Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia.

BACKGROUND: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis. METHODS: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines. RESULTS: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14, which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA]≥250). There was significant association between FGF14 (GAA)≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA)≥250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein. CONCLUSIONS: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.).

Genetic meta-analysis of cancer diagnosis following statin use identifies new associations and implicates human leukocyte antigen (HLA) in women.

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 (npooled = 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 × 10-8). Using the UK Biobank and focusing exclusively on women statin users with CAD (nfemale = 2952), rs13210472 remained significantly associated with incident cancer (HR: 1.71, 95% CI: 1.14-2.56, P = 9.0 × 10-3). 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.

rs73185306 C/T Is Not a Predisposing Risk Factor for Inherited Chromosomally Integrated Human Herpesvirus 6A/B.

Approximately 1% of people worldwide carry a copy of the human herpesvirus 6A or 6B (HHV-6A/B) in every cell of their body. This condition is referred to as inherited chromosomally integrated HHV-6A/B (iciHHV-6A/B). The mechanisms leading to iciHHV-6A/B chromosomal integration are yet to be identified. A recent report suggested that the rs73185306 C/T single-nucleotide polymorphism (SNP) represents a favorable predisposing factor leading to HHV-6A/B integration. After genotype analysis of an independent cohort (N = 11 967), we report no association between the rs73185306 C/T SNP and HHV-6A/B chromosomal integration (odds ratio, 0.90 [95% confidence interval, .54-1.51]; P = .69).

Lineage restriction analyses in CHIP indicate myeloid bias for TET2 and multipotent stem cell origin for DNMT3A.

We analyzed DNA from polymorphonuclear (PMN) cells, monocytes, B cells, and T cells of 107 individuals with clonal hematopoiesis of indeterminate potential (CHIP) to perform lineage restriction analysis of different gene mutations. Three lineage categories were defined: myeloid (PMN with or without monocytes), myelolympho-B (myeloid and B cells), and multipotent (myeloid, B and T cells). Six individuals with aberrant patterns were excluded from analysis. Ninety-four had a single mutation (56 in DNMT3A, 24 in TET2, 7 in other genes [JAK2, ASXL1, CBL or TP53]). Fourteen had multiple mutations. The lineage restriction patterns of single DNMT3A- or TET2-mutated individuals were different. The proportion of myeloid restricted mutations was higher for TET2 (54.2%, 13 of 24) than for DNMT3A (23.2%, 13 of 56) (P < .05). It was similar for myelolympho-B category but with a 1.5 fold greater proportion of myeloid cells for TET2 individuals (P < .05). Importantly, 0% (0 of 24) of the individuals with TET2 mutation in the multipotent category in contrast to 35.7% (20 of 56) for DNMT3A (P < .01). The clone size predicted multipotent pattern for DNMT3A suggesting a time delay for extensive lineage clonal dominance. These distinctive features may be important in deciphering the transformation mechanisms of these frequent mutations.

Nuclear receptor gene polymorphisms and warfarin dose requirements in the Quebec Warfarin Cohort.

Warfarin is primarily metabolized by cytochrome 2C9, encoded by gene CYP2C9. Here, we investigated whether variants in nuclear receptor genes which regulate the expression of CYP2C9 are associated with warfarin response. We used data from 906 warfarin users from the Quebec Warfarin Cohort (QWC) and tested the association of warfarin dose requirement at 3 months following the initiation of therapy in nine nuclear receptor genes: NR1I3, NR1I2, NR3C1, ESR1, GATA4, RXRA, VDR, CEBPA, and HNF4A. Three correlated SNPs in the VDR gene (rs4760658, rs11168292, and rs11168293) were associated with dose requirements of warfarin (P = 2.68 × 10-5, P = 5.81 × 10-4, and P = 5.94 × 10-4, respectively). Required doses of warfarin were the highest for homozygotes of the minor allele at the VDR variants (P < 0.0026). Variants in the VDR gene were associated with the variability in response to warfarin, emphasizing the possible clinical relevance of nuclear receptor gene variants on the inter-individual variability in drug metabolism.

DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions.

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.

Chronic disease prevention and management programs in primary care: Realist synthesis of 6 programs in Quebec.

