Age-associated clonal hematopoiesis caused by acquired mutations in myeloid cancer–associated genes is highly prevalent in the normal population. Its etiology, biological impact on hematopoiesis, and ...oncogenic risk is poorly defined at this time. To gain insight into this phenomenon, we analyzed a cohort of 2530 related and unrelated hematologically normal individuals (ages 55 to 101 years). We used a sensitive gene-targeted deep sequencing approach to gain precision on the exact prevalence of driver mutations and the proportions of affected genes. Mutational status was correlated with biological parameters. We report a higher overall prevalence of driver mutations (13.7%), which occurred mostly (93%) in DNMT3A or TET2 and were highly age-correlated. Mutation in these 2 genes had some distinctive effects on end points. TET2 mutations were more age-dependent, associated with a modest neutropenic effect (9%, P = .012), demonstrated familial aggregation, and associated with chronic obstructive pulmonary disease. Mutations in DNMT3A had no impact on blood counts or indices. Mutational burden of both genes correlated with X-inactivation skewing but no significant association with age-adjusted telomere length reduction was documented. The discordance between the high prevalence of mutations in these 2 genes and their limited biological impact raise the question of the potential role of dysregulated epigenetic modifiers in normal aging hematopoiesis, which may include support to failing hematopoiesis.
•Somatic mutations driving clonal hematopoiesis occur mainly in DNMT3A and TET2 and have no significant impact on hematological phenotypes.•There is a familial predisposition to acquire TET2 mutation.
Naturally occurring human genetic variants provide a valuable tool to identify drug targets and guide drug prioritization and clinical trial design. Ivabradine is a heart rate lowering drug with ...protective effects on heart failure despite increasing the risk of atrial fibrillation. In patients with coronary artery disease without heart failure, the drug does not protect against major cardiovascular adverse events prompting questions about the ability of genetics to have predicted those effects. This study evaluates the effect of a variant in HCN4, ivabradine's drug target, on safety and efficacy endpoints.
We used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes.
Using data from the UK Biobank and large GWAS consortia, we evaluated the effect of a heart rate-reducing genetic variant at the HCN4 locus encoding ivabradine's drug target. These genetic association analyses showed increases in risk for atrial fibrillation (OR 1.09, 95% CI: 1.06-1.13, P = 9.3 ×10-9) in the UK Biobank. In a cause-specific competing risk model to account for the increased risk of atrial fibrillation, the HCN4 variant reduced incident heart failure in participants that did not develop atrial fibrillation (HR 0.90, 95% CI: 0.83-0.98, P = 0.013). In contrast, the same heart rate reducing HCN4 variant did not prevent a composite endpoint of myocardial infarction or cardiovascular death (OR 0.99, 95% CI: 0.93-1.04, P = 0.61).
Genetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.
Cancer is the leading cause of death in Canada. Early cancer diagnosis could improve patients' prognosis and quality of life. This study aimed to analyze the factors influencing elapsed time between ...the first help-seeking trigger and cancer diagnosis with respect to the three most common and deadliest cancer types: lung, breast, and colorectal.
This paper presents the qualitative component of a larger project based on a sequential explanatory design. Twenty-two patients diagnosed were interviewed, between 2011 to 2013, in oncology clinics of four hospitals in the two most populous regions in Quebec (Canada). Transcripts were analyzed using the Model of Pathways to Treatment.
Pre-diagnosis elapsed time and phases are difficult to appraise precisely and vary according to cancer sites and symptoms specificity. This observation makes the Model of Pathways to Treatment challenging to use to analyze patients' experiences. Analyses identified factors contributing to elapsed time that are linked to type of cancer, to patients, and to health system organization.
This research allowed us to identify avenues for reducing the intervals between first symptoms and cancer diagnosis. The existence of inequities in access to diagnostic services, even in a universal healthcare system, was highlighted.
We sought to perform a genomic evaluation of the risk of incident cancer in statin users, free of cancer at study entry. Patients who previously participated in two phase IV trials (TNT and IDEAL) ...with genetic data were used (n
= 11,196). A GWAS meta-analysis using Cox modeling for the prediction of incident cancer was conducted in the pooled cohort and sex-stratified. rs13210472 (near HLA-DOA gene) was associated with higher risk of incident cancer amongst women with prevalent coronary artery disease (CAD) taking statins (hazard ratio HR: 2.66, 95% confidence interval CI: 1.88-3.76, P = 3.5 × 10
). Using the UK Biobank and focusing exclusively on women statin users with CAD (n
= 2952), rs13210472 remained significantly associated with incident cancer (HR: 1.71, 95% CI: 1.14-2.56, P = 9.0 × 10
). The association was not observed in non-statin users. In this genetic meta-analysis, we have identified a variant in women statin users with prevalent CAD that was associated with incident cancer, possibly implicating the human leukocyte antigen pathway.
Abstract
We conducted a genome-wide association study of time to remission of COVID-19 symptoms in 1723 outpatients with at least one risk factor for disease severity from the COLCORONA clinical ...trial. We found a significant association at 5p13.3 (rs1173773;
P
= 4.94 × 10
–8
) near the natriuretic peptide receptor 3 gene (
NPR3
). By day 15 of the study, 44%, 54% and 59% of participants with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. In 851 participants not treated with colchicine (placebo), there was a significant association at 9q33.1 (rs62575331;
P
= 2.95 × 10
–8
) in interaction with colchicine (
P
= 1.19 × 10
–5
) without impact on risk of hospitalisations, highlighting a possibly shared mechanistic pathway. By day 15 of the study, 46%, 62% and 64% of those with 0, 1, or 2 copies of the effect allele respectively, had symptom remission. The findings need to be replicated and could contribute to the biological understanding of COVID-19 symptom remission.
