Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Gudmundsson J
PROVIDER: S-EPMC3598012 | biostudies-literature | 2008 Mar
REPOSITORIES: biostudies-literature
Publications
Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer.
Gudmundsson Julius J Sulem Patrick P Rafnar Thorunn T Bergthorsson Jon T JT Manolescu Andrei A Gudbjartsson Daniel D Agnarsson Bjarni A BA Sigurdsson Asgeir A Benediktsdottir Kristrun R KR Blondal Thorarinn T Jakobsdottir Margret M Stacey Simon N SN Kostic Jelena J Kristinsson Kari T KT Birgisdottir Birgitta B Ghosh Shyamali S Magnusdottir Droplaug N DN Thorlacius Steinunn S Thorleifsson Gudmar G Zheng S Lilly SL Sun Jielin J Chang Bao-Li BL Elmore J Bradford JB Breyer Joan P JP McReynolds Kate M KM Bradley Kevin M KM Yaspan Brian L BL Wiklund Fredrik F Stattin Par P Lindström Sara S Adami Hans-Olov HO McDonnell Shannon K SK Schaid Daniel J DJ Cunningham Julie M JM Wang Liang L Cerhan James R JR St Sauver Jennifer L JL Isaacs Sara D SD Wiley Kathleen E KE Partin Alan W AW Walsh Patrick C PC Polo Sonia S Ruiz-Echarri Manuel M Navarrete Sebastian S Fuertes Fernando F Saez Berta B Godino Javier J Weijerman Philip C PC Swinkels Dorine W DW Aben Katja K KK Witjes J Alfred JA Suarez Brian K BK Helfand Brian T BT Frigge Michael L ML Kristjansson Kristleifur K Ober Carole C Jonsson Eirikur E Einarsson Gudmundur V GV Xu Jianfeng J Gronberg Henrik H Smith Jeffrey R JR Thibodeau Stephen N SN Isaacs William B WB Catalona William J WJ Mayordomo Jose I JI Kiemeney Lambertus A LA Barkardottir Rosa B RB Gulcher Jeffrey R JR Thorsteinsdottir Unnur U Kong Augustine A Stefansson Kari K
Nature genetics 20080210 3
We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than le ...[more]
Similar Datasets
Project description:We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totaling 2,019 cases and 2,105 controls. Using pooling, we identified a new melanoma risk locus on chromosome 20 (rs910873 and rs1885120), with replication in two further samples (combined P < 1 x 10(-15)). The per allele odds ratio was 1.75 (1.53, 2.01), with evidence for stronger association in early-onset cases.
| S-EPMC2755512 | biostudies-literature
Project description:BackgroundGenome-wide association studies have identified numerous single nucleotide polymorphisms (SNP) associated with the risk of prostate cancer. Our objective was to determine whether these SNPs affect the progression of prostate cancer.MethodsWe genotyped 26 SNPs previously associated with prostate cancer risk among 788 aggressive prostate cancer patients who were treated by radical prostatectomy or radiation therapy. Prostate cancer progression was defined as biochemical recurrence based on posttreatment prostate-specific antigen levels of >0.3 ng/mL for radical prostatectomy patients or a 2-ng/mL increase above the nadir for radiation therapy patients, initiation of hormone treatment, or metastases. We assessed the association between independent and combined SNPs and disease progression by Cox proportional hazards regression.ResultsFive SNPs showed independent associations with prostate cancer progression (rs12621278, rs629242, rs9364554, rs4430796, and rs5945572) based on stepwise regression analysis. The strongest SNP was rs12621278 in the ITGA6 locus, which was associated with a 2.4-fold increased risk of progression (P = 0.0003). When considering the sum of risk alleles across these five SNPs, each additional allele was associated with a 29% increase in risk of progression (95% confidence interval, 1.12-1-47).ConclusionsWe found that five of the recently highlighted prostate cancer susceptibility loci also influence prostate cancer progression beyond the known clinicopathologic predictors. If confirmed, these genetic variants might help clarify which tumors are likely to progress and require more aggressive treatment in contrast to those that might not have substantial effects on morbidity or mortality.ImpactGenetic susceptibility variants for prostate cancer development may also inform disease progression.
