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Sökning: WFRF:(Bjorge Line)

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1.
  • Hollestelle, Antoinette, et al. (författare)
  • No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
  • 2016
  • Ingår i: Gynecologic Oncology. - Academic Press. - 0090-8258. ; 141:2, s. 386-401
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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2.
  • Jiang, Xia, et al. (författare)
  • Shared heritability and functional enrichment across six solid cancers
  • 2019
  • Ingår i: Nature Communications. - Nature Publishing Group. - 2041-1723 .- 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (<em>r</em><em>g</em> = 0.57, <em>p</em> = 4.6 × 10−8), breast and ovarian cancer (<em>r</em><em>g</em> = 0.24, <em>p</em> = 7 × 10−5), breast and lung cancer (<em>r</em><em>g</em> = 0.18, <em>p </em>=1.5 × 10−6) and breast and colorectal cancer (<em>r</em><em>g</em> = 0.15, <em>p</em> = 1.1 × 10−4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.</p>
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3.
  • Jiang, Xia, et al. (författare)
  • Shared heritability and functional enrichment across six solid cancers
  • 2019
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.</p>
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4.
  • Kuchenbaecker, Karoline B., et al. (författare)
  • Identification of six new susceptibility loci for invasive epithelial ovarian cancer
  • 2015
  • Ingår i: Nature Genetics. - Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 47:2, s. 164-171
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P less than 5 x 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.</p>
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5.
  • Lawrenson, Kate, et al. (författare)
  • Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
  • 2016
  • Ingår i: Nature Communications. - Nature Publishing Group. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
6.
  • Lawrenson, Kate, et al. (författare)
  • Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
  • 2016
  • Ingår i: Nature Communications. - Nature Publishing Group. - 2041-1723 .- 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 <em>BRCA1</em> mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (<em>P</em>=9.2 × 10<sup>−20</sup>), ER-negative BC (<em>P</em>=1.1 × 10<sup>−13</sup>), <em>BRCA1</em>-associated BC (<em>P</em>=7.7 × 10<sup>−16</sup>) and triple negative BC (<em>P</em>-diff=2 × 10<sup>−5</sup>). Genotype-gene expression associations are identified for candidate target genes <em>ANKLE1</em> (<em>P</em>=2 × 10<sup>−3</sup>) and <em>ABHD8</em> (<em>P</em>&lt;2 × 10<sup>−3</sup>). Chromosome conformation capture identifies interactions between four candidate SNPs and <em>ABHD8</em>, and luciferase assays indicate six risk alleles increased transactivation of the <em>ADHD8</em> promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces <em>ANKLE1</em> downregulation; and mRNA stability assays indicate functional effects for an <em>ANKLE1</em> 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate <em>ABHD8</em> and perhaps <em>ANKLE1</em> expression, and indicate common mechanisms underlying breast and ovarian cancer risk.</p>
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7.
  • Lu, Yingchang, et al. (författare)
  • A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.
  • 2018
  • Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 78:18, s. 5419-5430
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>.</p><h2>Abstract</h2><p>Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their <em>cis</em>-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of <em>P</em> &lt; 2.2 × 10<sup>−6</sup>, we identified 35 genes, including <em>FZD4</em> at 11q14.2 (Z = 5.08, <em>P</em> = 3.83 × 10<sup>−7</sup>, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (<em>P</em> &lt; 1.47 × 10<sup>−3</sup>). These data identify one novel locus <em>(FZD4</em>) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.</p><p><strong>Significance:</strong> Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. <em>Cancer Res; 78(18); 5419–30. ©2018 AACR</em>.</p>
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8.
  • Macsali, Ferenc, et al. (författare)
  • Menstrual Cycle and Respiratory Symptoms in a General Nordic-Baltic Population
  • 2013
  • Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 187:4, s. 366-373
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Rationale: There is little knowledge of variations in respiratory symptoms during the menstrual cycle in a general population, and potential modifying factors are not investigated. Objectives: To investigate menstrual cycle variation in respiratory symptoms in a large general population, using chronobiology methodology, and stratifying by body mass index (BMI), smoking, and asthma status. Methods: A total of 3,926 women with regular cycles less than or equal to 28 days and not taking exogenous sex hormones answered a postal questionnaire regarding the first day of their last menstruation and respiratory symptoms in the last 3 days. Moving 4-day means were computed to smooth uneven records of daily sampling; best-fitting 28-day composite cosine curves were applied to each time series to describe rhythmicity. Measurements and Main Results: Significant rhythmic variations over the menstrual cycle were found in each symptom for all subjects and subgroups. Wheezing was higher on cycle Days 10-22, with a midcycle dip near the time of putative ovulation (approximately Days 14-16)-in most subgroups. Shortness of breath was higher on days 7-21, with a dip just before midcycle in many subgroups. Cough was higher just after putative ovulation for subjects with asthma, BMI greater than or equal to 23 kg/m(2), and smokers, or just before ovulation and menses onset for low symptomatic subgroups. Conclusions: Respiratory symptoms varied significantly during the menstrual cycle and were most frequent from the midluteal to mid-follicular stages, often with a dip near the time of ovulation. The patterns varied by BMI, smoking, and asthma status. These relations link respiratory symptoms with hormonal changes through the menstrual cycle and imply a potential for individualized chronotherapy for respiratory diseases.</p>
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9.
