A. V. Smith

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47u2009180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10−9). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10−4). The strongest combined association was at rs1823125 (P=1.5 × 10−10, minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1u2009min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the ‘missing heritability’ of complex traits. Here, we describe four independent analyses in 33u2009781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug–gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug–single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10−8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

De novo post-diagnosis statin use, breast cancer-specific and overall mortality in women with stage I-III breast cancer.

Background:Prior evidence suggests a role for statins in the management of cancer. However, the benefit of statin use in the adjuvant setting remains uncertain. This study investigates associations between statin use initiated after a breast cancer diagnosis and mortality.Methods:Women with stage I–III breast cancer were identified from the National Cancer Registry of Ireland (N=4243). Post-diagnostic statin initiators were identified from pharmacy claims data (N=837). Multivariate models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between de novo statin use and mortality.Results:The median duration of statin use was 6.7 years. No association was found between post-diagnostic statin use and breast cancer-specific (HR 0.88, 95% CI 0.66, 1.17) or all-cause mortality (HR 1.00, 95% CI 0.82, 1.21).Conclusions:The results from our study suggest that initiating statin use after a diagnosis of stage I–III breast cancer is not associated with a reduction in breast cancer-specific mortality.

Patterns of statin initiation and continuation in patients with breast or colorectal cancer, towards end-of-life

PurposeCross-sectional studies show that statins, used in cardiovascular disease prevention, are often discontinued approaching death. Studies investigating associations between statin exposure and cancer outcomes, not accounting for these exposure changes, are prone to reverse causation bias. The aim of this study was to describe longitudinally the changes in statin initiation and continuation prior to death in patients with breast or colorectal cancer, thus establishing an appropriate exposure lag time.MethodsThis study was carried out using linked cancer registry and prescribing data. We identified patients who died of their cancer (cases) and cancer survivors were used as controls. The probability of initiating or continuing statin use was estimated up to 5xa0years prior to death (or index date). Conditional binomial models were used to estimate relative risks and risk differences for associations between approaching cancer death and statin use.ResultsCompared to controls, the probability of continued statin use in breast cancer cases was significantly lower 3xa0months prior to death (RR 0.86 95% CI 0.79, 0.94). Similarly, in colorectal cancer cases, the probability of continued statin use was significantly lower 3xa0months prior to colorectal cancer death (RR 0.77 95% CI 0.68, 0.88).ConclusionA significant proportion of patients will cease statin treatment in the months prior to a colorectal or breast cancer death.

Pre-diagnostic statin use, lymph node status and mortality in women with stages I–III breast cancer

Background:Recent meta-analyses suggest that pre-diagnostic statin use is associated with reduced breast cancer-specific mortality. Studies have shown that high breast tumour expression of the statin target (3-hydroxy-3-methylglutaryl coenzyme-A reductase) is associated with lymph-node negative cancer. Therefore, we examined the association between pre-diagnostic statin use and; lymph node status, breast cancer-specific and all-cause mortality.Methods:Women with stages I–III breast cancer were identified from the National Cancer Registry of Ireland (N=6314). Pre-diagnostic statin users were identified from linked prescription claims data (N=2082). Relative risks were estimated for associations between pre-diagnostic statin use and lymph node status. Hazard ratios (HR) were estimated for associations between pre-diagnostic statin use and breast cancer-specific and all-cause mortality.Results:Pre-diagnostic statin use was not associated with lymph node negative status at diagnosis. In multivariate analyses, pre-diagnostic statin use was associated with reduced all-cause (HR 0.78 95% confidence interval (CI) 0.69, 0.89) and breast cancer-specific mortality (HR 0.81 95% CI 0.68, 0.96). This reduction in cancer-specific mortality was greatest in statin-users with oestrogen (ER) receptor-positive tumours (HR 0.69 95% CI 0.55, 0.85).Conclusion:Patients with pre-diagnostic statin exposure had a significant reduction in breast cancer-specific mortality, which was even more pronounced in women with ER+ tumours.

End-of-life prescribing of aspirin in patients with breast or colorectal cancer

Objectives The aim of this study was to evaluate the influence of an approaching cancer death on end-of-life aspirin use, a frequently prescribed medication for cardiovascular disease prevention. Methods This study was conducted using linked cancer registry and prescribing data. Breast (n=1151) and colorectal (n=1859) cancer decedents were matched to cancer survivors and the probability of either initiating aspirin, or continuing established aspirin use, was estimated in consecutive periods over the 5u2009years approaching a cancer-specific death (decedents) or matched index date (survivors). Results Using the linked data sets, we identified patients who died of their cancer (decedents) between 1 January 2001 and 31 December 2009. In the 5u2009years prior to death, we compared (1) the probability of initiating aspirin use for the first time, and (2) the probability of continuing aspirin use. In comparison to matched cancer survivors, an approaching cancer death was not associated with a reduction in aspirin initiation by breast or colorectal cancer decedents. However, the probability of continuing established aspirin use declined considerably in the 24 months approaching death and at the time of a death was significantly lower for breast (risk difference (RD) −0.26, 95%u2009CI −0.33 to −0.20) and colorectal (RD −0.38, 95%u2009CI −0.46 to −0.30) cancer decedents versus matched survivors. Conclusion A significant proportion of patients discontinue their aspirin in the time approaching a breast or colorectal cancer-specific death. The safety and benefits of this are unclear and empirical data are needed to guide decisions about aspirin use in the end of life.

Associations between obesity, smoking and lymph node status at breast cancer diagnosis in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial

Introduction There is evidence suggesting that smoking and obesity prior to a breast cancer diagnosis is associated with poorer outcomes. In this study, we investigate the associations between smoking and obesity prior to a breast cancer diagnosis and the presence of lymph node metastases at diagnosis. Methods Women with stage I-III breast cancer (n = 3,304) were identified from the National Cancer Institute’s Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Univariable and multivariable log-binomial models were used to estimate relative risks (RR) and 95% confidence intervals (CIs) for associations between lymph node positive breast cancer and; i) smoking, and ii) obesity prior to diagnosis. Results Pre-diagnostic smoking/obesity was not associated with lymph node metastasis at diagnosis in multivariable analyses; (RR 0.82, 95%CI 0.61, 1.10) and (RR 0.95, 95% CI 0.81, 1.12), respectively. Conclusion Obesity and smoking information was recorded a number of years prior to breast cancer diagnosis, therefore these findings should to be replicated in a larger cohort of women, with more detailed smoking and obesity information.

Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults

Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all‐cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity‐independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta‐analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow‐up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (nu2009=u2009169,551; 0.32u2009kgu2009m−2; 95% CI 0.28–0.32, Pu2009<u20091u2009×u200910−32), WC (nu2009=u2009152,631; 0.76u2009cm; 0.68–0.84, Pu2009<u20091u2009×u200910−32) and FMI (nu2009=u200948,192; 0.17u2009kgu2009m−2; 0.13–0.22, Pu2009=u20091.0u2009×u200910−13). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00–1.04, Pu2009=u20090.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98–1.03, Pu2009=u20090.662) and for FMI (HR: 1.00; 0.96–1.04, Pu2009=u20090.932). In conclusion, this study does not support that the FTO SNP is associated with all‐cause mortality independently of the adiposity phenotypes.