| S-EPMC2950095 | biostudies-literature
Project description:Kawasaki disease (KD; OMIM 611775) is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene (CASP3) that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5' untranslated region of CASP3 (rs72689236; P = 4.2 x 10(-8) in the Japanese and P = 3.7 x 10(-3) in the European Americans) abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.
| S-EPMC2893807 | biostudies-literature
Project description:The PI3K-Akt-mTOR pathway plays a central role in the development of non-medullary thyroid carcinoma (NMTC). Although somatic mutations have been identified in these genes in NMTC patients, the role of germline variants has not been investigated. Here, we selected frequently occurring genetic variants in AKT1, AKT2, AKT3, PIK3CA and MTOR and have assessed their effect on NMTC susceptibility, progression and clinical outcome in a Dutch discovery cohort (154 patients, 188 controls) and a Romanian validation cohort (159 patients, 260 controls). Significant associations with NMTC susceptibility were observed for AKT1 polymorphisms rs3803304, rs2494732 and rs2498804 in the Dutch discovery cohort, of which the AKT1 rs3803304 association was confirmed in the Romanian validation cohort. No associations were observed between PI3K-Akt-mTOR polymorphisms and clinical parameters including histology, TNM staging, treatment response and clinical outcome. Functionally, cells bearing the associated AKT1 rs3803304 risk allele exhibit increased levels of phosphorylated Akt protein, potentially leading to elevated signaling activity of the oncogenic Akt pathway. All together, germline encoded polymorphisms in the PI3K-Akt-mTOR pathway could represent important risk factors in development of NMTC.
| S-EPMC7774771 | biostudies-literature
Project description:Lattice degeneration of the retina is a vitreoretinal disorder characterized by a visible fundus lesion predisposing the patient to retinal tears and detachment. The etiology of this degeneration is still uncertain, but it is likely that both genetic and environmental factors play important roles in its development. To identify genetic susceptibility regions for lattice degeneration of the retina, we performed a genome-wide association study (GWAS) using a dense panel of 23,465 microsatellite markers covering the entire human genome. This GWAS in a Japanese cohort (294 patients with lattice degeneration and 294 controls) led to the identification of one microsatellite locus, D2S0276i, in the collagen type IV alpha 4 (COL4A4) gene on chromosome 2q36.3. To validate the significance of this observation, we evaluated the D2S0276i region in the GWAS cohort and in an independent Japanese cohort (280 patients and 314 controls) using D2S0276i and 47 single nucleotide polymorphisms covering the region. The strong associations were observed in D2S0276i and rs7558081 in the COL4A4 gene (Pc = 5.8 × 10(-6), OR = 0.63 and Pc = 1.0 × 10(-5), OR = 0.69 in a total of 574 patients and 608 controls, respectively). Our findings suggest that variants in the COL4A4 gene may contribute to the development of lattice degeneration of the retina.
