32. Analysis of GPRC6A variants in different pancreatitis etiologies
- Author
-
Markus M. Lerch, Emmanuelle Masson, Joost P.H. Drenth, Peter Bugert, Jian-Min Chen, Wen Bin Zou, Marko Damm, Matthias Sendler, Jonas Rosendahl, Heidi Griesmann, Holger Kirsten, Claudia Ruffert, Ewa Małecka-Panas, Markus Scholz, Nico Hesselbarth, Tom Kaune, Rene H. M. te Morsche, Péter Hegyi, Stanisław Głuszek, Zhuan Liao, Julian Cardinal von Widdern, Heiko Witt, Raffaella Alessia Zuppardo, Robert Grützmann, Louis Buscail, Sebastian Krug, Shun Jiang Deng, Frank Ulrich Weiss, Vinciane Rebours, Giulia Martina Cavestro, Claude Férec, Adrian Saftoiu, Patrick Michl, Kaune, T., Ruffert, C., Hesselbarth, N., Damm, M., Krug, S., Cardinal von Widdern, J., Masson, E., Chen, J. -M., Rebours, V., Buscail, L., Ferec, C., Grutzmann, R., te Morsche, R. H. M., Drenth, J. P., Cavestro, G. M., Zuppardo, R. A., Saftoiu, A., Malecka-Panas, E., Gluszek, S., Bugert, P., Lerch, M. M., Sendler, M., Weiss, F. U., Zou, W. -B., Deng, S. -J., Liao, Z., Scholz, M., Kirsten, H., Hegyi, P., Witt, H., Michl, P., Griesmann, H., and Rosendahl, J.
- Subjects
Adult ,Male ,Candidate gene ,Pancreatitis, Alcoholic ,Endocrinology, Diabetes and Metabolism ,Single-nucleotide polymorphism ,Polymorphism, Single Nucleotide ,White People ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Risk Factors ,Genetics ,Humans ,Medicine ,SNP ,Genetic Predisposition to Disease ,Aged ,Inflammation ,Hepatology ,G-Protein coupled receptor ,business.industry ,Gastroenterology ,Genetic Variation ,Inflammasome ,DNA ,Odds ratio ,Middle Aged ,Tag SNP ,medicine.disease ,Europe ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,Pancreatitis ,030220 oncology & carcinogenesis ,Cohort ,Immunology ,Female ,Calcium ,030211 gastroenterology & hepatology ,business ,Receptors, Calcium-Sensing ,Genome-Wide Association Study ,Signal Transduction ,medicine.drug - Abstract
Contains fulltext : 229360.pdf (Publisher’s version ) (Closed access) BACKGROUND: The G-protein-coupled receptor Class C Group 6 Member A (GPRC6A) is activated by multiple ligands and is important for the regulation of calcium homeostasis. Extracellular calcium is capable to increase NLRP3 inflammasome activity of the innate immune system and deletion of this proinflammatory pathway mitigated pancreatitis severity in vivo. As such this pathway and the GPRC6A receptor is a reasonable candidate gene for pancreatitis. Here we investigated the prevalence of sequence variants in the GPRC6A locus in different pancreatitis aetiologies. METHODS: We selected 6 tagging SNPs with the SNPinfo LD TAG SNP Selection tool and the functional relevant SNP rs6907580 for genotyping. Cohorts from Germany, further European countries and China with up to 1,124 patients and 1,999 controls were screened for single SNPs with melting curve analysis. RESULTS: We identified an association of rs1606365(G) with alcoholic chronic pancreatitis in a German (odds ratio (OR) 0.76, 95% confidence interval (CI) 0.65-0.89, p = 8 × 10(-5)) and a Chinese cohort (OR 0.78, 95% CI 0.64-0.96, p = 0.02). However, this association was not replicated in a combined cohort of European patients (OR 1.18, 95% CI 0.99-1.41, p = 0.07). Finally, no association was found with acute and non-alcoholic chronic pancreatitis. CONCLUSIONS: Our results support a potential role of calcium sensing receptors and inflammasome activation in alcoholic chronic pancreatitis development. As the functional consequence of the associated variant is unclear, further investigations might elucidate the relevant mechanisms.
