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Sökning: WFRF:(Giles Graham G.) > (2015-2019) > (2016)

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11.
  • 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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12.
  • Le Contel, O., et al. (författare)
  • Whistler mode waves and Hall fields detected by MMS during a dayside magnetopause crossing
  • 2016
  • Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 43:12, s. 5943-5952
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>We present Magnetospheric Multiscale (MMS) mission measurements during a full magnetopause crossing associated with an enhanced southward ion flow. A quasi-steady magnetospheric whistler mode wave emission propagating toward the reconnection region with quasi-parallel and oblique wave angles is detected just before the opening of the magnetic field lines and the detection of escaping energetic electrons. Its source is likely the perpendicular temperature anisotropy of magnetospheric energetic electrons. In this region, perpendicular and parallel currents as well as the Hall electric field are calculated and found to be consistent with the decoupling of ions from the magnetic field and the crossing of a magnetospheric separatrix region. On the magnetosheath side, Hall electric fields are found smaller as the density is larger but still consistent with the decoupling of ions. Intense quasi-parallel whistler wave emissions are detected propagating both toward and away from the reconnection region in association with a perpendicular anisotropy of the high-energy part of the magnetosheath electron population and a strong perpendicular current, which suggests that in addition to the electron diffusion region, magnetosheath separatrices could be a source region for whistler waves.</p>
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13.
  • Machiela, Mitchell J., et al. (författare)
  • Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes
  • 2016
  • Ingår i: Human Molecular Genetics. - Oxford University Press. - 0964-6906 .- 1460-2083. ; 25:8, s. 1663-1676
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82, P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51, P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.</p>
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14.
  • Travis, Ruth C., et al. (författare)
  • A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk
  • 2016
  • Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:8, s. 2288-2300
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (P-trend all &lt;= 0.005), and IGFBP-1 was inversely associated weakly with risk (P-trend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (P-heterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, P-heterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. </p>
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15.
  • Travis, Ruth C., et al. (författare)
  • A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk
  • 2016
  • Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:8, s. 2288-2300
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (P-trend all &lt;= 0.005), and IGFBP-1 was inversely associated weakly with risk (P-trend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (P-heterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, P-heterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development.</p>
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16.
  • Del Gobbo, Liana C., et al. (författare)
  • omega-3 Polyunsaturated Fatty Acid Biomarkers and Coronary Heart Disease Pooling Project of 19 Cohort Studies
  • 2016
  • Ingår i: JAMA Internal Medicine. - 2168-6106 .- 2168-6114. ; 176:8, s. 1155-1166
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>IMPORTANCE The role of omega-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. OBJECTIVE To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20: 5 omega-3), docosapentaenoic acid (DPA; 22: 5 omega-3), and docosahexaenoic acid (DHA; 22: 6 omega-3) and plant-derived alpha-linolenic acid (ALA; 18: 3 omega-3) for incident CHD. DATA SOURCES A global consortium of 19 studies identified by November 2014. STUDY SELECTION Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue omega-3 biomarkers and ascertained CHD. DATA EXTRACTION AND SYNTHESIS Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, omega-6 levels, and FADS desaturase genes. MAIN OUTCOMES AND MEASURES Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI). RESULTS The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with omega-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baseline was 59 years (range, 18-97 years), and 28 660 (62.8%) were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the omega-3 biomarkers ALA, DPA, and DHA were associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95% CI, 0.84-0.98) for ALA, 0.90 (95% CI, 0.85-0.96) for DPA, and 0.90 (95% CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95% CI, 0.90-0.99), ALA (RR, 1.00; 95% CI, 0.95-1.05), EPA (RR, 0.94; 95% CI, 0.87-1.02), and DHA (RR, 0.95; 95% CI, 0.91-1.00) were not. Significant associations with nonfatal MI were not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses. CONCLUSIONS AND RELEVANCE On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived omega-3 fatty acids are associated with a modestly lower incidence of fatal CHD.</p>
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17.