  • Macsali, Ferenc, et al. (författare)
  • Menstrual Cycle and Respiratory Symptoms in a General Nordic-Baltic Population
  • 2013
  • Ingår i: American Journal of Respiratory and Critical Care Medicine. - 1073-449X .- 1535-4970. ; 187:4, s. 366-373
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Rationale: There is little knowledge of variations in respiratory symptoms during the menstrual cycle in a general population, and potential modifying factors are not investigated. Objectives: To investigate menstrual cycle variation in respiratory symptoms in a large general population, using chronobiology methodology, and stratifying by body mass index (BMI), smoking, and asthma status. Methods: A total of 3,926 women with regular cycles less than or equal to 28 days and not taking exogenous sex hormones answered a postal questionnaire regarding the first day of their last menstruation and respiratory symptoms in the last 3 days. Moving 4-day means were computed to smooth uneven records of daily sampling; best-fitting 28-day composite cosine curves were applied to each time series to describe rhythmicity. Measurements and Main Results: Significant rhythmic variations over the menstrual cycle were found in each symptom for all subjects and subgroups. Wheezing was higher on cycle Days 10-22, with a midcycle dip near the time of putative ovulation (approximately Days 14-16)-in most subgroups. Shortness of breath was higher on days 7-21, with a dip just before midcycle in many subgroups. Cough was higher just after putative ovulation for subjects with asthma, BMI greater than or equal to 23 kg/m(2), and smokers, or just before ovulation and menses onset for low symptomatic subgroups. Conclusions: Respiratory symptoms varied significantly during the menstrual cycle and were most frequent from the midluteal to mid-follicular stages, often with a dip near the time of ovulation. The patterns varied by BMI, smoking, and asthma status. These relations link respiratory symptoms with hormonal changes through the menstrual cycle and imply a potential for individualized chronotherapy for respiratory diseases.</p>
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10.
  • Macsali, Ferenc, et al. (författare)
  • Oral contraception, body mass index, and asthma : a cross-sectional Nordic-Baltic population survey
  • 2009
  • Ingår i: Journal of Allergy and Clinical Immunology. - 0091-6749 .- 1097-6825. ; 123:2, s. 391-397
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>BACKGROUND: Emerging evidence suggests that sex steroid hormones may influence airways obstruction, and that metabolic status may modify potential effects. OBJECTIVE: This study investigated the association between use of oral contraceptive pills (OCPs) and asthma in a Nordic-Baltic population-based study, while taking into account possible interplay with body mass index (BMI). METHODS: Postal questionnaires were sent to subjects in Denmark, Estonia, Iceland, Norway, and Sweden from 1999 to 2001 (response rate in women, 77%). Pregnant women, women using hormone replacement therapy, and women &gt;45 years were excluded. Analyses included 5791 women 25 to 44 years old, of whom 961 (17%) used OCP. Logistic regression analyses included adjustment for smoking, irregular menstruation, BMI, age, type of dwelling, and center. RESULTS: Oral contraceptive pills were associated with increased risk for asthma (odds ratio, 1.42; 95% CI, 1.09-1.86), asthma with hay fever (1.48; 1.08-2.03), wheeze with shortness of breath (1.27; 1.02-1.60), hay fever (1.25; 1.06-1.48), and &gt;/=3 asthma symptoms (1.29; 1.05-1.58). The findings were consistent between centers. The associations were present only among normal weight women (BMI 20-25 kg/m(2), asthma: 1.45; 1.02-2.05) and overweight women (BMI &gt;25kg/m(2): 1.91; 1.20-3.02), but not among lean women (BMI &lt;20 kg/m(2): 0.41; 0.12-1.40). Interaction between BMI and OCP in association with asthma was significant (P(interaction) &lt; .05). CONCLUSIONS: Women using oral contraceptive pills had more asthma. This was found only in normal weight and overweight women, indicating interplay between sex hormones and metabolic status in effect on the airways. The findings originate from a cross-sectional postal survey and should be interpreted with caution; it is recommended that asthma symptoms are included in clinical trials of oral contraception.</p>
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