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Background: Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared with the general population. We sought to evaluate the impact of mosaic chromosomal alterations (mCA) on death of CVD causes, coronary artery disease (CAD) causes, and of any cause in patients with a cancer diagnosis. Methods: The study was a prospective cohort analysis of 48,919 UK Biobank participants with a cancer diagnosis. mCAs were characterized using DNA genotyping array intensity data and long-range chromosomal phase inference. Multivariable Cox regression models were used to ascertain the associations of mCAs. Exploratory endpoints included various incident cardiovascular phenotypes. Results: Overall, 10,070 individuals (20.6%) carried ≥ 1 mCA clone. In adjusted analyses, mCA was associated with an increased risk of death of CAD causes [HR, 1.37; 95% confidence interval (CI), 1.09–1.71; P = 0.006]. In sub-analyses, we found that carriers of mCAs diagnosed with kidney cancer had an increased risk of death of CVD causes (HR, 2.03; 95% CI, 1.11–3.72; P = 0.022) and CAD causes (HR, 3.57; 95% CI, 1.44–8.84; P = 0.006). Women diagnosed with breast cancer who carried a mCA also had a higher risk of death of CAD causes (HR, 2.46; 95% CI, 1.23–4.92; P = 0.011). Conclusions: Among cancer survivors, carriers of any mCA are at an increased risk of CAD death compared with noncarriers. Mechanistic studies should be considered to better ascertain the biological mechanisms underneath the observed associations between mCAs and cardiovascular events for specific cancer types. Impact: There may be clinical relevance in considering mCAs in patients diagnosed with cancer and undergoing treatment.

Congenital amusia is a lifelong disorder that compromises the normal development of musical abilities in 1.5-4% of the general population. There is a substantial genetic contribution to congenital amusia, and it bears similarities to neurodevelopmental disorders of language. Here, we examine the extent to which variants in the forkhead box P2 gene (FOXP2)-the first gene to be identified as causal in developmental speech deficits-are associated with the amusic trait. Using a cohort of 49 individuals with amusia, of which 27 were unrelated, the role of FOXP2 variants in amusia was evaluated. Fourteen variants were examined in the cohort. None segregated with the amusic trait among participants for whom family information was available; nor were they predicted to be deleterious to protein function. Thus, variants in FOXP2 are not likely to cause amusia. Implications for ongoing debates about the distinction between musicality and language are discussed.

Supplementary Figure 2: Visual mapping of mosaic chromosomal alterations

Supplementary Table 6: Cox regression analyses evaluating the effect of mosaic chromosomal alterations on the risk of death of cardiovascular disease causes, coronary artery disease causes, from cancer, and any cause of death by chemotherapy status

Supplementary Table 1: Primary diagnostic codes for selected cancers

Supplementary Table 7: The effect of autosomal mosaic chromosomal alterations on death of cardiovascular disease causes, coronary artery disease causes, from cancer and any cause of death

Background:Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared with the general population. We sought to evaluate the impact of mosaic chromosomal alterations (mCA) on death of CVD causes, coronary artery disease (CAD) causes, and of any cause in patients with a cancer diagnosis.Methods:The study was a prospective cohort analysis of 48,919 UK Biobank participants with a cancer diagnosis. mCAs were characterized using DNA genotyping array intensity data and long-range chromosomal phase inference. Multivariable Cox regression models were used to ascertain the associations of mCAs. Exploratory endpoints included various incident cardiovascular phenotypes.Results:Overall, 10,070 individuals (20.6%) carried ≥ 1 mCA clone. In adjusted analyses, mCA was associated with an increased risk of death of CAD causes [HR, 1.37; 95% confidence interval (CI), 1.09–1.71; P = 0.006]. In sub-analyses, we found that carriers of mCAs diagnosed with kidney cancer had an increased risk of death of CVD causes (HR, 2.03; 95% CI, 1.11–3.72; P = 0.022) and CAD causes (HR, 3.57; 95% CI, 1.44–8.84; P = 0.006). Women diagnosed with breast cancer who carried a mCA also had a higher risk of death of CAD causes (HR, 2.46; 95% CI, 1.23–4.92; P = 0.011).Conclusions:Among cancer survivors, carriers of any mCA are at an increased risk of CAD death compared with noncarriers. Mechanistic studies should be considered to better ascertain the biological mechanisms underneath the observed associations between mCAs and cardiovascular events for specific cancer types.Impact:There may be clinical relevance in considering mCAs in patients diagnosed with cancer and undergoing treatment.

