Modifier Genes in Hypertrophic Cardiomyopathy: Tag SNP Analysis of ACE, ACE2 and Chymase
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ABSTRACTS Heart, Lung and Circulation S81 2009;18S:S1–S286 Abstracts Conclusion: Dead in bed syndrome is a poorly understood mode of sudden death in patients with T1D. This is the first step towards identifying possible genetic factors under- lying this syndrome. Further investigation into other risk factors, such as a histopathological predisposition will pro- vide additional insight into the pathogenic mechanisms leading to the dead in bed syndrome. doi:10.1016/j.hlc.2009.05.180 179 MAPPING OF FAMILIAL VENTRICULAR SEPTAL DEFECTS AND ANEURYSMS TO CHROMOSOME 10 D. Radford 1 , G. Andelfinger 2 , J. Ginns 1 , M. Nicolae 1 , T. Malpas 1 , M. Thibeault 2 , R. Gendron 2 , S. Yang 2 , M. Hitz 2 , G. Asselin 3 , M. Dube 3 1 The Prince Charles Hospital, Brisbane, Australia 2 Sainte Justine Hospital, Montreal, Canada 3 Montreal Heart Institute, Canada Background: Although ventricular septal defects (VSD) are the most common congenital heart lesion, familial clustering has been described only in rare instances. We have ascertained an extended family with VSDs and septal aneurysms requiring surgical intervention. Methods: Detailed family history, physical examination, electrocardiogram, echocardiography and chart reviews were performed. Blood and saliva were sampled for genetic studies. Informed consent was obtained from all participants. Genotyping was performed using the Illu- mina Linkage12 panel. MERLIN was used for statistical analysis, with standard parameters for a rare autosomal dominant trait (penetrance set to 0.90, phenocopy set to 0.01 and disease allele frequency set to 0.001). Results: 18 family members in three generations could be ascertained, out of whom 10 are affected with VSD or septal aneurysm (3). One had Tetralogy of Fallot and 2 had additional atrial septal defects. Parametric mul- tipoint LOD scores reach significance on chromosome 10p15.3–10p15.2 (max. 3.13). The LOD score support inter- val is in a gene-poor region which overlaps with numerous known cytogenetic anomalies causative in septal defects, but not the Di George syndrome 2 region on 10p. Conclusion: The successful mapping of a rare familial form of VSDs/septal aneurysms provides evidence for fur- ther genetic heterogeneity of Mendelian cardiovascular traits. Fine-mapping, haplotype construction and rese- quencing will provide a unique opportunity to assess the pathogenesis of septal defects and shed light on candidate genes of heart development. doi:10.1016/j.hlc.2009.05.181 180 MODIFIER GENES IN HYPERTROPHIC CARDIOMY- OPATHY: TAG SNP ANALYSIS OF ACE, ACE2 AND CHYMASE Matthew Kelly 1,2 , Richard D. Bagnall 1 , Sheila K. Patel 3 , Laura Yeates 1 , Louise M. Burrell 3 , Chris Semsarian 1,2,4 1 Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia 2 Faculty of Medicine, University of Sydney, Sydney, Australia 3 Department of Medicine (Austin Health), University of Mel- bourne, Melbourne, Australia 4 Department of Cardiology, Royal Prince Alfred Hospital, Syd- ney, Australia Background: Hypertrophic cardiomyopathy (HCM) is characterized by clinical heterogeneity. Phenotype sever- ity varies considerably even in patients with identical causal mutations, implying the existence of modify- ing factors. Possible modifiers include common single nucleotide polymorphisms (SNPs) in the genes of the Renin-Angiotensin System. This study sought to inves- tigate the effects of common SNPs in the angiotensin converting enzyme (ACE), ACE2 and chymase genes on phenotype severity in patients with HCM. Methods: HapMap data and Halpoview were used to select tag SNPs for the genes encoding ACE (rs4305, rs4309, rs4363), ACE2 (rs2074192, rs233575, rs4646156) and chy- mase (rs5248, rs1951133). SNPs were genotyped in HCM patients (n = 292) using the TaqMan 5’ nuclease assay. SNP associations were adjusted for age and sex. Results: Applying the dominant model of inheritance to the ACE SNPs, the rare allele of rs4305, and the common alleles of rs4309 and rs4363 were significantly associ- ated with greater interventricular septal (IVS; mean ± SE) wall thickness in HCM patients (Table). No association between ACE2 or chymase and IVS was observed. rs4305 rs4309 rs4363 Allele AA AG + GG TT TC + CC AA AG + GG n 83 208 108 183 85 204 IVS (mm) 19.0 ± 0.7 21.4 ± 0.4 22.4 ± 0.6 19.6 ± 0.4 22.4 ± 0.7 20.0 ± 0.4 p-value 0.004 <0.001 0.002 Conclusions: The association of the ACE tag SNP geno- types with IVS indicates components of the ACE gene are capable of modifying the HCM phenotype. Fine-mapping and functional studies are required to identify the vari- ants that are responsible for this modification and reveal the mechanisms by which they act. doi:10.1016/j.hlc.2009.05.182
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Transcript of Modifier Genes in Hypertrophic Cardiomyopathy: Tag SNP Analysis of ACE, ACE2 and Chymase
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Heart, Lung and Circulation S812009;18S:S1–S286 Abstracts
Conclusion: Dead in bed syndrome is a poorly understoodmode of sudden death in patients with T1D. This is the firststep towards identifying possible genetic factors under-lying this syndrome. Further investigation into other riskfactors, such as a histopathological predisposition will pro-vide additional insight into the pathogenic mechanismsleading to the dead in bed syndrome.
