Dataset Information

Genome-Wide Analysis of Left Ventricular Maximum Wall Thickness in the UK Biobank Cohort Reveals a Shared Genetic Background With Hypertrophic Cardiomyopathy.

ABSTRACT:

Background

Left ventricular maximum wall thickness (LVMWT) is an important biomarker of left ventricular hypertrophy and provides diagnostic and prognostic information in hypertrophic cardiomyopathy (HCM). Limited information is available on the genetic determinants of LVMWT.

Methods

We performed a genome-wide association study of LVMWT measured from the cardiovascular magnetic resonance examinations of 42 176 European individuals. We evaluated the genetic relationship between LVMWT and HCM by performing pairwise analysis using the data from the Hypertrophic Cardiomyopathy Registry in which the controls were randomly selected from UK Biobank individuals not included in the cardiovascular magnetic resonance sub-study.

Results

Twenty-one genetic loci were discovered at P<5×10^-8. Several novel candidate genes were identified including PROX1, PXN, and PTK2, with known functional roles in myocardial growth and sarcomere organization. The LVMWT genetic risk score is predictive of HCM in the Hypertrophic Cardiomyopathy Registry (odds ratio per SD: 1.18 [95% CI, 1.13-1.23]) with pairwise analyses demonstrating a moderate genetic correlation (r_g=0.53) and substantial loci overlap (19/21).

Conclusions

Our findings provide novel insights into the genetic underpinning of LVMWT and highlight its shared genetic background with HCM, supporting future endeavours to elucidate the genetic etiology of HCM.

SUBMITTER: Aung N

PROVIDER: S-EPMC9946169 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Publications

Genome-Wide Analysis of Left Ventricular Maximum Wall Thickness in the UK Biobank Cohort Reveals a Shared Genetic Background With Hypertrophic Cardiomyopathy.

Aung Nay N Lopes Luis R LR van Duijvenboden Stefan S Harper Andrew R AR Goel Anuj A Grace Christopher C Ho Carolyn Y CY Weintraub William S WS Kramer Christopher M CM Neubauer Stefan S Watkins Hugh C HC Petersen Steffen E SE Munroe Patricia B PB

Circulation. Genomic and precision medicine 20230104 1

<h4>Background</h4>Left ventricular maximum wall thickness (LVMWT) is an important biomarker of left ventricular hypertrophy and provides diagnostic and prognostic information in hypertrophic cardiomyopathy (HCM). Limited information is available on the genetic determinants of LVMWT.<h4>Methods</h4>We performed a genome-wide association study of LVMWT measured from the cardiovascular magnetic resonance examinations of 42 176 European individuals. We evaluated the genetic relationship between LVM ...[more]

PMID: 36598836

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Project description:BackgroundMaximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort.MethodsThe study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1-16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids).ResultsMLVWT Z score was <10 in 598 (58.1%), ≥10 to <20 in 334 (31.1%), and ≥20 in 143 (13.3%). Higher MLVWT Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3-9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores <10, ≥10 to <20, and ≥20 was 95.6%, 87.4%, and 86.0, respectively. The estimated SCD risk at 5 years had a nonlinear, inverted U-shaped relationship with MLVWT Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk.ConclusionsIn children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM.

Project description:ObjectivesMyocardial strain is reported to be a sensitive indicator of myocardial mechanical changes in patients with hypertrophic cardiomyopathy (HCM). The changes in the mechanics of the myocardium of normal wall thickness (< 12 mm) have yet to be well studied. This study aimed to evaluate the function of myocardial segments of normal thickness in patients with HCM.MethodsSixty-three patients with HCM and 30 controls were retrospectively enrolled in this retrospective study. Cine imaging, native and post-contrast T1 maps, T2 maps, and late gadolinium enhancement were performed. In addition, regional myocardial strain was assessed by cardiac magnetic resonance-tissue tracking. Strain parameters were compared between the controls and HCM patients with segments of the myocardium of normal thickness. Subgroup analysis was conducted in obstructive and non-obstructive HCM. Lastly, p < 0.05 was considered statistically significant.ResultsIn normal-thickness myocardial segments of HCM (n = 716), diastolic peak strain rates (PSRs) were significantly lower than in the control group (n = 480) (radial, - 2.43 [- 3.36, - 1.78] vs. - 2.67 [- 3.58, - 1.96], p = 0.002; circumferential, 1.28 [1.01,1.60] vs. 1.39 [1.14, 1.78], p < 0.001; and longitudinal, 1.16 [0.75,1.51] vs. 1.28 [0.90, 1.71], p < 0.001). The normal-thickness segments showed no significant difference in systolic PSRs between HCM and the controls. In the subgroup analysis, significantly decreased diastolic PSRs were noted in both obstructive and non-obstructive HCM, compared with the controls (p < 0.05).ConclusionsDiastolic changes in myocardial mechanics were observed in normal-thickness segments of HCM, occurring before morphological remodeling and systolic dysfunction developed. This finding contributed to a better understanding of the mechanical pathophysiology of HCM with preserved left ventricular ejection fraction. It may potentially aid in predicting disease progression and risk stratification.

