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- Seyed Khoei, Nazlisadat, et al.
(författare)
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Circulating bilirubin levels and risk of colorectal cancer : serological and Mendelian randomization analyses
- 2020
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Ingår i: BMC Medicine. - : Springer Nature. - 1741-7015. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.METHODS: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.RESULTS: The associations between circulating UCB levels and CRC risk differed by sex (Pheterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (Pheterogeneity ≥ 0.2).CONCLUSIONS: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.
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| 2. |
- Murphy, Neil, et al.
(författare)
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Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1300-1312.e20
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.Methods: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls])Results: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05–1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03–1.12; P = 3.3 × 10–4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06–1.18; P = 4.2 × 10–5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.Conclusions: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.
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| 3. |
- Bosse, Yohan, et al.
(författare)
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Transcriptome-wide association study reveals candidate causal genes for lung cancer
- 2020
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:7, s. 1862-1878
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Tidskriftsartikel (refereegranskat)abstract
- We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large‐scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome‐wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never‐ and ever‐smokers). We performed replication analysis using lung data from the Genotype‐Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever‐smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E−99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E−6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3‐adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E−5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.
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| 4. |
- Ji, Xuemei, et al.
(författare)
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Protein-altering germline mutations implicate novel genes related to lung cancer development
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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| 5. |
- Prats-Uribe, Albert, et al.
(författare)
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High-density lipoprotein characteristics and coronary artery disease : a Mendelian randomization study
- 2020
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Ingår i: Metabolism. - : W B SAUNDERS CO-ELSEVIER INC. - 0026-0495 .- 1532-8600. ; 112
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Tidskriftsartikel (refereegranskat)abstract
- Background: To assess whether genetically determined quantitative and qualitative HDL characteristics were independently associated with coronary artery disease (CAD). Methods: We designed a two-sample multivariate Mendelian randomization study with available genome-wide association summary data. We identified genetic variants associated with HDL cholesterol and apolipoprotein A-I levels, HDL size, particle levels, and lipid content to define our genetic instrumental variables in one sample (Kettunen et al. study, n = 24,925) and analyzed their association with CAD risk in a different study (CARDloGRAMplusC4D, n = 184,305). We validated these results by defining our genetic variables in another database (METSINI, n = 8372) and studied their relationship with CAD in the CARDloGRAMplusC4D dataset. To estimate the effect size of the associations of interest adjusted for other lipoprotein traits and minimize potential pleiotropy, we used the Multi-trait-based Conditional & Joint analysis. Results: Genetically determined HDL cholesterol and apolipoprotein A-I levels were not associated with CAD. HDL mean diameter (beta = 027 [95%CI = 0.19; 0.35]), cholesterol levels in very large HDLs (beta = 0.29 (95%CI = 0.17; 0.40]), and triglyceride content in very large HDIs (beta = 0.14 [95%CI = 0.040; 025]) were directly associated with CAD risk, whereas the cholesterol content in medium-sized HDLs (beta = -0.076 [95%CI = -0.10; -0.052]) was inversely related to this risk. These results were validated in the METSIM-CARDloGRAMplu5C4D data. Conclusions: Some qualitative HDL characteristics (related to size, particle distribution, and cholesterol and triglyceride content) are related to CAD risk while HDL cholesterol levels are not. (C) 2020 Elsevier Inc. All rights reserved.
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