In the Western world, between 1940 and 1970, more than 2 million people were exposed in utero to diethylstilbestrol (DES). In exposed individuals, and in their descendants, adverse outcomes have been ...linked to such exposure, including cancers, genital malformations, and less consistently, psychiatric disorders. We aimed to explore whether prenatal DES exposure would be associated with DNA methylation changes, and whether these epigenetic modifications would be associated with increased risk of psychosis.
From 247 individuals born from mothers exposed to DES, we selected 69 siblings from 30 families. In each family, at least one sibling was exposed in utero to DES. We performed a methylome-wide association study using HumanMethylation450 DNA Analysis BeadChip® in peripheral blood. We analyzed methylation changes at individual CpGs or regions in exposed (n = 37) versus unexposed individuals (n = 32). We also compared exposed individuals with (n = 7) and without psychosis (n = 30).
There were more individuals with schizophrenia in the DES-exposed group. We found no significant differences between exposed and unexposed individuals with respect to differentially methylated CpGs or regions. The largest difference was in a region near the promoter of an ADAMTS proteoglycanase gene (ADAMTS9). Compared to exposed individuals without psychosis, exposed individuals with psychosis had differential methylation in the region encompassing the gene encoding the zinc finger protein 57 (ZFP57).
In utero exposure to DES was not associated with methylation changes at specific CpG or regions. In exposed individuals, however, psychosis was associated with specific methylomic modifications that could impact neurodevelopment and neuroplasticity.
Nonrandom X-chromosome inactivation (XCI), also known as skewing, has been documented in the blood cells of a significant proportion of normal aging women by the use of methylation-based assays at ...the polymorphic human androgen receptor locus (HUMARA). Recent data obtained with a new transcription-based XCI determination method, termed suppressive polymerase chain reaction (PCR), has shed controversy over the validity of XCI ratio results obtained with HUMARA. To resolve this disparity, we analyzed XCI in polymorphonuclear leukocytes of a large cohort of women aged 43 to 100 years with the use of HUMARA (n = 100), a TaqMan single nucleotide polymorphism (SNP) assay (n = 90), and the suppressive polymerase chain reaction (PCR) assay (n = 67). The 3 methods yielded similar skewing incidences (42%, 38%, and 40%, respectively), and highly concordant XCI ratios. This confirms that the skewing of XCI ratio seen in blood cells of aging women is a bona fide and robust biologic phenomenon.
Schnyder crystalline corneal dystrophy (SCCD, MIM 121800) is a rare autosomal dominant disease characterized by progressive opacification of the cornea resulting from the local accumulation of ...lipids, and associated in some cases with systemic dyslipidemia. Although previous studies of the genetics of SCCD have localized the defective gene to a 1.58 Mbp interval on chromosome 1p, exhaustive sequencing of positional candidate genes has thus far failed to reveal causal mutations. We have ascertained a large multigenerational family in Nova Scotia affected with SCCD in which we have confirmed linkage to the same general area of chromosome 1. Intensive fine mapping in our family revealed a 1.3 Mbp candidate interval overlapping that previously reported. Sequencing of genes in our interval led to the identification of five putative causal mutations in gene UBIAD1, in our family as well as in four other small families of various geographic origins. UBIAD1 encodes a potential prenyltransferase, and is reported to interact physically with apolipoprotein E. UBIAD1 may play a direct role in intracellular cholesterol biochemistry, or may prenylate other proteins regulating cholesterol transport and storage.
Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to ...identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10−8). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy.
In 2011, the Agence de la santé et des services sociaux de Montréal (ASSSM), in partnership with the region's Centres de santé et de services sociaux (CSSS), coordinated the implementation of a ...program on cardiometabolic risk based on the Chronic Care Model. The program, intended for patients suffering from diabetes or hypertension, involved a series of individual follow-up appointments, group classes and exercise sessions. Our study assesses the impact on patient health outcomes of variations in the implementation of some aspects of the program among the six CSSSs taking part in the study.
The evaluation was carried out using a quasi-experimental "before and after" design. Implementation variables were constructed based on data collected during the implementation analysis regarding resources, compliance with the clinical process set out in the regional program, the program experience and internal coordination within the care team. Differences in differences using propensity scores were calculated for HbA1c results, achieving the blood pressure (BP) target, and two lifestyle targets (exercise level and carbohydrate distribution) at the 6- and 12-month follow-ups, based on greater or lesser patient exposure to the implementation of various aspects of the program under study.
The results focus on 1185 patients for whom we had data at the 6-month follow- up and the 992 patients from the 12-month follow-up. The difference in differences analysis shows no clear association between the extent of implementation of the various aspects of the program under study and patient health outcomes.
The program produces effects on selected health indicators independent of variations in program implementation among the CSSSs taking part in the study. The results suggest that the effects of this type of program are more highly dependent on the delivery of interventions to patients than on the organizational aspects of its implementation.
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