OBJECTIVE: To identify the mechanisms associated with success and failure of chronic disease prevention and management (CDPM) programs, as well as their key contexts. DESIGN: Realist synthesis. SETTING: Six primary care CDPM programs funded between 2011 and 2013 in Quebec. PARTICIPANTS: Patients, health providers, program leaders, and other stakeholders involved in CDPM programs. METHODS: A collaborative research process was implemented, involving representatives from the executive and advisory committees: researchers, health care providers, decision makers, and patients and families. Leaders were asked to provide all documents related to their programs to the research team. The documents were selected depending on their relevance and rigour. The thematic analysis of each program consisted of identifying the outcomes and mechanisms, as well as the specific contexts associated with these outcomes. Results for each program were validated by its leader before synthesizing the results of all programs together. MAIN FINDINGS: A total of 108 documents (eg, grant applications, scientific reports) were collected from the programs. Positive and negative outcomes were observed at the patient, health care provider, and health care system levels. Four main mechanism categories were associated with outcomes: patient-centred interdisciplinary care; self-management support and a motivational approach; professional support; and care coordination and relationships with partners. The main contextual factors that influenced the successes of these mechanisms were related to patients (multimorbidity, involvement of family caregivers), to health care providers (professional training, culture of interprofessional collaboration, mobilization of family physician), and to health care organizations (coordination between services, history of collaboration between partners, funding). CONCLUSION: This study confirms the essential role of patient-centred interdisciplinary care; self-management support and a motivational approach; professional support; and care coordination and relationships with partners when caring for patients with chronic diseases. It constitutes a relevant contribution for stakeholders involved in primary care transformation and should be used to inform the sustainability and scaling up of CDPM programs.

Explaining time elapsed prior to cancer diagnosis: patients' perspectives.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

What can organizations do to improve family physicians' interprofessional collaboration? Results of a survey of primary care in Quebec.

OBJECTIVE: To assess the degree of collaboration in primary health care organizations between FPs and other health care professionals; and to identify organizational factors associated with such collaboration. DESIGN: Cross-sectional survey. SETTING: Primary health care organizations in the Montreal and Monteregie regions of Quebec. PARTICIPANTS: Physicians or administrative managers from 376 organizations. MAIN OUTCOME MEASURES: Degree of collaboration between FPs and other specialists and between FPs and nonphysician health professionals. RESULTS: Almost half (47.1%) of organizations reported a high degree of collaboration between FPs and other specialists, but a high degree of collaboration was considerably less common between FPs and nonphysician professionals (16.5%). Clinic collaboration with a hospital and having more patients with at least 1 chronic disease were associated with higher FP collaboration with other specialists. The proportion of patients with at least 1 chronic disease was the only factor associated with collaboration between FPs and nonphysician professionals. CONCLUSION: There is room for improvement regarding interprofessional collaboration in primary health care, especially between FPs and nonphysician professionals. Organizations that manage patients with more chronic diseases collaborate more with both non-FP specialists and nonphysician professionals.

Whole-genome sequencing in French Canadians from Quebec.

Genome-wide association studies (GWAS) have had a tremendous success in the identification of common DNA sequence variants associated with complex human diseases and traits. However, because of their design, GWAS are largely inappropriate to characterize the role of rare and low-frequency DNA variants on human phenotypic variation. Rarer genetic variation is geographically more restricted, supporting the need for local whole-genome sequencing (WGS) efforts to study these variants in specific populations. Here, we present the first large-scale low-pass WGS of the French-Canadian population. Specifically, we sequenced at ~5.6× coverage the whole genome of 1970 French Canadians recruited by the Montreal Heart Institute Biobank and identified 29 million bi-allelic variants (31 % novel), including 19 million variants with a minor allele frequency (MAF) <0.5 %. Genotypes from the WGS data are highly concordant with genotypes obtained by exome array on the same individuals (99.8 %), even when restricting this analysis to rare variants (MAF <0.5, 99.9 %) or heterozygous sites (98.9 %). To further validate our data set, we showed that we can effectively use it to replicate several genetic associations with myocardial infarction risk and blood lipid levels. Furthermore, we analyze the utility of our WGS data set to generate a French-Canadian-specific imputation reference panel and to infer population structure in the Province of Quebec. Our results illustrate the value of low-pass WGS to study the genetics of human diseases in the founder French-Canadian population.

Impact of regular physical activity on weekly warfarin dose requirement.

