A Comprehensive Genetic Study on Left Atrium Size in Caribbean Hispanics Identifies Potential Candidate Genes in 17p10

Abstract

Background-Left atrial (LA) enlargement is associated with cardiovascular disease and stroke. Genetic factors contributing to the LA dimension are poorly understood. We sought to map susceptibility genes for LA size in a large Dominican family data set and an independent population-based sample from the Northern Manhattan Study. Methods and Results-One hundred Dominican families comprising 1350 individuals were studied to estimate heritability and map quantitative trait loci for LA size using variance components analysis. LA dimension was measured by transthoracic echocardiography. A polygenic covariate screening was used to identify significant covariates. LA size had a moderate estimate of heritability (h 2 ϭ0.42) after adjusting for significant covariates. Linkage analysis revealed suggestive evidence on chromosome 10p19 (D10S1423, MLODϭ2.00) and 17p10 (D17S974, MLODϭ2.05). Ordered subset analysis found significantly enhanced (PϽ0.05 for increase of LOD score) evidence for linkage at 17p10 (MLODϭ2.9) in families with lower LDL level. Single nucleotide polymophisms (nϭ2233)were used to perform a peak-wide association mapping across 17p10 in 825 NOMAS individuals. Evidence for association were found in NTN1, MYH10, COX10, and MYOCD genes (Pϭ0.00005 to 0.005). Conclusions-Using nonbiased genome-wide linkage followed by peak-wide association analysis, we identified several possible susceptibility genes affecting LA size. Among them, MYOCD has been shown to serve as a key transducer of hypertrophic signals in cardiomyocytes. Our data support that polymorphisms in MYOCD modify LA size. (Circ Cardiovasc Genet. 2010;3:386-392.)Key Words: left atrium Ⅲ genetics Ⅲ myocardin Ⅲ MYH10 Ⅲ COX10 L eft atrial (LA) enlargement has been associated with increased mortality in high-risk patients with left ventricular dysfunction 1 or atrial arrhythmias 2 but also in the general population. 3,4 An enlarged LA is also associated with the development of atrial fibrillation, 5,6 a strong determinant of ischemic stroke and death. 3,4,7 Even among subjects without atrial fibrillation, LA enlargement has been associated with an increased risk of ischemic stroke. 8 -10 We have previously shown an increased stroke risk in subjects with increased LA size, whether measured directly by echocardiography 10 or inferred by electric abnormalities detected on ECG. 11 Clinical Perspective on p 392Multiple conditions have been associated with LA enlargement, 12 including mitral valve disease, arterial hypertension, and any condition that increases the left ventricular filling pressures. 12 Elucidating the genetic influences on LA size would help to identify subjects at risk for developing an enlarged LA. In addition, this knowledge is essential for understanding cardiac structure and function at the molecular level and identifying therapeutic targets in the management of LA enlargement.Little is known about the genetic basis of LA size, with sparse studies mainly among Caucasian populations. [13][14][15][16][17] Therefore, we estimated the heritab...

A MicroRNA-Transcription Factor Blueprint for Early Atrial Arrhythmogenic Remodeling

“…TFs, such as Pitx2 and Tbx5 , are increasingly recognized as potentially important contributors to atrial arrhythmia susceptibility (recently reviewed in [ 42 ]). Enlargement of the LA is widely regarded to be an epidemiological risk indicator for AF, and a transcription cofactor, myocardin ( Myocd ), has been identified as a possible susceptibility gene affecting LA size and function [ 43 ]. Our objective in this regard was to study whether these genes (with potential roles in arrhythmogenesis) are involved in early response of LA myocardium to induction of paroxysmal-like AF.…”

“…Alterations in atrial miRNAs can contribute to transcription factor (TF) deregulations underlying early atrial remodeling. Genome-wide association studies and other approaches have identified the TFs, Pitx2 and Tbx5 as candidate genes linked to susceptibility for early development of AF (reviewed in [ 41 , 42 ]) and myocardin ( Myocd ) as a transcription cofactor linked with LA functional and structural remodeling [ 43 ]. Interestingly, Pitx2 , Tbx5 , and Myocd expression is markedly downregulated in the LA in response to ectopic tachyarrhythmia.…”

Normal percentile curves for left atrial size in healthy children and adolescents

“…It has been demonstrated that ethnicity and genetic factors contribute to explain the variability in LA dimensions. A recent systematic review based on 36 studies (only one with data from South America) including 30 607 children and adolescents underlined the importance of using race‐specific reference ranges for left cardiac chamber dimensions, as well as the need for standardizing echocardiographic methods in deriving the reference ranges .…”

Factors Associated With Left Atrial Remodeling in the General Population

“…This suggests that left atrial remodeling may be influenced by genetic variants that are reflected by race/ethnicity. Prior studies of White 24 and Caribbean Hispanic 25 populations estimated moderate heritability of LA size after adjusting for covariates, and identified several possible susceptibility genes. LV hypertrophy and remodeling also differ substantially by race/ethnicity 21 with gene variants identified in causal pathways limited to specific race/ethnic groups.…”