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Published on: June 21, 2018
Pharmacogenetic effects of 'candidate gene complexes' on stroke in the GenHAT study
Izel F Sørensen1, Ana I Vazquez, Marguerite R Irvin
1Departments of aBiostatistics bEpidemiology, University of Alabama at Birmingham, Birmingham, Alabama cDepartment of Biostatistics dDepartment of Epidemiology, Human Genetics & Environmental Sciences, The University of Texas Health Science Center at Houston, Houston, Texas eDepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA fDepartment of Molecular Biology and Genetics, Center for Quantitative Genetics and Genomics, Aarhus University, Denmark.
Insights
Genetic differences in stroke patients suggest a genotype-by-treatment interaction with antihypertensive drugs. Further research is needed to confirm these findings for personalized medicine approaches.
Area of Science:
- Pharmacogenomics
- Cardiovascular Genetics
- Stroke Research
Background:
- Stroke patients often receive antihypertensive medications like chlorthalidone, amlodipine, or lisinopril.
- Understanding genetic influences on drug response is crucial for optimizing stroke treatment.
- Previous studies have not fully explored genotype-by-treatment interactions in diverse stroke populations.
Purpose of the Study:
- To investigate potential genotype-by-treatment interactions in stroke patients receiving chlorthalidone, amlodipine, or lisinopril.
- To identify specific genetic variations associated with differential responses to antihypertensive therapies.
- To explore gene and gene complex associations with drug treatment outcomes in stroke survivors.
Main Methods:
- Genotyping of 768 single nucleotide polymorphisms (SNPs) in 280 candidate genes among 436 African Americans and 539 white stroke patients from the GenHAT study.
- Utilized Pearson's chi-squared test to assess genotype frequency differences across three drug treatment groups.
- Employed empirical P-values derived from data simulation to determine statistical significance at SNP, gene, and gene complex levels.
Main Results:
- Significant genetic differences were observed between antihypertensive drug treatment groups in stroke patients.
- In African Americans, SNP rs12143842 showed a significant association with drug treatment (P<0.001).
- Genes HNRNPA1P4 and NOS1AP (African Americans) and PRICKLE1 and NINJ2 (non-Hispanic whites) were significantly associated with drug treatment (P<0.01).
Conclusions:
- Evidence suggests a potential interaction between specific genotypes and antihypertensive treatment in stroke patients.
- Identified genetic variations may influence treatment efficacy, warranting further investigation.
- Replication in independent studies is essential to validate these genotype-by-treatment interaction findings.
Objective:
The aim of this study was to investigate whether there is a genotype-by-treatment interaction in patients experiencing stroke and treated with one of three antihypertensive drugs, that is chlorthalidone, amlodipine, or lisinopril.
Participants And Methods:
A population of 436 African Americans and 539 whites who had experienced stroke in the GenHAT study were genotyped for 768 single nucleotide polymorphisms (SNPs) in 280 candidate genes. To detect a genotype-by-treatment interaction, we used the Pearson's χ-test to assess whether the genotype frequencies differed at the single SNP level for the three drug treatment groups. From these single SNP analyses, we derived a summary statistic for the degree of association at the gene and gene complex levels. This was done by grouping SNPs using information on gene locations and defining gene complexes on the basis of protein-protein interactions. To assess the statistical significance of the observed test statistic, we derived an empirical P-value by simulating data under the null hypothesis.
Results:
We found that, in patients who have experienced stroke, there is a significant genetic difference between hypertension drug treatment groups. In African Americans, SNP rs12143842 showed a significant association (P<0.001) with drug treatment. At the gene level, HNRNPA1P4 and NOS1AP in African Americans and PRICKLE1 and NINJ2 in non-Hispanic whites were significantly associated (P<0.01) with drug treatment, whereas none of the gene complexes tested showed significance.
Conclusion:
On the basis of the genetic differences between drug treatment groups, we conclude that there may be an interaction between certain genotypes and antihypertensive treatment in stroke patients. This needs to be replicated in other studies.
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