Supplementary Table 5: Cox regression analyses evaluating the effect of mosaic chromosomal alterations on the risk of death of cardiovascular disease causes, coronary artery disease causes, from cancer, and any cause of death stratified by smoking status groups

Supplementary Table 9: The effect of mosaic loss of Y chromosome on death of cardiovascular disease causes, coronary artery disease causes, from cancer and any cause of death

Supplementary Table 8: The effect of mosaic loss of X chromosome on death of cardiovascular disease causes, coronary artery disease causes, from cancer, and any cause of death

Supplementary Table 3: Sensitivity analyses by Cox regression considering additional covariates

Supplementary Figure 1: Visual depiction of the proportion of patients with at least 1 mosaic chromosomal alteration

Supplementary Table 4: Multivariable competing-risks regression model for the prediction of death of CVD causes and CAD causes

Supplementary Table 2: ICD-9 and ICD-10 diagnostic and procedure codes for inpatient cardiovascular-related endpoints and for the primary endpoints

Cancer survivors are at an increased risk of cardiovascular disease (CVD) compared to the general population. Here, we evaluated the impact of somatic mosaic chromosomal alterations (mCAs) on death of CVD causes, coronary artery disease (CAD) causes, from cancer, and of any cause in patients with a cancer diagnosis within the UK Biobank (n=48 919). mCAs were derived from DNA genotyping array intensity data and long-range chromosomal phase inference from participants. Overall, 10 070 individuals (20.6%) carried ≥1 mCA clone. In adjusted analyses, mCA was associated with an increased risk of death of CAD causes (hazard ratio [HR]: 1.37, 95% confidence interval [CI]: 1.09-1.71, P=0.006), from cancer (HR: 1.06, 95% CI: 1.00-1.11, P=0.041), and death of any cause (HR: 1.07, 95% CI: 1.02-1.12, P=0.005). Among cancer survivors, carriers of any mCA are at an increased risk of death of CAD causes and of any cause as compared to non-carriers.

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.

Genetic variants in drug targets can be used to predict the effect of drugs. Here, we extend this principle to assess how sex and body mass index may modify the effect of a genetically predicted lower CETP levels on biomarkers and cardiovascular outcomes. We found sex and BMI to be modifiers of the association between genetically predicted lower CETP and lipid biomarkers in UK Biobank participants. Female sex and lower BMI were associated with higher HDL-cholesterol and lower LDL-cholesterol for a same genetically predicted reduction in CETP concentration. We found that sex also modulated the effect of genetically lower CETP on cholesterol efflux capacity in samples from the Montreal Heart Institute Biobank. However, these modifying effects did not extend to sex-differences in cardiovascular outcomes in our data. Our results provide insight on the clinical effects of CETP inhibitors in the presence of effect modification based on observational genetic data. The approach can support precision medicine applications and help assess the external validity of clinical trials.

Genetic variants in drug targets can be used to predict the effect of drugs. Here, we extend this principle to assess how sex and body mass index may modify the effect of a genetically predicted lower CETP levels on biomarkers and cardiovascular outcomes.We found sex and BMI to be modifiers of the association between genetically predicted lower CETP and lipid biomarkers in UK Biobank participants. Female sex and lower BMI were associated with higher HDL-cholesterol and lower LDL-cholesterol for a same genetically predicted reduction in CETP concentration. We found that sex also modulated the effect of genetically lower CETP on cholesterol efflux capacity in samples from the Montreal Heart Institute Biobank. However, these modifying effects did not extend to sex-differences in cardiovascular outcomes in our data.Our results provide insight on the clinical effects of CETP inhibitors in the presence of effect modification based on observational genetic data. The approach can support precision medicine applications and help assess the external validity of clinical trials.

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

Structured AbstractMotivationThe relationship between protein coding genes and phenotypes has the potential to inform on the underlying molecular function in disease etiology. We conducted a phenome-wide association study (pheWAS) of protein coding genes using a principal components analysis-based approach in the UK Biobank.ResultsWe tested the association between 19,114 protein coding gene regions and 1,210 phenotypes including anthropometric measurements, laboratory biomarkers, cancer registry data, hospitalization and death record codes and algorithmically-defined cardiovascular outcomes. We report the pheWAS results in a user-friendly web-based browser. Taking atrial fibrillation, a common cardiac arrhythmia, as an example, ExPheWas identified genes that are known drug targets for the treatment of arrhythmias and genes involved in biological processes implicated in cardiac muscle function. We also identified MYOT as a possible atrial fibrillation gene.Availability and implementationThe ExPheWas browser and API are available at http://exphewas.statgen.org/ContactMarie-Pierre.Dube@mhi-rc.org

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.