Project description:BackgroundClinical data on myocardial function in HCM mutation carriers (carriers) is sparse but suggests that subtle functional abnormalities can be measured with tissue Doppler imaging before the development of overt hypertrophy. We aimed to confirm the presence of functional abnormalities using cardiovascular magnetic resonance (CMR), and to investigate if sensitive functional assessment could be employed to identify carriers.Results28 carriers and 28 controls were studied. Global left atrial (LA) and left ventricular (LV) dimensions, segmental peak systolic circumferential strain (SCS) and peak diastolic circumferential strain rate (DCSR), as well as the presence of late Gadolinium enhancement (LGE) were determined with CMR. Septal and lateral myocardial velocities were measured with echocardiographic tissue Doppler imaging. LV mass and volumes were comparable between groups. Maximal septal to lateral wall thickness ratio (SL ratio) was larger in carriers than in controls (1.3+/-0.2 versus 1.1+/-0.1, p<0.001). Also, LA volumes were larger in carriers compared to controls (p<0.05). Both peak SCS (p<0.05) and peak DCSR (p<0.01) were lower in carriers compared to controls, particularly in the basal lateral wall. Focal LGE was present in 2 carriers and not in controls. The combination of a SL ratio>1.2 and a peak DCSR<105%.s-1 was present in 45% of carriers and in none of the controls, yielding a positive predictive value of 100%. Two carriers and 18 controls had a SL ratio<1.2 and peak DCSR>105%.s-1, yielding a negative predictive value of 90%. With multivariate analysis, HCM mutation carriership was an independent determinant of reduced peak SCS and peak DCSR.ConclusionsHCM mutation carriership is an independent determinant of reduced peak SCS and peak DCSR when LV wall thickness is within normal limits, and is associated with increased LA volumes and SL ratio. Using SL ratio and peak DCSR has a high accuracy to identify carriers. However, since carriers also display structural abnormalities and focal LGE, we advocate to also evaluate morphology and presence of LGE when screening for carriers.