- Published
- 2020
33. Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk
- Author
-
Ugo Boggi, Cosmeri Rizzato, Krzysztof Jamroziak, Andrea Mambrini, Gabriele Capurso, Yogesh K. Vashist, Valerio Pazienza, Christoph W. Michalski, Giulia Martina Cavestro, Keitaro Matsuo, Ewa Małecka-Panas, Jakob R. Izbicki, Harald Klüter, Timothy J. Key, Ludmila Vodickova, Vincenzo Corbo, Kenji Yamao, Domenica Gioffreda, Anna Stępień, Milena Di Leo, Willem Niesen, Audrius Ivanauskas, Cosimo Sperti, Carlo Federico Zambon, Peter Bugert, Beatrice Mohelnikova-Duchonova, Satoyo Hosono, Angelo Andriulli, Renata Talar-Wojnarowska, Maria Gazouli, John P. Neoptolemos, Franco Bambi, Francesca Tavano, Claudio Pasquali, Yasuhiro Shimizu, Manuela Pastore, Federico Canzian, Rudolf Kaaks, Daniele Campa, Gianfranco Delle Fave, Frederike Dijk, George Theodoropoulos, Raffaele Pezzilli, Paola Pacetti, Eithne Costello, Pavel Vodicka, Verena Katzke, Stefano Landi, Juozas Kupcinskas, Oliver Strobel, Martin Lovecek, Thilo Hackert, Manuel Gentiluomo, Markus W. Büchler, Pavel Soucek, Roberto Valente, Bas Bueno-de-Mesquita, Hidemi Ito, Kay-Tee Khaw, Olivier R. Busch, Daniela Basso, Campa, D, Pastore, M, Gentiluomo, M, Talar Wojnarowska, R, Kupcinskas, J, Malecka Panas, E, Neoptolemos, Jp, Niesen, W, Vodicka, P, Delle Fave, G, Bas Bueno de Mesquita, H, Gazouli, M, Pacetti, P, Di Leo, M, Ito, H, Klüter, H, Soucek, P, Corbo, V, Yamao, K, Hosono, S, Kaaks, R, Vashist, Y, Gioffreda, D, Strobel, O, Shimizu, Y, Dijk, F, Andriulli, A, Ivanauskas, A, Bugert, P, Tavano, F, Vodickova, L, Zambon, Cf, Lovecek, M, Landi, S, Key, Tj, Boggi, U, Pezzilli, R, Jamroziak, K, Mohelnikova Duchonova, B, Mambrini, A, Bambi, F, Busch, O, Pazienza, V, Valente, R, Theodoropoulos, G, Hackert, T, Capurso, G, Cavestro, GIULIA MARTINA, Pasquali, C, Basso, D, Sperti, C, Matsuo, K, Büchler, M, Khaw, Kt, Izbicki, J, Costello, E, Katzke, V, Michalski, C, Stepien, A, Rizzato, C, Canzian, F., CCA -Cancer Center Amsterdam, Pathology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Surgery
- Subjects
0301 basic medicine ,Pancreatic disease ,CDKN2A ,association study ,miRSNP ,pancreatic cancer ,single nucleotide polymorphisms ,Alleles ,Asian Continental Ancestry Group ,Binding Sites ,Carcinoma, Pancreatic Ductal ,Case-Control Studies ,Cyclin-Dependent Kinase Inhibitor p15 ,Cyclin-Dependent Kinase Inhibitor p18 ,DNA Methylation ,Disease Progression ,European Continental Ancestry Group ,Genetic Predisposition to Disease ,Genotype ,Germ-Line Mutation ,Humans ,International Cooperation ,Japan ,Odds Ratio ,Pancreatic Neoplasms ,Prognosis ,Retrospective Studies ,Polymorphism, Single Nucleotide ,Bioinformatics ,0302 clinical medicine ,Medicine ,Single Nucleotide ,3. Good health ,Oncology ,Pancreatic Ductal ,030220 oncology & carcinogenesis ,Research Paper ,Single-nucleotide polymorphism ,White People ,03 medical and health sciences ,Germline mutation ,Asian People ,Pancreatic cancer ,Allele ,Polymorphism ,Cyclin-Dependent Kinase Inhibitor p16 ,business.industry ,Carcinoma ,Cancer ,medicine.disease ,030104 developmental biology ,Cancer research ,business - Abstract
The CDKN2A(p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (OR het=1.14, 95% CI 1.01-1.27, p=0.026, ORhom =1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/Blocus could represent a genetic link between diabetes and pancreatic cancer risk.
- Published
- 2016
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.