doi:10.1016/j.hlc.2009.05.180
179MAPPING OF FAMILIAL VENTRICULAR SEPTALDEFECTS AND ANEURYSMS TO CHROMOSOME 10
D. Radford 1, G. Andelfinger 2, J. Ginns 1, M. Nicolae 1,T. Malpas 1, M. Thibeault 2, R. Gendron 2, S. Yang 2, M.Hitz 2, G. Asselin 3, M. Dube 3
1 The Prince Charles Hospital, Brisbane, Australia2 Sainte Justine Hospital, Montreal, Canada3 Montreal Heart Institute, Canada
Background: Although ventricular septal defects (VSD)are the most common congenital heart lesion, familialclustering has been described only in rare instances. Wehave ascertained an extended family with VSDs and septalaneurysms requiring surgical intervention.
Methods: Detailed family history, physical examination,electrocardiogram, echocardiography and chart reviewswere performed. Blood and saliva were sampled forgenetic studies. Informed consent was obtained from allparticipants. Genotyping was performed using the Illu-mina Linkage12 panel. MERLIN was used for statisticalanalysis, with standard parameters for a rare autosomaldominant trait (penetrance set to 0.90, phenocopy set to0.01 and disease allele frequency set to 0.001).
Results: 18 family members in three generations couldbe ascertained, out of whom 10 are affected with VSDor septal aneurysm (3). One had Tetralogy of Fallot and2 had additional atrial septal defects. Parametric mul-tipoint LOD scores reach significance on chromosome10p15.3–10p15.2 (max. 3.13). The LOD score support inter-val is in a gene-poor region which overlaps with numerousknown cytogenetic anomalies causative in septal defects,but not the Di George syndrome 2 region on 10p.
Conclusion: The successful mapping of a rare familialform of VSDs/septal aneurysms provides evidence for fur-ther genetic heterogeneity of Mendelian cardiovasculartraits. Fine-mapping, haplotype construction and rese-quencing will provide a unique opportunity to assess thepathogenesis of septal defects and shed light on candidategenes of heart development.
doi:10.1016/j.hlc.2009.05.181
180MODIFIER GENES IN HYPERTROPHIC CARDIOMY-OPATHY: TAG SNP ANALYSIS OF ACE, ACE2 ANDCHYMASE
Matthew Kelly 1,2, Richard D. Bagnall 1, Sheila K. Patel 3,
Laura Yeates 1, Louise M. Burrell 3, Chris Semsarian 1,2,4
1 Agnes Ginges Centre for Molecular Cardiology, CentenaryInstitute, Sydney, Australia2 Faculty of Medicine, University of Sydney, Sydney, Australia3 Department of Medicine (Austin Health), University of Mel-bourne, Melbourne, Australia4 Department of Cardiology, Royal Prince Alfred Hospital, Syd-ney, Australia
Background: Hypertrophic cardiomyopathy (HCM) ischaracterized by clinical heterogeneity. Phenotype sever-ity varies considerably even in patients with identicalcausal mutations, implying the existence of modify-ing factors. Possible modifiers include common singlenucleotide polymorphisms (SNPs) in the genes of theRenin-Angiotensin System. This study sought to inves-tigate the effects of common SNPs in the angiotensinconverting enzyme (ACE), ACE2 and chymase genes onphenotype severity in patients with HCM.
Methods: HapMap data and Halpoview were used toselect tag SNPs for the genes encoding ACE (rs4305, rs4309,rs4363), ACE2 (rs2074192, rs233575, rs4646156) and chy-mase (rs5248, rs1951133). SNPs were genotyped in HCMpatients (n = 292) using the TaqMan 5’ nuclease assay. SNPassociations were adjusted for age and sex.
Results: Applying the dominant model of inheritance tothe ACE SNPs, the rare allele of rs4305, and the commonalleles of rs4309 and rs4363 were significantly associ-ated with greater interventricular septal (IVS; mean ± SE)wall thickness in HCM patients (Table). No associationbetween ACE2 or chymase and IVS was observed.
rs4305 rs4309 rs4363
Allele AA AG + GG TT TC + CC AA AG + GGn 83 208 108 183 85 204IVS (mm) 19.0 ± 0.7 21.4 ± 0.4 22.4 ± 0.6 19.6 ± 0.4 22.4 ± 0.7 20.0 ± 0.4p-value 0.004 <0.001 0.002
Conclusions: The association of the ACE tag SNP geno-types with IVS indicates components of the ACE gene arecapable of modifying the HCM phenotype. Fine-mappingand functional studies are required to identify the vari-ants that are responsible for this modification and revealthe mechanisms by which they act.
doi:10.1016/j.hlc.2009.05.182