Project description:ImportanceSarcomere mutations and left ventricular (LV) hypertrophy (LVH) are cardinal features of hypertrophic cardiomyopathy (HCM). However, little is known about the full spectrum of phenotypic manifestations or how LVH influences disease expression.Objectives(1) To characterize and assess phenotypic burden in sarcomere mutation carriers (genotype positive [G+]) and (2) to investigate the correlation between LV wall thickness (LVWT) and other disease features in mutation carriers.Design, setting, and participantsThis investigation was a cross-sectional, multicenter observational study in the setting of the HCMNet network of HCM clinical centers. Mutation carriers with LVH (G+/LVH+), mutation carriers without LVH (G+/LVH-), and healthy related control individuals (G-/LVH-) were enrolled through HCMNet sites. A total of 193 participants were enrolled and underwent study procedures. Participants were enrolled between April 9, 2010, and January 30, 2012. Study analysis was performed between June 2015 and May 2016.ExposuresThe primary stratifying variables were the presence of a sarcomere mutation and measures of LVWT.Main outcomes and measuresVariables from standardized exercise testing, echocardiography, cardiac magnetic resonance imaging, serum biomarker measurement, and electrocardiography were compared across study cohorts.ResultsAnalyses were performed in 178 participants, including 81 G+/LVH+ (mean [SD] age at baseline, 27 [14] years), 55 G+/LVH- (20 [10] years), and 42 G-/LVH- (18 [8] years). All mutation carriers had smaller LV cavity, higher ratio of LVWT to diastolic diameter, and higher echocardiographic LV ejection fraction than controls. A phenotypic burden score was evaluated as the cumulative number of 7 traits (changes on electrocardiography; decreased LV systolic, diastolic diameter, or septal E' velocity; higher ratio of LVWT to diastolic diameter; serum troponin level; and natriuretic peptide level) in each individual. The mean (SE) phenotypic burden was 4.9 (0.2) phenotypes per individual in G+/LVH+, 2.4 (0.2) in G+/LVH-, and 1.3 (0.2) in controls (P < .001). Classification and regression tree analysis identified an LV end-diastolic dimension z score less than -1.85 or the combination of an LV end-diastolic dimension z score of -1.85 or higher and a septal E' velocity z score less than -0.52 as having 74% accuracy in discriminating G+/LVH- participants from controls. In mutation carriers, clinical variables demonstrated a continuous correlation with LVWT, generally without a clear cutoff signifying pathologic transition.Conclusions and relevanceG+/LVH- individuals demonstrated altered cardiac dimensions and function and a higher burden of early phenotypes than healthy G- controls. Two methods discriminated phenotypic subgroups, namely, a sum across 7 traits and a regression tree-based rule that identifies constellations of distinguishing factors. Greater LVWT is associated with more prominent cardiac abnormalities in a continuous, although not always linear, manner. A single value of LVWT could not dichotomize the presence or absence of disease.

Project description:Objectives: To identify previously unrecognized genetic variants and clinical variables associated with the ICD-10 (International Classification of Diseases 10)-based diagnosis of hypertrophic cardiomyopathy in the UK Biobank cohort. Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disorder with more than 2000 known mutations in one of eight genes encoding sarcomeric proteins. However, there is considerable variation in disease manifestation, suggesting the role of additional unrecognized contributors, genetic and otherwise. There is substantial interest in the use of real-world data, such as electronic health records to better understand disease mechanisms and discover new treatment strategies, but whether ICD-10-based diagnosis can be used to study HCM genetics is unknown. Methods: In a genome-wide association study (GWAS) using the UK Biobank, we analyzed the genomes of 363 individuals diagnosed with HCM based on ICD-10 coding compared to 7,260 age, ancestry, and sex-matched controls in a 1:20 case:control design. Genetic variants were analyzed by Plink's firth logistic regression and assessed for association with HCM. We also examined 61 biomarkers and other diagnoses in the 363 HCM cases and matched controls. Results: The prevalence of ICD-10-based diagnosis of HCM in the UK Biobank cohort was 1 in 1,342, suggesting disease assignment based on the two ICD-10 codes underestimates HCM prevalence. In addition, common cardiovascular comorbidities were more prevalent in ICD-10-based HCM cases in comparison to controls. We identified two novel, non-sarcomeric genetic variants in KMT2C rs78630626, and PARD3B rs188937806 that were associated with ICD-10 codes for HCM with genome-wide significance (p < 5 x 10-8). These are associated with an increased odds ratio (OR) of ∼3.8 for being diagnosed with HCM. Minor allele frequency (MAF) of each variant was >1%. Discussion: Disease assignment based strictly on ICD-10 codes may underestimate HCM prevalence. Individuals with HCM were more frequently diagnosed with several comorbid conditions, such as hypertension, atherosclerotic heart disease, diabetes, and kidney failure, suggesting they may contribute to disease manifestation. This UK Biobank database-based GWAS identified common variants in KMT2C and PARD3B that are associated with HCM diagnosis, which may represent novel modifier genes. Our study demonstrates the feasibility and limitations of conducting phenotypic and genotypic characterization of HCM based on ICD-10 diagnosis in a large population-based cohort.

Dataset Information

Genome-Wide Analysis of Left Ventricular Maximum Wall Thickness in the UK Biobank Cohort Reveals a Shared Genetic Background With Hypertrophic Cardiomyopathy.

Background

Methods

Results

Conclusions

Publications

Genome-Wide Analysis of Left Ventricular Maximum Wall Thickness in the UK Biobank Cohort Reveals a Shared Genetic Background With Hypertrophic Cardiomyopathy.

Similar Datasets

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