Supplemental Digital Content is available in the text., Background: The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. Methods: There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study’s primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients’ DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients. Results: None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52–2.35], P=7.41×10−9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82–3.47]; P=2.70×10−8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. Conclusions: We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.

BackgroundNaturally 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 mutation in HCN4, ivabradine’s drug target, on safety and efficacy endpoints.MethodsWe used genetic association testing and Mendelian randomization to predict the effect of ivabradine and heart rate lowering on cardiovascular outcomes.ResultsUsing 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).ConclusionGenetic modelling of ivabradine recapitulates its benefits in heart failure, promotion of atrial fibrillation, and neutral effect on myocardial infarction.CONDENSED ABSTRACTThe effects of drugs can sometimes be predicted from the effects of mutations in genes encoding drug targets. We tested the effect of a heart rate reducing allele at the HCN4 locus encoding ivabradine’s drug target and found results coherent with the SHIFT and SIGNIFY clinical trials of ivabradine. The genetic variant increased the risk of atrial fibrillation and cardioembolic stroke and protected against heart failure in a competing risk model accounting for the increased risk of atrial fibrillation. The variant had a neutral effect on a composite of myocardial infarction and cardiovascular death.

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

Background Little is known about the mid-term prognosis of nonelderly patients (≤60 years) after the surgical treatment of isolated aortic valve infective endocarditis (IE). Better characterization of these outcomes could help in tailoring the surgical management in these patients. Methods From 2000 to 2015, 164 adult patients ≤60 years of age (mean 46 ± 11 years, 81% male) underwent surgical treatment for isolated aortic valve IE in 2 high-volume Canadian centers. Twenty-three patients (14%) were intravenous drug users (IVDUs). Patients with recurrent IE or concomitant endocarditis on other valves were excluded. The aortic valve was replaced with a mechanical prosthesis (44%), a tissue valve (30%), a homograft (18%), or a Ross procedure (9%). Mean follow-up was 6.2 ± 4.6 years (92% complete). Results Thirty-day mortality was 7%. Actuarial survival rates at 5 and 10 years were 80 ± 3% and 71 ± 4%, respectively. IVDU (hazard ratio [HR] 3.8, 95% CI 1.4-10.1; P = 0.01) and prosthetic valve endocarditis (HR 2.6, 95% CI 1.1-6.4; P = 0.04) were associated with increased mid-term mortality. Mid-term survival was best in non-IVDU patients with native valve endocarditis, yet lower than a matched elective aortic valve replacement (AVR) population. Overall, freedom from recurrence of IE at 1, 5, and 10 years was 94 ± 2%, 91 ± 3%, and 89 ± 3%, respectively. IVDU was associated with higher rates of recurrence, especially in the first year after surgery. Conclusions In nonelderly adults undergoing surgery for aortic valve IE, mid-term survival is suboptimal. Although non-IVDU patients with native valve endocarditis have better mid-term outcomes, survival remains lower than a matched population of elective AVR in nonelderly patients.

Aim: We have evaluated the pharmacogenetic content of commercial human genome-wide genotyping arrays, as it is a critical determinant to enabling pharmacogenomic discoveries. Methods: Using bioinformatics approaches, we assessed 27,811 genetic variants in 3146 genes for their presence in 18 Illumina and 15 Affymetrix genome-wide arrays. Results: The pharmacogenetic content of the arrays varied greatly. The combination of the Affymetrix precision medicine array and PharmacoScan arrays (Affymetrix) had the highest coverage for a set of clinically actionable absorption, distribution, metabolism and excretion (ADME) variants, single nucleotide ADME variants and ADME insertions/deletions, with a physical coverage of 125/130 (96.2%), 9924/24,138 (41.1%) and 2252/3994 (56.4%), respectively. Conclusion: The combination of the Affymetrix precision medicine array and PharmacoScan arrays provided both genome-wide and pharmacogene coverage, which is crucial in the discovering of new variants responsible for drug adverse effects. These results will help in the design of pharmacogenomic studies and will enable a critical review of results from past studies.

