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Evaluation of Candidate Genes as Susceptibility Genes for Left Ventricular Hypertrophy and Cardiac Failure in Man
Poster Title: Evaluation of Candidate Genes as Susceptibility Genes for Left Ventricular Hypertrophy and Cardiac Failure in Man
Submitted on 25 Nov 2015
Author(s): Shapour Jalilzadeh*; Kimbely Adams; Farahnaz Nematkhah; Martin Farrall; Hugh Watkins
Affiliations: University of Oxford
This poster was presented at RDM Annual Symposium
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Poster Information
Abstract: Candidate genes were genotyped in two cohorts, HTO1-2 and HTO3. Overall 345 SNPs (including htSNPs, cSNP, potentially functional SNP and singletons) were selected to capture all possible haplotypes, functional variants and also flanking region to cover putative regulator y elements. Haplotypes were constructed by Haploview and htSNP were selected using Tagger. MALDI-TOF iPLEX assay (Sequenom) was used as the method of choice due to cost/reaction and speed up of the project. Assays were designed with Sequenom’s MassARRAY Designer software with average plexity of 35.
Genotype calling and correction were done automatically and manually using SpectroTYPER software. Pedstats( was used to validate and detect any inconsistencies in pedigree, and QTDT (Abecasis et al. 2000) was used for statistical analysis.

After genotyping, data comparison, imputation and Mendelian error correction, an extensive statistical analysis was performed using QTDT on HTO1-2 (Echo, ECG and IMT) and
HTO3 (ECG, MRI) to assess heritability and association. The results appeared encouraging as top signals showing association with cardiac hypertrophy indices were concentrated
in 3 functionally related genes; PPARGC1A, FRAP1 and RAPGEF3. The heritabilities were calculated for Sokolow-Lyon voltage (h2=0.32), ecglvh (h2 =0.24) and ecglvm (h2=0.14).

There are strong evidences to support association findings including
transgenic animal models and data from partners in EUGeneHeart
Consortium1. Top hit genes are involved in cardiac energetics and
pathophysiology according to literature. Also data analysis suggests that a number of families have developed Left Ventricular Hypertrophy over a 12 years period. Our findings regarding association of The rs8192678 (Gly482Ser) with LVM have been recently replicated in another population2.
We have performed a candidate-based association study in two cohorts aiming at "Evaluation of Candidate Genes as Susceptibility Genes for Left Ventricular Hypertrophy and Cardiac Failure in Man", HTO1-2 and HTO3 composed of British families with a history of hypertension. HTO3 is a subset of the collection composed of ~400 individuals re-studied by MRI and ECG, 12 years after HTO1-2 collection, allowing comparison with Echo and ECG data from HTO1-2
References: 1-Song X, Kusakari Y, Xiao CY, Kinsella SD, Rosenberg MA, Scherrer -Crosbie M, Hara K, Rosenzweig A, Matsui T. mTOR attenuates the inflammatory response in cardiomyocytes and prevents cardiac dysfunction in pathological hypertrophy. Am J Physiol Cell Physiol. 2010 Dec;299(6):C1256-66
2-Rojek A, Cielecka-Prynda M, Przewlocka-Kosmala M, Laczmanski L, Mysiak A1 Kosmala W. Impact of the PPARGC1A Gly482Ser polymorphism on left ventricular structural and functional abnormalities in patients with hypertension. J Hum Hypertens. 2014 Sep;28(9):557-63
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