Angiotensin-converting enzyme tag single nucleotide polymorphisms in patients with intracerebral hemorrhage

Dardiotis, Efthimios; Jagiełła, Jeremiasz; Xiromerisiou, Georgia; Dardioti, Maria; Vogiatzi, Christina; Urbanik, Andrzej; Paterakis, Konstantinos; Komnos, Apostolos; Fountas, Kostas N.; Słowik, Agnieszka; Hadjigeorgiou, Georgios M.

doi:10.1097/fpc.0b013e328343ab15

Cited by 15 publications

(8 citation statements)

References 30 publications

(49 reference statements)

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“…Given our limited sample size, we used a candidate gene approach and did not evaluate the impact of genetic variability on other related proteins in the pathway, such as the Sur1 regulated channel Trpm4. Moreover, although we are limited in terms of sample size due to the incidence of severe TBI, this is one of the largest polymorphism studies reported in this disease[1,14,21,25,40]. We eagerly anticipate validation in future cohorts facilitated by emerging multi-center studies such as Transforming Research and Clinical Knowledge in TBI (TRACK-TBI).…”

Section: Discussionmentioning

confidence: 99%

“…Logistic regression models evaluated the independent relationship between ABCC8 SNPs and categorical outcomes (CT edema, decompressive craniotomy). Odds ratios, β-coefficients, and 95% confidence intervals (CI) were calculated based on modes of inheritance: dominant (AA vs Ab+bb), recessive (bb vs AA+Ab), heterogzygous (Ab vs AA+bb), as well as by an allele difference model (A vs b)[1,25]. Multiple variable logistic and linear regression models were developed with clinically relevant variables (age, gender, initial GCS score) to control for confounders in evaluating the independent relationship between ABCC8 SNPs and CE development.…”

Section: Methodsmentioning

confidence: 99%

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ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

et al. 2016

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Objective Cerebral Edema (CE) in TBI is the consequence of multiple underlying mechanisms, and is associated with unfavorable outcomes. Genetic variability in these pathways likely explains some of the clinical heterogeneity observed in edema development. A role for Sulfonylurea-receptor-1 (Sur1) in CE is supported. However, there are no prior studies examining the effect of genetic variability in the Sur1 gene (ABCC8) on the development of CE. We hypothesize that ABCC8 single nucleotide polymorphisms (SNP) are predictive of CE. Methods DNA was extracted from 385 patients. SNPs in ABCC8 were genotyped using the Human Core Exome v1.2 (Illumina). CE measurements included acute CT edema, mean and peak intracranial pressure (ICP), and need for decompressive craniotomy. Results 14 SNPs with minor-allele frequency>0.2 were identified. 4 SNPS rs2283261, rs3819521, rs2283258 and rs1799857 were associated with CE measures. In multiple regression models, homozygote-variant genotypes in rs2283261, rs3819521, and rs2283258 had increased odds of CT edema (OR=2.45, p=0.007; OR=2.95, p=0.025; OR=3.00, p=0.013), had higher mean (β=3.13,p=0.000; β=2.95,p=0.005; β=3.20,p=0.008) and peak (β=8.00,p=0.001; β=7.64,p=0.007; β=6.89,p=0.034) ICP. The homozygote wild-type genotype of rs1799857 had decreased odds of decompressive craniotomy (OR=0.47, p=0.004). Conclusions This is the first report assessing the impact of ABCC8 genetic variability on CE development in TBI. Minor allele ABCC8 SNP genotypes had increased risk of CE, while major SNP alleles were protective—potentially suggesting an evolutionary advantage. These findings could guide risk stratification, treatment responders, and the development of novel targeted or gene-based therapies against CE in TBI and other neurological disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

et al. 2016

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“…Pair-wise D' and r2 LD measures between SNPs were made using the JLIN program. 20 Univariate and multivariate logistic regression models were used to evaluate possible associations between individual tag SNPs 21 Although conservative for tightly linked SNPs, 22 the Bonferroni correction for multiple comparisons was applied, and the significance threshold was set to 0.05 divided by the number of the tested SNPs. Statistical analysis was performed with the SPSS software version 17.0 (SPSS Inc., Chicago, IL).…”

