Thesis
Genetics of sudden cardiac death and role of dipeptidyl peptidase like 6 gene
University of Iowa
Master of Science (MS), University of Iowa
Spring 2022
DOI: 10.25820/etd.006488
Abstract
This research project started with a GWAS as an exploratory expedition to the nature of genetic variations that increase SCD in HF patients. We used an appropriate ICD shock phenotype as a surrogate for SCD phenotype that is difficult to study directly. Although no SNP in the GWAS reached the genome-wide significance (5E-8), rs10251943 in the DPP6 gene was chosen for further analysis and investigation because the literature review revealed that the (T) allele of a different SNP (rs606231226) in DPP6 is associated with overexpression of the gene, gain-of-function effect i.e. increase in the transient outward current (Ito) in Purkinje fibers, and IVF/SCD events in several members of a big family in the Netherland. We conducted a Kaplan-Meier survival analysis to estimate the association of different genotypes of rs10251943 with the Freedom from shock phenotype i.e. survival from shock in HF patients of European and African descents. The (TT) genotype was associated with more shocks than other genotypes in both descents. In other words, the minor allele (T) is a potential pathological SNP or a tag SNP associated with a pathological SNP. We thought of many hypotheses to answer the question of why rs10251943 increases shock events. We hypothesized that this SNP might be associated with increasing the frequency of shocks through the same mechanism as rs606231226. We also hypothesized that the rs606231226 (not included in the GWAS) might be in linkage disequilibrium with rs10251943 and that the subjects of our cohort may be genealogically linked to the family in the Netherlands (founder effect). To investigate these hypotheses, we sequenced the whole genome of 9 subjects in GRADE including 4 GG individuals that suffered no shocks versus 5 TT individuals that suffered multiple shocks during the 5 year follow-up period of the study. The sequencing results disproved the founder effect hypothesis because none of the sequenced subjects had a C>T substitution in rs606231226. It also unveiled a haplotype of 10 SNPs that are in LD with rs10251943. One of the SNPs in this haplotype overlaps with the enhancer (GH07J154195). This finding increased our desire to investigate the shock mechanism hypothesis mentioned above. We examined the differential expression of the DPP6 mRNA in healthy subjects comprising the 3 genotypes for rs10251943. We measured the mRNA using TaqMan Probe-based qPCR in 10 GG, 10 GT, and 4 TT samples. The differential expression analysis showed that there is no significant difference among the 3 groups. We conclude that the SNP rs10251943 has no or very low effect on regulating DPP6 mRNA expression. In the future, we will test the difference in protein expression among the 3 genotypic groups
Details
- Title: Subtitle
- Genetics of sudden cardiac death and role of dipeptidyl peptidase like 6 gene
- Creators
- Mohamed Elmonzer
- Contributors
- Barry London (Advisor)Ethan Anderson (Committee Member)Marie Gaine (Committee Member)Aliasger Salem (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Pharmacy
- Date degree season
- Spring 2022
- DOI
- 10.25820/etd.006488
- Publisher
- University of Iowa
- Number of pages
- x, 65 pages
- Copyright
- Copyright 2021 Mohamed Elmonzer
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 62-65).
- Public Abstract (ETD)
In this research, we were interested in identifying a novel mutation for Idiopathic ventricular fibrillation (IVF) and sudden cardiac death (SCD). Sudden cardiac death (SCD) is sudden unexpected death caused by loss of heart function due to electrical instability. In young (≤ 35), it is most frequently caused by sudden arrhythmia death syndromes (SADS); a group of genetic heart conditions that can cause SCD in people with an apparently healthy heart. When the origin of SCD is unknown despite exhausting all the diagnostic tools, the physician concludes idiopathic ventricular fibrillation (IVF). Every SADS was once IVF but advances in genetic testing have facilitated the differentiation between different sudden arrhythmia death syndromes and IVF, and it showed that each has its own pathophysiology. Currently, 4 genes are linked to IVF and SCD. Genome-wide association study (GWAS) was our approach to identify any genetic associations in a population with high cardiac arrhythmia encounters. GWAS allowed us to identify a signal in one of the genes already linked to the IVF/SCD. The signal was the intronic SNP rs10251943 in the DPP6 gene. We carried out a survival analysis to identify whether any of the SNP genotypes are linked to increased shock (surrogate phenotype for IVF/SCD) in our study population. We found that the (TT) genotype is associated with more shocks than other genotypes in patients of European and African descent. In other words, the minor allele (T) is a potential pathological SNP or a tag SNP associated with a pathological SNP. We carried whole-genome sequencing to get a better resolution of this genetic locus and to identify the causal SNP. We also wanted to uncover the pathophysiological mechanism by which the SNP in DPP6 cause IVF so we carried out RT-qPCR to measure the differential expression among the genotypes. There was no statistically significant difference between different genotypes.
- Academic Unit
- Pharmacy; Craniofacial Anomalies Research Center
- Record Identifier
- 9984271055902771
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