Minerva Elements Records
Permanent URI for this collection
Search Results
1 - 10 of 92
-
ItemDNA methylation-based biological aging and cancer risk and survival: Pooled analysis of seven prospective studies(WILEY, 2018-04-15)The association between aging and cancer is complex. Recent studies have developed measures of biological aging based on DNA methylation and called them "age acceleration." We aimed to assess the associations of age acceleration with risk of and survival from seven common cancers. Seven case-control studies of DNA methylation and colorectal, gastric, kidney, lung, prostate and urothelial cancer and B-cell lymphoma nested in the Melbourne Collaborative Cohort Study were conducted. Cancer cases, vital status and cause of death were ascertained through linkage with cancer and death registries. Conditional logistic regression and Cox models were used to estimate odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals (CI) for associations of five age acceleration measures derived from the Human Methylation 450 K Beadchip assay with cancer risk (N = 3,216 cases) and survival (N = 1,726 deaths), respectively. Epigenetic aging was associated with increased cancer risk, ranging from 4% to 9% per five-year age acceleration for the 5 measures considered. Heterogeneity by study was observed, with stronger associations for risk of kidney cancer and B-cell lymphoma. An associated increased risk of death following cancer diagnosis ranged from 2% to 6% per five-year age acceleration, with no evidence of heterogeneity by cancer site. Cancer risk and mortality were increased by 15-30% for the fourth versus first quartile of age acceleration. DNA methylation-based measures of biological aging are associated with increased cancer risk and shorter cancer survival, independently of major health risk factors.
-
Item
-
ItemMaternal educational inequalities in measured body mass index trajectories in three European countries(WILEY, 2019-05)BACKGROUND: Social inequalities in the prevalence of childhood overweight and obesity are well-established, but less is known about when the social gradient first emerges and how it evolves across childhood and adolescence. OBJECTIVE: This study examines maternal education differentials in children's body mass trajectories in infancy, childhood and adolescence using data from four contemporary European child cohorts. METHODS: Prospective data on children's body mass index (BMI) were obtained from four cohort studies-Generation XXI (G21-Portugal), Growing Up in Ireland (GUI) infant and child cohorts, and the Millennium Cohort Study (MCS-UK)-involving a total sample of 41,399 children and 120,140 observations. Children's BMI trajectories were modelled by maternal education level using mixed-effect models. RESULTS: Maternal educational inequalities in children's BMI were evident as early as three years of age. Children from lower maternal educational backgrounds were characterised by accelerated BMI growth, and the extent of the disparity was such that boys from primary-educated backgrounds measured 0.42 kg/m2 (95% CI 0.24, 0.60) heavier at 7 years of age in G21, 0.90 kg/m2 (95% CI 0.60, 1.19) heavier at 13 years of age in GUI and 0.75 kg/m2 (95% CI 0.52, 0.97) heavier in MCS at 14 years of age. The corresponding figures for girls were 0.71 kg/m2 (95% CI 0.50, 0.91), 1.31 kg/m2 (95% CI 1.00, 1.62) and 0.76 kg/m2 (95% CI 0.53, 1.00) in G21, GUI and MCS, respectively. CONCLUSIONS: Maternal education is a strong predictor of BMI across European nations. Socio-economic differentials emerge early and widen across childhood, highlighting the need for early intervention.
-
ItemGenome-wide association study of peripheral blood DNA methylation and conventional mammographic density measures(WILEY, 2019-10-01)Age- and body mass index (BMI)-adjusted mammographic density is one of the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie inter-individual variation in mammographic density. We aimed to investigate the association between breast cancer risk-predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, nondense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed-effect meta-analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome-wide significant (p < 10-7 ) association for any mammographic density measure from the meta-analysis, or from the cohort-specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all p > 0.05/299 = 1.7 × 10-4 ). In summary, our study did not find evidence for associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk.
-
ItemIs high vitamin B12 status a cause of lung cancer?(WILEY, 2019-09-15)Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [ORlog2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [ORSD ] = 1.08, 95%CI = 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer.