Warfarin is an oral anticoagulant agent with a narrow therapeutic index. There is a marked inter- and intra-patient variability in warfarin dose requirement. All factors influencing warfarin response are not known and this study aims to evaluate if regular physical activity (RPA) is a determining factor. RPA level was collected with the Stanford Brief Activity Survey in 1064 incident warfarin users, as part of the Quebec Warfarin Cohort (QWC), and with the Global Physical Activity Questionnaire in 618 patients from the Montreal Heart Institute (MHI) Biobank. Linear regression was performed to model relationship of warfarin dose after 3 months of therapy in the QWC with RPA, while controlling for height, weight, age, CYP2C9 (*2 and *3 alleles) and VKORC1 (*2 allele) genotype. Warfarin dose of prevalent users was modeled in the MHI Biobank for replication. A higher level of physical activity was associated with higher doses of warfarin in both cohorts. In the QWC, physical activity could explain 5.4 % (P < 0.001) and 0.9 % (P = 3.23 × 10(-5)) of variance in dose, in univariate and multivariable models, respectively. Similarly, RPA was found to be associated with 1.7 % (P = 0.0012) and 0.5 % (P = 0.0391) of inter-individual variability in warfarin dose requirement before and after adjustment for other covariables, respectively. RPA is associated with higher warfarin dose requirement. The relevance of clinical recommendations on RPA to maintain a steady response to warfarin should be assessed in further studies.

The impact of primary healthcare reform on equity of utilization of services in the province of Quebec: a 2003-2010 follow-up.

INTRODUCTION: In 2003, the Quebec government made important changes in its primary healthcare (PHC) system. This reform included the creation of new models of PHC, Family Medicine Groups (e.g. multidisciplinary health teams with extended opening hours and enrolment of patients) and Network Clinics (clinics providing access to investigation and specialist services). Considering that equity is one of the guiding principles of the Quebec health system, our objectives are to assess the impact of the PHC reform on equity by examining the association between socio-economic status (SES) and utilization of healthcare services between 2003 and 2010; and to determine how the organizational model of PHC facilities impacts utilization of services according to SES. METHODS: We held population surveys in 2005 (n = 9206) and 2010 (n = 9180) in the two most populated regions of Quebec province, relating to utilization and experience of care during the preceding two years, as well as organizational surveys of all PHC facilities. We performed multiple logistical regression analyses comparing levels of SES for different utilization variables, controlling for morbidity and perceived health; we repeated the analyses, this time including type of PHC facility (older vs newer models). RESULTS: Compared with the lowest SES, highest SES is associated with less emergency room visits (OR 0.80) and higher likelihood of at least one visit to a PHC facility (OR 2.17), but lower likelihood of frequent visits to PHC (OR 0.69), and higher affiliation to a family doctor (OR 2.04). Differences remained stable between the 2005 and 2010 samples except for likelihood of visit to PHC source which deteriorated for the lowest SES. Greater improvement in affiliation to family doctor was seen for the lowest SES in older models of PHC organizations, but a deterioration was seen for that same group in newer models. CONCLUSIONS: Differences favoring the rich in affiliation to family doctor and likelihood of visit to PHC facility likely represent inequities in access to PHC which remained stable or deteriorated after the reform. New models of PHC organizations do not appear to have improved equity. We believe that an equity-focused approach is needed in order to address persisting inequities.

[Are new forms of primary health care organization (PHLU) associated with a better health care experience for patients with chronic diseases in Quebec?]. / Les nouvelles formes d'organisations de soins de santé primaires (OSSP) sont-elles associées à une meilleure expérience de soins chez les patients atteints de maladies chroniques au Québec ?

AIM: To assess the extent to which new forms of PHC organization - Family medicine groups (FMG) and Network clinics (NC) - established in Quebec since 2003, are associated with a better experience of care than other forms of PHC organization, for patients with chronic diseases. METHODS: Two surveys were conducted in 2010 in two regions of Quebec: the first among 9,180 residents and the second among 606 PHC organizations. Indices of experience of care were constructed concerning accessibility, continuity, comprehensiveness and perceived outcomes. Five categories of chronic diseases were selected. Descriptive analyses and multilevel regression analyses were conducted to compare the different forms of PHC organization. RESULTS: Individuals with chronic diseases tend to report a better experience of care than those without chronic diseases for all dimensions except for accessibility. FMGs compare to group practices on all dimensions and NCs are associated with a poorer experience of care on most dimensions. CONCLUSION: Experience of care associated with FMGs and NCs is not superior to that associated with group practices.

