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Benjamin A Salisbury

Publications and source records attributed to Benjamin A Salisbury.

7 recordsLinked to original sources
PubMed2006

Candidate-gene association study of mothers with pre-eclampsia, and their infants, analyzing 775 SNPs in 190 genes.

Pre-eclampsia (PE) affects 5-7% of pregnancies in the US, and is a leading cause of maternal death and perinatal morbidity and mortality worldwide. To identify genes with a role in PE, we conducted a large-scale association study evaluating 775 SNPs in 190 candidate genes selected for a potential role in obstetrical complications. SNP discovery was performed by DNA sequencing, and genotyping was carried out in a high-throughput facility using the MassARRAY(TM) System. Women with PE (n = 394) and their offspring (n = 324) were compared with control women (n = 602) and their offspring (n = 631) from the same hospital-based population. Haplotypes were estimated for each gene using the EM algorithm, and empirical p values were obtained for a logistic regression-based score test, adjusted for significant covariates. An interaction model between maternal and offspring genotypes was also evaluated. The most significant findings for association with PE were COL1A1 (p = 0.0011) and IL1A (p = 0.0014) for the maternal genotype, and PLAUR (p = 0.0008) for the offspring genotype. Common candidate genes for PE, including MTHFR and NOS3, were not significantly associated with PE. For the interaction model, SNPs within IGF1 (p = 0.0035) and IL4R (p = 0.0036) gave the most significant results. This study is one of the most comprehensive genetic association studies of PE to date, including an evaluation of offspring genotypes that have rarely been considered in previous studies. Although we did not identify statistically significant evidence of association for any of the candidate loci evaluated here after adjusting for multiple testing using the false discovery rate, additional compelling evidence exists, including multiple SNPs with nominally significant p values in COL1A1 and the IL1A region, and previous reports of association for IL1A, to support continued interest in these genes as candidates for PE. Identification of the genetic regulators of PE may have broader implications, since women with PE are at increased risk of death from cardiovascular diseases later in life.

Adult↗
PubMed2006

Allelic dropout in long QT syndrome genetic testing: a possible mechanism underlying false-negative results.

BACKGROUND: Genetic testing for congenital long QT syndrome (LQTS) has been performed in research laboratories for the past decade. Approximately 75% of patients with high clinical probability for LQTS have a mutation in one of five LQTS-causing cardiac channel genes. Possible explanations for the remaining genotype-negative cases include LQTS mimickers, novel LQTS-causing genes, unexplored regions of the known genes, and genetic testing detection failures. OBJECTIVES: The purpose of this study was to explore the possibility of allelic dropout as a possible mechanism underlying false-negative test results. METHODS: The published primers currently used by many research laboratories to conduct a comprehensive analysis of the 60 translated exons in the KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6) genes were analyzed for the presence of common intronic single nucleotide polymorphisms (SNPs). Repeat mutational analysis, following primer/amplicon redesign using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing, was performed on a cohort of 541 consecutive, unrelated patients referred for LQTS genetic testing. RESULTS: Common (>1% minor allele frequency) intronic SNPs were discovered within the primer sequences of five of 60 translated exons. Following primer redesign to eliminate the possibility of allelic dropout, four previously genotype-negative index cases were found to possess LQTS-causing mutations: R591H-KCNQ1 and R594Q-KCNQ1 for exon 15 and E229X-KCNH2 in two unrelated cases. Repeat examination of these two amplicons in 400 reference alleles did not identify these or any additional amino acid variants. CONCLUSION: Allelic dropout secondary to intronic SNP-primer mismatch prevented the discovery of LQTS-causing mutations in four cases. Considering that many LQTS genetic testing research laboratories have used these primers, patients who reportedly are genotype negative may benefit from re-examination of those regions susceptible to allelic dropout due to primer-disrupting SNPs, particularly exon 15 in KCNQ1 and exon 4 in KCNH2.

Adolescent↗
PubMed2006

Pharmacogenetic issues in thorough QT trials.