Summary: Genotype imputation is now commonly performed following genome-wide genotyping experiments. Imputation increases the density of analyzed genotypes in the dataset, enabling fine-mapping across the genome. However, the process of imputation using the most recent publicly available reference datasets can require considerable computation power and the management of hundreds of large intermediate files. We have developed genipe, a complete genome-wide imputation pipeline which includes automatic reporting, imputed data indexing and management, and a suite of statistical tests for imputed data commonly used in genetic epidemiology (Sequence Kernel Association Test, Cox proportional hazards for survival analysis, and linear mixed models for repeated measurements in longitudinal studies). Availability and Implementation: The genipe package is an open source Python software and is freely available for non-commercial use (CC BY-NC 4.0) at https://github.com/pgxcentre/genipe. Documentation and tutorials are available at http://pgxcentre.github.io/genipe. Contact: louis-philippe.lemieux.perreault@statgen.org or marie-pierre.dube@statgen.org Supplementary information: Supplementary data are available at Bioinformatics online.

Hematological traits are important clinical parameters. To test the effects of rare and low-frequency coding variants on hematological traits, we analyzed hemoglobin concentration, hematocrit levels, white blood cell (WBC) counts and platelet counts in 31,340 individuals genotyped on an exome array. We identified several missense variants in CXCR2 associated with reduced WBC count (gene-based P = 2.6 × 10(-13)). In a separate family-based resequencing study, we identified a CXCR2 frameshift mutation in a pedigree with congenital neutropenia that abolished ligand-induced CXCR2 signal transduction and chemotaxis. We also identified missense or splice-site variants in key hematopoiesis regulators (EPO, TFR2, HBB, TUBB1 and SH2B3) associated with blood cell traits. Finally, we were able to detect associations between a rare somatic JAK2 mutation (encoding p.Val617Phe) and platelet count (P = 3.9 × 10(-22)) as well as hemoglobin concentration (P = 0.002), hematocrit levels (P = 9.5 × 10(-7)) and WBC count (P = 3.1 × 10(-5)). In conclusion, exome arrays complement genome-wide association studies in identifying new variants that contribute to complex human traits.

Background: Prenatal alcohol exposure is the leading preventable cause of behavioral and cognitive deficits, which may affect between 2 and 5 % of children in North America. While the underlying mechanisms of alcohol’s effects on development remain relatively unknown, emerging evidence implicates epigenetic mechanisms in mediating the range of symptoms observed in children with fetal alcohol spectrum disorder (FASD). Thus, we investigated the effects of prenatal alcohol exposure on genome-wide DNA methylation in the NeuroDevNet FASD cohort, the largest cohort of human FASD samples to date. Methods: Genome-wide DNA methylation patterns of buccal epithelial cells (BECs) were analyzed using the Illumina HumanMethylation450 array in a Canadian cohort of 206 children (110 FASD and 96 controls). Genotyping was performed in parallel using the Infinium HumanOmni2.5-Quad v1.0 BeadChip. Results: After correcting for the effects of genetic background, we found 658 significantly differentially methylated sites between FASD cases and controls, with 41 displaying differences in percent methylation change >5 %. Furthermore, 101 differentially methylated regions containing two or more CpGs were also identified, overlapping with 95 different genes. The majority of differentially methylated genes were highly expressed at the level of mRNA in brain samples from the Allen Brain Atlas, and independent DNA methylation data from cortical brain samples showed high correlations with BEC DNA methylation patterns. Finally, overrepresentation analysis of genes with up-methylated CpGs revealed a significant enrichment for neurodevelopmental processes and diseases, such as anxiety, epilepsy, and autism spectrum disorders. Conclusions: These findings suggested that prenatal alcohol exposure is associated with distinct DNA methylation patterns in children and adolescents, raising the possibility of an epigenetic biomarker of FASD.

De novo mutations (DNM) are an important source of rare variants and are increasingly being linked to the development of many diseases. Recently, the paternal age effect has been the focus of a number of studies that attempt to explain the observation that increasing paternal age increases the risk for a number of diseases. Using disease-free familial quartets we show that there is a strong positive correlation between paternal age and germline DNM in healthy subjects. We also observed that germline CNVs do not follow the same trend, suggesting a different mechanism. Finally, we observed that DNM were not evenly distributed across the genome, which adds support to the existence of DNM hotspots.

BACKGROUND: \ud \ud The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets.\ud \ud METHODS: \ud \ud Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes.\ud \ud RESULTS: \ud \ud We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P=4.2×10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P=4.0×10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P=0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P=0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P=2.0×10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P=2.5×10(-7)).\ud \ud CONCLUSIONS: \ud \ud We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease. (Funded by the National Institutes of Health and others.).