Comparison of genotype clustering tools with rare variants.

BACKGROUND: Along with the improvement of high throughput sequencing technologies, the genetics community is showing marked interest for the rare variants/common diseases hypothesis. While sequencing can still be prohibitive for large studies, commercially available genotyping arrays targeting rare variants prove to be a reasonable alternative. A technical challenge of array based methods is the task of deriving genotype classes (homozygous or heterozygous) by clustering intensity data points. The performance of clustering tools for common polymorphisms is well established, while their performance when conducted with a large proportion of rare variants (where data points are sparse for genotypes containing the rare allele) is less known. We have compared the performance of four clustering tools (GenCall, GenoSNP, optiCall and zCall) for the genotyping of over 10,000 samples using the Illumina's HumanExome BeadChip, which includes 247,870 variants, 90% of which have a minor allele frequency below 5% in a population of European ancestry. Different reference parameters for GenCall and different initial parameters for GenoSNP were tested. Genotyping accuracy was assessed using data from the 1000 Genomes Project as a gold standard, and agreement between tools was measured. RESULTS: Concordance of GenoSNP's calls with the gold standard was below expectations and was increased by changing the tool's initial parameters. While the four tools provided concordance with the gold standard above 99% for common alleles, some of them performed poorly for rare alleles. The reproducibility of genotype calls for each tool was assessed using experimental duplicates which provided concordance rates above 99%. The inter-tool agreement of genotype calls was high for approximately 95% of variants. Most tools yielded similar error rates (approximately 0.02), except for zCall which performed better with a 0.00164 mean error rate. CONCLUSIONS: The GenoSNP clustering tool could not be run straight "out of the box" with the HumanExome BeadChip, as modification of hard coded parameters was necessary to achieve optimal performance. Overall, GenCall marginally outperformed the other tools for the HumanExome BeadChip. The use of experimental replicates provided a valuable quality control tool for genotyping projects with rare variants.

Modifiers of (CAG)(n) instability in Machado-Joseph disease (MJD/SCA3) transmissions: an association study with DNA replication, repair and recombination genes.

Twelve neurological disorders are caused by gene-specific CAG/CTG repeat expansions that are highly unstable upon transmission to offspring. This intergenerational repeat instability is clinically relevant since disease onset, progression and severity are associated with repeat size. Studies of model organisms revealed the involvement of some DNA replication and repair genes in the process of repeat instability, however, little is known about their role in patients. Here, we used an association study to search for genetic modifiers of (CAG)n instability in 137 parent-child transmissions in Machado-Joseph disease (MJD/SCA3). With the hypothesis that variants in genes involved in DNA replication, repair or recombination might alter the MJD CAG instability patterns, we screened 768 SNPs from 93 of these genes. We found a variant in ERCC6 (rs2228528) associated with an expansion bias of MJD alleles. When using a gene-gene interaction model, the allele combination G-A (rs4140804-rs2972388) of RPA3-CDK7 is also associated with MJD instability in a direction-dependent manner. Interestingly, the transcription-coupled repair factor ERCC6 (aka CSB), the single-strand binding protein RPA, and the CDK7 kinase part of the TFIIH transcription repair complex, have all been linked to transcription-coupled repair. This is the first study performed in patient samples to implicate specific modifiers of CAG instability in humans. In summary, we found variants in three transcription-coupled repair genes associated with the MJD mutation that points to distinct mechanisms of (CAG)n instability.

pyGenClean: efficient tool for genetic data clean up before association testing.

UNLABELLED: Genetic association studies making use of high-throughput genotyping arrays need to process large amounts of data in the order of millions of markers per experiment. The first step of any analysis with genotyping arrays is typically the conduct of a thorough data clean up and quality control to remove poor quality genotypes and generate metrics to inform and select individuals for downstream statistical analysis. We have developed pyGenClean, a bioinformatics tool to facilitate and standardize the genetic data clean up pipeline with genotyping array data. In conjunction with a source batch-queuing system, the tool minimizes data manipulation errors, accelerates the completion of the data clean up process and provides informative plots and metrics to guide decision making for statistical analysis. AVAILABILITY AND IMPLEMENTATION: pyGenClean is an open source Python 2.7 software and is freely available, along with documentation and examples, from http://www.statgen.org.