Section: Discussionmentioning

confidence: 99%

AQP4 Tag Single Nucleotide Polymorphisms in Patients with Traumatic Brain Injury

Dardiotis

Paterakis

Tsivgoulis

et al. 2014

Journal of Neurotrauma

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Accumulating evidence suggests that the extent of brain injury and the clinical outcome after traumatic brain injury (TBI) are modulated, to some degree, by genetic variants. Aquaporin-4 (AQP4) is the predominant water channel in the central nervous system and plays a critical role in controlling the water content of brain cells and the development of brain edema after TBI. We sought to investigate the influence of the AQP4 gene region on patient outcome after TBI by genotyping tag single nucleotide polymorphisms (SNPs) along AQP4 gene. A total of 363 patients with TBI (19.6% female) were prospectively evaluated. Data including the Glasgow Coma Scale (GCS) scores at admission, the presence of intracranial hemorrhage, and the 6-month Glasgow Outcome Scale (GOS) scores were collected. Seven tag SNPs across the AQP4 gene were identified based on the HapMap data. Using logistic regression analyses, SNPs and haplotypes were tested for associations with 6-month GOS after adjusting for age, GCS score, and sex. Significant associations with TBI outcome were detected for rs3763043 (OR [95% confidence interval (CI)]: 5.15 [1.60-16.5], p=0.006, for recessive model), rs3875089 (OR [95% CI]: 0.18 [0.07-0.50] p=0.0009, for allele difference model), and a common haplotype of AQP4 tag SNPs (OR [95% CI]: 2.94, [1.34-6.36], p=0.0065). AQP4 tag SNPs were not found to influence the initial severity of TBI or the presence of intracranial hemorrhages. In conclusion, the present study provides evidence for possible involvement of genetic variations in AQP4 gene in the functional outcome of patients with TBI.

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“…While GWA methods allow for unbiased evaluation of the entire genome, many of the genotyping platforms available do not provide uniform coverage of all chromosomes or chromosomal regions (20). In addition, several candidate gene studies have used HapMap as a resource to obtain tagging SNPs to comprehensively evaluate genetic variation in genes of interest (21) and HapMap is routinely used as the SNP set into which many GWA studies are imputed.. Therefore, evaluating which HapMap and high-throughput genotyping platforms contain sufficient genotypic information to successfully capture all the variation found in resequencing data for pharmacogenes, would provide investigators with much needed knowledge of coverage.…”

Section: Discussionmentioning

confidence: 99%

The limits of genome-wide methods for pharmacogenomic testing

Gamazon

Skol

Perera

2012

Pharmacogenetics and Genomics

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Objective The goal of pharmacogenomics is the translation of genomic discoveries to individualized patient care. Recent advances in the means to survey human genetic variation are fundamentally transforming our understanding of the genetic basis of interindividual variation in therapeutic response. The goal of this study was to systematically evaluate high-throughput genotyping technologies for their ability to assay variation in pharmacogenetically important genes (pharmacogenes). These platforms are either being proposed for or are already widely used for clinical implementation; therefore, knowledge of coverage of pharmacogenes on these platforms would serve to better evaluate current or proposed pharmacogenetic association studies. Method Among the genes included in our study are drug metabolizing enzymes, transporters, receptors, and drug targets, of interest to the entire pharmacogenetic community. We considered absolute and LD-informed coverage, minor allele frequency spectrum and functional annotation for a Caucasian population. We also examined the effect of linkage disequilibrium, effect size and cohort size on power to detect SNP associations. Results In our analysis of 253 pharmacogenes, we found that no platform showed more than 85% coverage of these genes (after accounting for LD). Furthermore the lack of coverage showed a dramatic increase at minor allele frequencies of less than 20%. Even after accounting for LD, only 30% of missense polymorphisms (which are enriched for low frequency alleles) were covered by HapMap with still lower coverage on the other platforms. Conclusion We have conducted the first systematic evaluation of the Axiom Genomic Database, Omni 2.5M and the DMET chip. This study is the first to utilize the 1000 Genomes Project to present a comprehensive evaluative framework. Our results provide a much-needed assessment of microarray-based genotyping and next-generation sequencing technologies’ ability to survey fully the variation in genes of particular interest to the pharmacogenetics community. Our findings demonstrate the limitations of genome-wide methods and the challenges of implementing pharmacogenomic tests into the clinical context.

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Angiotensin-converting enzyme tag single nucleotide polymorphisms in patients with intracerebral hemorrhage

Abstract: Our results did not provide clear evidence for a role of ACE gene in the development of ICH.

Cited by 15 publications

References 30 publications

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

ABCC8 Single Nucleotide Polymorphisms are Associated with Cerebral Edema in Severe TBI

AQP4 Tag Single Nucleotide Polymorphisms in Patients with Traumatic Brain Injury

The limits of genome-wide methods for pharmacogenomic testing

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