Background and Aim: The marked inter-individual variability in warfarin dose requirement is mainly attributed to the variants of the main target genes across the warfarin pharmacological pathway, i.e. cytochrome P-450 (CYP) 2C9, CYP3A4, ABCB1, vitamin K epoxide reductase complex subunit 1 (VKORC1) and epoxide hydrolase 1 (EPHX1). The expression of these genes is primarily regulated by a complex network of nuclear receptors (NR) which are encoded, in turn, by polymorphic genes. Furthermore, microRNAs (miRNA) can reduce the expression of both warfarin target genes and the genes encoding NRs. We investigated whether the variants of genes encoding i) warfarin targets, ii) NRs involved in the regulation of the targets and iii) miRNA involved in the regulation of NRs and the targets, are associated with warfarin dose requirements. Methods and Results: The study was performed using the Quebec Warfarin Cohort consisting of 988 new warfarin users who were recruited over a period of 3 years and were followed-up for 12 months. The candidate genes were selected according to the literature and included 5 warfarin target genes, 9 NRs genes and 29 miRNA genes. SNPs with MAF>0.01 within these genes were selected for the present study from the NCBI database. Genotyping was previously performed using Omni 2.5 array (Illumina, CA) and iPLEX ADME CYP2C9/VKORC1 panel (Agena, CA) and missing SNPs were imputed. We tested the effect of SNPs on the log-transformed values of dose at 3-month post-initiation using multivariate linear regression analysis, and the adjusted significance threshold was set to 2.49 x 10-4. A total of 3970 SNPs, including 702 in target genes, 3162 in NRs and 106 in miRNA genes were studied. For the association with warfarin dose, 137 SNPs in CYP2C9 and VKORC1 were significant, as well as 3 SNPs in nuclear vitamin D receptor (VDR) gene: rs4760658, β = -0,0852, P = 7,32x10-5; rs11168293, β = -0,0809, P = 1,78x10-4; rs4760655, β = -0,0799, P = 2,15x10-4. None of the variants in miRNA genes showed a significant association with warfarin dose. Conclusions: Variants in the gene encoding VDR, a nuclear receptor which has been previously shown to be involved in the regulation of CYP2C9, CYP3A4 and ABCB1, may contribute to the variability in response to warfarin.

Background— Dalcetrapib did not improve clinical outcomes, despite increasing high-density lipoprotein cholesterol by 30%. These results differ from other evidence supporting high-density lipoprotein as a therapeutic target. Responses to dalcetrapib may vary according to patients’ genetic profile. Methods and Results— We conducted a pharmacogenomic evaluation using a genome-wide approach in the dal-OUTCOMES study (discovery cohort, n=5749) and a targeted genotyping panel in the dal-PLAQUE-2 imaging trial (support cohort, n=386). The primary endpoint for the discovery cohort was a composite of cardiovascular events. The change from baseline in carotid intima-media thickness on ultrasonography at 6 and 12 months was evaluated as supporting evidence. A single-nucleotide polymorphism was found to be associated with cardiovascular events in the dalcetrapib arm, identifying the ADCY9 gene on chromosome 16 (rs1967309; P =2.41×10 –8 ), with 8 polymorphisms providing P –6 in this gene. Considering patients with genotype AA at rs1967309, there was a 39% reduction in the composite cardiovascular endpoint with dalcetrapib compared with placebo (hazard ratio, 0.61; 95% confidence interval, 0.41–0.92). In patients with genotype GG, there was a 27% increase in events with dalcetrapib versus placebo. Ten single-nucleotide polymorphism in the ADCY9 gene, the majority in linkage disequilibrium with rs1967309, were associated with the effect of dalcetrapib on intima-media thickness ( P ADCY9 , in linkage disequilibrium with rs1967309 ( r 2 =0.8), was associated with both the effects of dalcetrapib on intima-media thickness in dal-PLAQUE-2 ( P =0.009) and events in dal-OUTCOMES ( P =8.88×10 –8 ; hazard ratio, 0.67; 95% confidence interval, 0.58–0.78). Conclusions— The effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the ADCY9 gene. Clinical Trial Information— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT00658515 and NCT01059682

Summary: 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. Contact: ac.laertnomu@tluaerrep.xueimel.eppilihp-siuol or gro.negtats@ebud.erreip-eiram

Philip Awadalla, Julie Hussin, and Youssef Idaghdour should be included in the author byline. Philip Awadalla should be listed as the 19th author and contributed materials/analysis tools, Julie Hussin should be listed as the 20th author and contributed by analysing the data, and Youssef Idaghdour should be listed as the 21st author and contributed reagents/materials/analysis tools. The affiliation of these three authors is 1: Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte Justine, Universite de Montreal, Montreal, Quebec, Canada.