Genetic Variants and Risk in Sudden Cardiac Death Syndromes

Sudden cardiac death is a major public health burden and is often the first manifestation of heart disease. Several cardiac conditions that confer a predisposition to sudden cardiac death (SCD) have a known genetic basis, including for example long QT syndrome (LQTS) and hypertrophic cardiomyopathy (HCM), and clinicians strive to identify the patients at highest risk of SCD events. Incomplete penetrance and variable expressivity even amongst individuals with the same diseasecausing mutation indicates the presence of genetic modifiers, including single nucleotide polymorphisms (SNPs). The majority of SCDs occur in patients with acquired rather than inherited cardiovascular disease and the risk in this group may also be affected by modifier polymorphisms. The aim of the research contained within this thesis was to explore the role of genetic variants in the risk of SCD in both inherited and acquired cardiovascular disease. Four research studies were undertaken. Firstly an evaluation of the effectiveness of detecting LQTS in the community via a cardiac genetic registry, and then three studies investigating the role of SNPs in SCD in three separate cohorts incorporating the relevant clinical data: patients with LQTS, patients with HCM, and patients surviving an hospital admission for an acute coronary syndrome. The primary findings were: 1) the prevalence of LQTS detected in New Zealand by the Cardiac Inherited Diseases Group registry is 1.5 per 10,000, and is 2.2 per 10,000 in central Auckland. Thus far an average of 2.1 family members who are definitely or probably affected by LQTS have been identified per registered proband. 2) The minor alleles of SNPs at two loci (NOS1AP and KCNQ1) increased the risk of SCD and cardiac arrest in patients with LQTS, independently of the QTc interval. 3) In patients with HCM, marked QTc prolongation was associated with an increased risk of SCD events, and the minor alleles of SNPs at the NOS1AP locus influenced QTc length but were not directly associated with SCD events. 4) In patients surviving an admission for an acute coronary syndrome, the minor alleles of three SNPs from three loci (KCNJ2, C14orf64, and GPC5) were associated with SCD or cardiac arrest, and repolarisation time was associated with variation in the NOS1AP gene 12 months after the acute event but not at earlier time points. These studies indicate that the investigated SNPs can modify the risk of SCD directly, and may also influence risk through altering repolarisation time. Thus, these variants have utility in risk stratification to identify the individuals at highest risk of SCD, though the relevance of each modifier SNP may depend on the underlying cardiac condition and its manifestation.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2014

Author dc:creator

• Earle, Nicola

Advisors dc:contributor.advisor

• Doughty, R
• Skinner, J
• Shelling, A
• Love, D

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/27831

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/27831