Drug-induced QT prolongation (DI-LQT), through its associated arrhythmias, is a leading cause of drugs being withdrawn from the market. As a consequence, the US FDA and other regulatory agencies are mandating that all new drugs go through a so-called 'Thorough QT' (TQT) study to evaluate the potential for 'QT liability', specifically the potential for a drug to cause a discernible increase in the QT interval. Several genetic factors that modulate the risk of DI-LQT have been discovered. These are genes responsible for the congenital long QT syndrome, drug metabolism genes (mainly CYP2D6 and CYP3A4), and genes in other regulatory pathways. Here, we briefly review the links between genetic variants and drug-induced QT risk, and propose approaches to consider for using pharmacogenetics in planning and analyzing TQT studies.

Arrhythmias, Cardiac↗
PubMed2004

Genetic variability and evolution of two pharmacologically important classes of genes.

We have studied the human genetic variability of single nucleotide polymorphisms (SNPs) and haplotypes in two pharmaceutically important classes of genes that might be expected to experience different evolutionary pressures: antigen presentation and processing (APP) and nuclear hormone receptor (NHR) genes. We compared the variation pattern in these two classes of genes with 5119 reference (REF) genes. We assessed this variability by sequencing and discovering SNPs in 5'-upstream, 5'-untranslated region (5'UTR), exon, intron, 3'UTR and 3'-downstream regions of all these genes in 79 unrelated humans from diverse ethnic backgrounds, one chimpanzee (Pan troglodytes) and a gorilla (Gorilla gorilla). SNP density and nucleotide diversity were higher in the APP genes than the REF genes. Relative to the REF genes, APP SNP density was significantly higher in the coding and 3'UTR regions. Higher variation in the coding region of the APP genes was due specifically to having more non-synonymous changes, which suggests that natural selection may be acting to promote change or diversity in these proteins. In contrast, the NHR genes showed lower SNP density and diversity relative to REF genes. The NHR genes consistently showed lower nucleotide diversity in all the genomic regions except in the 3'downstream region. SNP frequency data on the non-synonymous SNPs also suggested that the coding region in the NHR genes is conserved to a higher degree than the coding region in the REF genes. Significantly lower SNP density was observed in the 5'-upstream and 5'UTR regions of the NHR genes, perhaps reflecting selective conservation of these regions. Heterozygosity in the APP genes was significantly higher than in the NHR genes in each of the three species tested. Moreover, between species there were more fixed differences in the APP genes than in the NHR genes. Substantial variability exists in these two classes of genes. It is important to consider this interindividual variability pattern while developing drugs that act on such targets.

Alleles↗
PubMed2003

SNP and haplotype variation in the human genome.

We have surveyed and summarized several aspects of DNA variability among humans. The variation described is the result of mutation followed by a combination of drift, migration and selection bringing the frequencies high enough to be observed. This paper describes what we have learned about how DNA variability differs among genes and populations. We sequenced functional regions of a set of 3950 genes. DNA was sampled from 82 unrelated humans: 20 African-Americans, 20 East Asians, 21 Caucasians, 18 Hispanic-Latinos and 3 Native Americans. Different aspects of variability showed a great deal of concordance. In particular, we studied patterns of single nucleotide polymorphism (SNP) allele and haplotype sharing among the four, large sample populations. We also examined how linkage disequilibrium (LD) between SNPs relates to physical distance in the different populations. It is clear from our findings that while many variants are common to all populations, many others have a more restricted distribution. Research that attempts to find genetic variants that explain phenotypic variants must be careful in their choice of study population.

Alleles↗
PubMed2003

DNA variability of human genes.

We have investigated the level of DNA-based variation (both SNPs and haplotypes) for several thousand human genes. In addition, we have characterized how this variation is distributed in a number of biologically and clinically important ways. First, we have determined how SNPs are distributed within human genes: where they occur relative to various functional regions; levels of variability of human SNPs; pattern of the molecular sequence of SNPs; and how these compare with the corresponding sequence of a chimpanzee. Second, we have determined how these aspects of SNP distribution vary among four human population samples. All genes were sequenced on DNA obtained from 82 unrelated individuals: 20 African-Americans, 20 East Asians, 21 European-Americans, 18 Hispanic-Latinos and three Native Americans. In particular, we looked at patterns of SNP and haplotype sharing among the four larger population samples. Third, we have determined the patterns of linkage disequilibrium among SNPs, which also determines the haplotype variability of each gene. These characteristics also vary substantially among populations. A deeper understanding of these aspects of human genetic variation will be of vital importance when trying to identify the genetic contribution to complex phenotypes such as aging.

Aging↗