Impact of Québec's healthcare reforms on the organization of primary healthcare (PHC): a 2003-2010 follow-up.

BACKGROUND: Healthcare reforms initiated in the early 2000s in Québec involved the implementation of new modes of primary healthcare (PHC) delivery and the creation of Health and Social Services Centers (HSSCs) to support it. The objective of this article is to assess and explain the degree of PHC organizational change achieved following these reforms. METHODS: We conducted two surveys of PHC organizations, in 2005 and 2010, in two regions of the province of Québec, Canada. From the responses to these surveys, we derived a measure of organizational change based on an index of conformity to an ideal type (ICIT). One set of explanatory variables was contextual, related to coercive, normative and mimetic influences; the other consisted of organizational variables that measured receptivity towards new PHC models. Multilevel analyses were performed to examine the relationships between ICIT change in the post-reform period and the explanatory variables. RESULTS: Positive results were attained, as expressed by increase in the ICIT score in the post-reform period, mainly due to implementation of new types of PHC organizations (Family Medicine Groups and Network Clinics). Organizational receptivity was the main explanatory variable mediating the effect of coercive and mimetic influences. Normative influence was not a significant factor in explaining changes. CONCLUSION: Changes were modest at the system level but important with regard to new forms of PHC organizations. The top-down decreed reform was a determining factor in initiating change whereas local coercive and normative influences did not play a major role. The exemplar role played by certain PHC organizations through mimetic influence was more important. Receptivity of individual organizations was both a necessary condition and a mediating factor in influencing change. This supports the view that a combination of top-down and bottom-up strategy is best suited for achieving substantial changes in PHC local organization.

A Genome-Wide Association Study of Oxypurinol Concentrations in Patients Treated with Allopurinol.

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.

Interplay between hereditary and acquired factors determines the neutrophil counts in older individuals.

Blood cell production is a complex process, partly genetically determined and influenced by acquired factors. However, there is a paucity of data on how these factors interplay in the context of aging, which is associated with a myeloid proliferation bias, clonal hematopoiesis (CH), and an increased incidence of myeloid cancers. We investigated hereditary and acquired factors underlying blood cell trait variability in a cohort of 2996 related and unrelated women from Quebec aged from 55 to 101 years. We performed a genome-wide association study, evaluated the impact of chronic diseases, and performed targeted deep sequencing of CH driver genes and X-chromosome inactivation (XCI)-based clonality analyses. Multivariable analyses were conducted using generalized linear mixed models. We document that aging is associated with increasing neutrophil and monocyte counts and decreasing lymphocyte counts. Neutrophil counts were influenced by the variants in the region of GSDMA and PSMD3-CSF3, but this association decreased with age; in parallel, older individuals with cardiometabolic comorbidities exhibited significantly higher neutrophil counts (4.1 × 109/L vs 3.83 × 109/L; P < .001) than younger individuals. These age-related diseases were also associated with an increase in other myeloid-derived cells. Neither CH nor XCI clonality correlated with neutrophil counts. In conclusion, we show that neutrophil counts are genetically influenced, but as individuals age, this contribution decreases in favor of acquired factors. Aging is associated with a myeloid proliferation bias which is greater in the presence of cardiometabolic comorbidities but not of CH. These findings support that cell-extrinsic factors may contribute to the myeloid shift possibly through low-grade inflammation.

Pharmacogenomic markers of metoprolol and α-OH-metoprolol concentrations: a genome-wide association study.

Aim: Few genome-wide association studies (GWASs) have been conducted to identify predictors of drug concentrations. The authors therefore sought to discover the pharmacogenomic markers involved in metoprolol pharmacokinetics. Patients & methods: The authors performed a GWAS of a cross-sectional study of 993 patients from the Montreal Heart Institute Biobank taking metoprolol. Results: A total of 391 and 444 SNPs reached the significance threshold of 5 × 10-8 for metoprolol and α-OH-metoprolol concentrations, respectively. All were located on chromosome 22 at or near the CYP2D6 gene, encoding CYP450 2D6, metoprolol's main metabolizing enzyme. Conclusion: The results reinforce previous findings of the importance of the CYP2D6 locus for metoprolol concentrations and confirm that large biobanks can be used to identify genetic determinants of drug pharmacokinetics at a GWAS significance level.