-
ItemHeritable methylation marks associated with breast and prostate cancer risk(WILEY, 2018-09-15)BACKGROUND: DNA methylation can mimic the effects of germline mutations in cancer predisposition genes. Recently, we identified twenty-four heritable methylation marks associated with breast cancer risk. As breast and prostate cancer share genetic risk factors, including rare, high-risk mutations (eg, in BRCA2), we hypothesized that some of these heritable methylation marks might also be associated with the risk of prostate cancer. METHODS: We studied 869 incident prostate cancers (430 aggressive and 439 non-aggressive) and 869 matched controls nested within a prospective cohort study. DNA methylation was measured in pre-diagnostic blood samples using the Illumina Infinium HM450K BeadChip. Conditional logistic regression models, adjusted for prostate cancer risk factors and blood cell composition, were used to estimate odds ratios and 95% confidence intervals for the association between the 24 methylation marks and the risk of prostate cancer. RESULTS: Five methylation marks within the VTRNA2-1 promoter region (cg06536614, cg00124993, cg26328633, cg25340688, and cg26896946), and one in the body of CLGN (cg22901919) were associated with the risk of prostate cancer. In stratified analyses, the five VTRNA2-1 marks were associated with the risk of aggressive prostate cancer. CONCLUSIONS: This work highlights a potentially important new area of investigation for prostate cancer susceptibility and adds to our knowledge about shared risk factors for breast and prostate cancer.
-
ItemImpaired functional vitamin B6 status is associated with increased risk of lung cancer(WILEY, 2018-06-15)Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR4thvs.1st ) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status.
-
ItemSocioeconomic position, lifestyle habits and biomarkers of epigenetic aging: a multi-cohort analysis(IMPACT JOURNALS LLC, 2019-04-15)Differences in health status by socioeconomic position (SEP) tend to be more evident at older ages, suggesting the involvement of a biological mechanism responsive to the accumulation of deleterious exposures across the lifespan. DNA methylation (DNAm) has been proposed as a biomarker of biological aging that conserves memory of endogenous and exogenous stress during life.We examined the association of education level, as an indicator of SEP, and lifestyle-related variables with four biomarkers of age-dependent DNAm dysregulation: the total number of stochastic epigenetic mutations (SEMs) and three epigenetic clocks (Horvath, Hannum and Levine), in 18 cohorts spanning 12 countries.The four biological aging biomarkers were associated with education and different sets of risk factors independently, and the magnitude of the effects differed depending on the biomarker and the predictor. On average, the effect of low education on epigenetic aging was comparable with those of other lifestyle-related risk factors (obesity, alcohol intake), with the exception of smoking, which had a significantly stronger effect.Our study shows that low education is an independent predictor of accelerated biological (epigenetic) aging and that epigenetic clocks appear to be good candidates for disentangling the biological pathways underlying social inequalities in healthy aging and longevity.
-
ItemHOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG)(SPRINGER, 2013-01)Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.
-
ItemIdentification of a novel prostate cancer susceptibility variant in the KLK3 gene transcript(SPRINGER, 2011-06)Genome-wide association studies (GWAS) have identified more than 30 prostate cancer (PrCa) susceptibility loci. One of these (rs2735839) is located close to a plausible candidate susceptibility gene, KLK3, which encodes prostate-specific antigen (PSA). PSA is widely used as a biomarker for PrCa detection and disease monitoring. To refine the association between PrCa and variants in this region, we used genotyping data from a two-stage GWAS using samples from the UK and Australia, and the Cancer Genetic Markers of Susceptibility (CGEMS) study. Genotypes were imputed for 197 and 312 single nucleotide polymorphisms (SNPs) from HapMap2 and the 1000 Genome Project, respectively. The most significant association with PrCa was with a previously unidentified SNP, rs17632542 (combined P = 3.9 × 10(-22)). This association was confirmed by direct genotyping in three stages of the UK/Australian GWAS, involving 10,405 cases and 10,681 controls (combined P = 1.9 × 10(-34)). rs17632542 is also shown to be associated with PSA levels and it is a non-synonymous coding SNP (Ile179Thr) in KLK3. Using molecular dynamic simulation, we showed evidence that this variant has the potential to introduce alterations in the protein or affect RNA splicing. We propose that rs17632542 may directly influence PrCa risk.