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| 2. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 3. |
- McKay, James D., et al.
(författare)
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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
- 2017
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
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Tidskriftsartikel (refereegranskat)abstract
- Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
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| 4. |
- Ji, Xuemei, et al.
(författare)
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Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
- 2018
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
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| 5. |
- Koh, Angela S., et al.
(författare)
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A comprehensive population-based characterization of heart failure with mid-range ejection fraction
- 2017
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Ingår i: European Journal of Heart Failure. - : WILEY. - 1388-9842 .- 1879-0844. ; 19:12, s. 1624-1634
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Clinical features and outcomes in the novel phenotype heart failure with mid-range ejection fraction [HFmrEF, ejection fraction (EF) 40-49%] were compared with heart failure with reduced EF (HFrEF, EF < 40%) and preserved EF (HFpEF, EF >= 50%).Methods and results: In the Swedish Heart Failure Registry, we assessed the association between baseline characteristics and EF group using multivariable logistic regressions, and the association between EF group and all-cause mortality using multivariable Cox regressions. Of 42 061 patients, 56% had HFrEF, 21% had HFmrEF, and 23% had HFpEF. Characteristics were continuous for age (72 +/- 12 vs. 74 +/- 12 vs. 77 +/- 11 years), proportion of women (29% vs. 39% vs. 55%), and 13 other characteristics. Coronary artery disease (CAD) was distinctly more common in HFrEF (54%) and HFmrEF (53%) vs. HFpEF (42%); adjusted odds ratio for CAD in HFmrEF vs. HFpEF was 1.52 [95% confidence interval (CI) 1.41-1.63]. For six additional characteristics HFmrEF resembled HFrEF, for seven characteristics HFmrEF resembled HFpEF, and for 10 characteristics there was no pattern. The adjusted hazard ratio (HR) for mortality in HFrEF vs. HFpEF was 1.35 (95% CI 1.14-1.60) at 30 days, 1.26 (95% CI 1.17-1.35) at 1 year, and 1.20 (95% CI 1.14-1.26) at 3 years. In contrast, HFmrEF and HFpEF had a similar prognosis (HR 1.06, 95% CI 0.86-1.30 at 30 days; HR 1.08, 95% CI 1.00-1.18 at 1 year; and HR 1.06, 95% CI 1.00-1.12 at 3 years). Three-year mortality was higher in HFmrEF than in HFpEF in the presence of CAD (HR 1.11, 95% CI 1.02-1.21), but not in the absence of CAD (HR 1.02, 95% CI 0.94-1.12; P for interaction < 0.001).Conclusions: HFmrEF was an intermediate phenotype, except that CAD was more common in HFmrEF and HFrEF vs. HFpEF, crude all-cause mortality was lower in HFmrEF and HFrEF, adjusted all-cause mortality was lower in HFmrEF and HFpEF, and CAD portended a higher adjusted risk of death in HFmrEF and HFrEF.
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| 6. |
- Vedin, Ola, et al.
(författare)
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Significance of Ischemic Heart Disease in Patients with Heart Failure and Preserved, Midrange, and Reduced Ejection Fraction : A Nationwide Cohort Study
- 2017
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Ingår i: Circulation: Heart Failure. - : LIPPINCOTT WILLIAMS & WILKINS. - 1941-3289 .- 1941-3297. ; 10:6
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Tidskriftsartikel (refereegranskat)abstract
- Background - The pathogenic role of ischemic heart disease (IHD) in heart failure (HF) with reduced ejection fraction (HFrEF; EF <40%) is well established, but its pathogenic and prognostic significance in HF with midrange (HFmrEF; EF 40%-50%) and preserved EF (HFpEF; EF ≥50%) has been much less explored. Methods and Results - We evaluated 42 987 patients from the Swedish Heart Failure Registry with respect to baseline IHD, outcomes (IHD, HF, cardiovascular events, and all-cause death), and EF change during a median follow-up of 2.2 years. Overall, 23% had HFpEF (52% IHD), 21% had HFmrEF (61% IHD), and 55% had HFrEF (60% IHD). After multivariable adjustment, associations with baseline IHD were similar for HFmrEF and HFrEF and lower in HFpEF (risk ratio, 0.91 [0.89-0.93] versus HFmrEF and risk ratio, 0.90 [0.88-0.92] versus HFrEF). The adjusted risk of IHD events was similar for HFmrEF versus HFrEF and lower in HFpEF (hazard ratio, 0.89 [0.84-0.95] versus HFmrEF and hazard ratio, 0.84 [0.80-0.90] versus HFrEF). After adjustment, prevalent IHD was associated with increased risk of IHD events and all other outcomes in all EF categories except all-cause mortality in HFpEF. Those with IHD, particularly new IHD events, were also more likely to change to a lower EF category and less likely to change to a higher EF category over time. Conclusions - HFmrEF resembled HFrEF rather than HFpEF with regard to both a higher prevalence of IHD and a greater risk of new IHD events. Established IHD was an important prognostic factor across all HF types.
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