| S-EPMC3378527 | biostudies-literature
Project description:BackgroundCancers arising within the gastrointestinal tract are complex disorders involving genetic events that cause the conversion of normal tissue to premalignant lesions and malignancy. Shared genetic features are reported in epithelial-based gastrointestinal cancers which indicate common susceptibility among this group of malignancies. In addition, the contribution of rare variants may constitute parts of genetic susceptibility.MethodsA cross-cancer analysis of 38,171 shared rare genetic variants from genome-wide association assays was conducted, which included data from 3,194 cases and 1,455 controls across three cancer sites (esophageal, gastric and colorectal). The SNP-level association was performed by multivariate logistic regression analyses for single cancer, followed by association analysis for SubSETs (ASSET) to adjust the bias of overlapping controls. Gene-level analyses were conducted by SKAT-O, with multiple comparison adjustments by false discovery rate (FDR). Based on the significant genes indicated by SKATO analysis, pathways analysis was conducted using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases.ResultsMeta-analysis in three gastrointestinal (GI) cancers identified 13 novel susceptibility loci that reached genome-wide significance (P ASSET< 5×10-8). SKAT-O analysis revealed EXOC6, LRP5L and MIR1263/LINC01324 to be significant genes shared by GI cancers (P adj<0.05, P FDR<0.05). Furthermore, GO pathway analysis identified significant enrichment of synaptic transmission and neuron development pathways shared by all three cancer types.ConclusionRare variants and the corresponding genes potentially contribute to shared susceptibility in different GI cancer types. The discovery of these novel variants and genes offers new insights for the carcinogenic mechanisms and missing heritability of GI cancers.
| S-EPMC10358854 | biostudies-literature
Project description:Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23?790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR)=1.21; P=1.4 × 10(-11)) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR=1.22; P=3.9 × 10(-10)) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR=1.28; P=1.30 × 10(-3), DQB1*02: OR=1.32; P=9.00 × 10(-4)). These findings support a role of HLA class II alleles in the risk of AMD.
| S-EPMC5070898 | biostudies-literature
Project description:A recent genome-wide association study (GWAS) identified association with variants in X-linked CLDN2 and MORC4, and PRSS1-PRSS2 loci with chronic pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525-OR 1.71, P = 1.38 x 10-09; rs12008279-OR 1.56, P = 1.53 x 10-04) and 2 variants in MORC4 gene (rs12688220-OR 1.72, P = 9.20 x 10-09; rs6622126-OR 1.75, P = 4.04x10-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31-0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients.
| S-EPMC4731142 | biostudies-literature
Project description:We conducted a large-scale genome-wide association study in UK Caucasians to identify susceptibility alleles for lung cancer, analyzing 1529 cases and 2707 controls. To increase the likelihood of identifying disease-causing alleles, we genotyped 1476 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 871 candidate cancer genes, biasing SNP selection toward those predicted to be deleterious. Statistically significant associations were identified for 64 nsSNPs, generating a genome-wide significance level of P=0.002. Eleven of the 64 SNPs mapped to genes encoding pivotal components of the growth hormone/insulin-like growth factor (GH-IGF) pathway, including CAMKK1 E375G (OR=1.37, P=5.4x10(-5)), AKAP9 M463I (OR=1.32, P=1.0x10(-4)) and GHR P495T (OR=12.98, P=0.0019). Significant associations were also detected for SNPs within genes in the DNA damage-response pathway, including BRCA2 K3326X (OR=1.72, P=0.0075) and XRCC4 I137T (OR=1.31, P=0.0205). Our study provides evidence that inherited predisposition to lung cancer is in part mediated through low-penetrance alleles and specifically identifies variants in GH-IGF and DNA damage-response pathways with risk of lung cancer.
| S-EPMC1473180 | biostudies-literature
Project description:BACKGROUND:The NADH-ubiquinone oxidoreductase flavoprotein gene (NDUFV2), which encodes a 24 kD mitochondrial complex I subunit, has been reported to be positively associated with schizophrenia and bipolar disorder in different populations. METHODS:We genotyped the promoter variants of this gene (rs6506640 and rs1156044) by direct sequencing in 529 unrelated Han Chinese schizophrenia patients and 505 matched controls. Fisher's Exact test was performed to assess whether these two reported single nucleotide polymorphisms (SNPs) confer susceptibility to schizophrenia in Chinese. RESULTS:Allele, genotype and haplotype comparison between the case and control groups showed no statistical significance, suggesting no association between the NDUFV2 gene promoter variants and schizophrenia in Han Chinese. CONCLUSION:The role of NDUFV2 played in schizophrenia needs to be further studied. Different racial background and/or population substructure might account for the inconsistent results between studies.
| S-EPMC3022841 | biostudies-literature