  • Del Gobbo, Liana C., et al. (författare)
  • ω-3 Polyunsaturated fatty acid biomarkers and coronary heart disease : Pooling project of 19 cohort studies
  • 2016
  • Ingår i: JAMA Internal Medicine. - American Medical Association. - 2168-6106. ; 176:8, s. 1155-1166
  • Tidskriftsartikel (refereegranskat)abstract
    • Importance: The role of ω-3 polyunsaturated fatty acids for primary prevention of coronary heart disease (CHD) remains controversial. Most prior longitudinal studies evaluated self-reported consumption rather than biomarkers. Objective: To evaluate biomarkers of seafood-derived eicosapentaenoic acid (EPA; 20:5 ω-3), docosapentaenoic acid (DPA; 22:5 ω-3), and docosahexaenoic acid (DHA; 22:6 ω-3) and plant-derived α-linolenic acid (ALA; 18:3 ω-3) for incident CHD. Data Sources: A global consortium of 19 studies identified by November 2014. Study Selection: Available prospective (cohort, nested case-control) or retrospective studies with circulating or tissue ω-3 biomarkers and ascertained CHD. Data Extraction and Synthesis: Each study conducted standardized, individual-level analysis using harmonized models, exposures, outcomes, and covariates. Findings were centrally pooled using random-effects meta-analysis. Heterogeneity was examined by age, sex, race, diabetes, statins, aspirin, ω-6 levels, and FADS desaturase genes. Main Outcomes and Measures: Incident total CHD, fatal CHD, and nonfatal myocardial infarction (MI). Results: The 19 studies comprised 16 countries, 45 637 unique individuals, and 7973 total CHD, 2781 fatal CHD, and 7157 nonfatal MI events, with ω-3 measures in total plasma, phospholipids, cholesterol esters, and adipose tissue. Median age at baselinewas 59 years (range, 18-97 years), and 28 660 (62.8%)were male. In continuous (per 1-SD increase) multivariable-adjusted analyses, the ω-3 biomarkers ALA, DPA, and DHAwere associated with a lower risk of fatal CHD, with relative risks (RRs) of 0.91 (95%CI, 0.84-0.98) for ALA, 0.90 (95%CI, 0.85-0.96) for DPA, and 0.90 (95%CI, 0.84-0.96) for DHA. Although DPA was associated with a lower risk of total CHD (RR, 0.94; 95%CI, 0.90-0.99), ALA (RR, 1.00; 95%CI, 0.95-1.05), EPA (RR, 0.94; 95%CI, 0.87-1.02), and DHA (RR, 0.95; 95%CI, 0.91-1.00)were not. Significant associations with nonfatal MIwere not evident. Associations appeared generally stronger in phospholipids and total plasma. Restricted cubic splines did not identify evidence of nonlinearity in dose responses. Conclusions and Relevance: On the basis of available studies of free-living populations globally, biomarker concentrations of seafood and plant-derived ω-3 fatty acids are associated with a modestly lower incidence of fatal CHD.
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18.
  • Dunning, Alison M., et al. (författare)
  • Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170
  • 2016
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 48:4, s. 374-386
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor a) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER-) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER-tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.</p>
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19.
  • Gaudet, Mia M., et al. (författare)
  • Interactions between breast cancer susceptibility loci and menopausal hormone therapy in relationship to breast cancer in the Breast and Prostate Cancer Cohort Consortium
  • 2016
  • Ingår i: Breast Cancer Research and Treatment. - 0167-6806 .- 1573-7217. ; 155:3, s. 531-540
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Current use of menopausal hormone therapy (MHT) has important implications for postmenopausal breast cancer risk, and observed associations might be modified by known breast cancer susceptibility loci. To provide the most comprehensive assessment of interactions of prospectively collected data on MHT and 17 confirmed susceptibility loci with invasive breast cancer risk, a nested case-control design among eight cohorts within the NCI Breast and Prostate Cancer Cohort Consortium was used. Based on data from 13,304 cases and 15,622 controls, multivariable-adjusted logistic regression analyses were used to estimate odds ratios (OR) and 95 % confidence intervals (CI). Effect modification of current and past use was evaluated on the multiplicative scale. P values &lt; 1.5 x 10(-3) were considered statistically significant. The strongest evidence of effect modification was observed for current MHT by 9q31-rs865686. Compared to never users of MHT with the rs865686 GG genotype, the association between current MHT use and breast cancer risk for the TT genotype (OR 1.79, 95 % CI 1.43-2.24; P (interaction) = 1.2 x 10(-4)) was less than expected on the multiplicative scale. There are no biological implications of the sub-multiplicative interaction between MHT and rs865686. Menopausal hormone therapy is unlikely to have a strong interaction with the common genetic variants associated with invasive breast cancer.</p>
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20.
  • Graham, Daniel B., et al. (författare)
  • Electron currents and heating in the ion diffusion region of asymmetric reconnection
  • 2016
  • Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 43:10, s. 4691-4700
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>In this letter the structure of the ion diffusion region of magnetic reconnection at Earth's magnetopause is investigated using the Magnetospheric Multiscale (MMS) spacecraft. The ion diffusion region is characterized by a strong DC electric field, approximately equal to the Hall electric field, intense currents, and electron heating parallel to the background magnetic field. Current structures well below ion spatial scales are resolved, and the electron motion associated with lower hybrid drift waves is shown to contribute significantly to the total current density. The electron heating is shown to be consistent with large-scale parallel electric fields trapping and accelerating electrons, rather than wave-particle interactions. These results show that sub-ion scale processes occur in the ion diffusion region and are important for understanding electron heating and acceleration.</p>
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