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Biomedical subjects

David B Goldstein

Publications and source records attributed to David B Goldstein.

At least 19 recordsLinked to original sources
PubMed2026

Precision Diagnosis in APOL1 Kidney Disease With the p.N264K M1 Protective Variant.

IMPORTANCE: The APOL1 M1 (p.N264K) variant protects against G2-associated APOL1 focal segmental glomerulosclerosis (FSGS) and chronic kidney disease (CKD). However, the utility of knowing an individual's M1 status in guiding kidney disease diagnosis and other clinical scenarios remains underexplored. OBJECTIVE: To test 2 hypotheses: (1) in patients with APOL1 high-risk (HR) genotype kidney disease with at least 1 G2 allele, M1 can distinguish APOL1 CKD from non-APOL1 CKD; (2) in people with APOL1 low-risk (LR) genotypes, M1 is independently associated with protection against FSGS and CKD. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-control study using data from 2 tertiary care hospitals (Columbia University Irving Medical Center and Mass General Brigham Biobank) and population-based data (the UK Biobank [UKB], Electronic Medical Records and Genomics [eMERGE-III], and All of Us [AoU]). Participants were individuals with a diagnosis of FSGS or steroid-resistant nephrotic syndrome (SRNS), individuals with CKD, and controls. EXPOSURES: Exposures included the M1 variant (p.N264K) obtained from exome or genome sequencing data, sex, and genetic ancestry. MAIN OUTCOME AND MEASURE: The main outcome was the presence or absence of kidney disease, defined as FSGS or non-FSGS CKD, compared with non-kidney disease controls. Association between the M1 variant and disease status was assessed using odds ratios (ORs). RESULTS: A total of 107 696 individuals (54 994 [51.1%] female; 8779 [8.2%] with African ancestry, 78 475 [72.9%] with European ancestry, and 16 129 [15.0%] with multiethnic ancestry), including 3460 with FSGS or SRNS, 24 382 with non-FSGS CKD kidney disease, and 79 854 controls were enrolled in the discovery cohort. In the APOL1-HR group (1413 participants), M1 was significantly inversely associated with FSGS or SRNS cases compared with controls without kidney disease (OR, 0.20; 95% CI, 0.04-0.63; P = 3.69 × 10-3). Among individuals with CKD with APOL1-HR genotypes, M1 was 4 times more frequent in those whose CKD was not due to FSGS or SRNS. Importantly, electronic health record and biopsy review identified an alternative, non-APOL1 cause for CKD in nearly all APOL1-HR-M1 cases. There was no association between individuals with APOL1-LR genotypes with M1 and protection against CKD or FSGS. CONCLUSIONS AND RELEVANCE: In this case-control study of 107 696 individuals, presence of an APOL1-HR genotype M1 was significantly associated with protection against kidney disease, suggesting that it may have a role as a genetic modifier. Patients with CKD with an APOL1-HR genotype and M1 should be evaluated for an alternative and potentially treatable cause of their CKD.

Humans↗
PubMed2021

High-impact rare genetic variants in severe schizophrenia.

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10-5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10-9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10-3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10-7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10-8). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

Aged↗
PubMed2006

Genomics meets HIV-1.

Genomics is now a core element in the effort to develop a vaccine against HIV-1. Thanks to unprecedented progress in high-throughput genotyping and sequencing, in knowledge about genetic variation in humans, and in evolutionary genomics, it is finally possible to systematically search the genome for common genetic variants that influence the human response to HIV-1. The identification of such variants would help to determine which aspects of the response to the virus are the most promising targets for intervention. However, a key obstacle to progress remains the scarcity of appropriate human cohorts available for genomic research.

AIDS Vaccines↗
PubMed2006

Examining the role of common genetic variation in the gamma2 subunit of the GABA(A) receptor in epilepsy using tagging SNPs.

INTRODUCTION: Mutations in the gamma2 subunit gene of the GABA(A) receptor, GABRG2, have been shown to cause generalised epilepsy syndromes in rare familial cases. Here we set out to examine whether common variation in GABRG2 predisposes to the development of common, complex forms of epilepsy in two large independent cohorts. METHODS: We have applied a tagging single nucleotide polymorphism (tSNP) technique allowing us to satisfactorily represent common variation in the gene. However, to ensure maximal representation of functional variation and in particular in cases of low minor allele frequency (MAF), we have identified and forced known functional variation as tagging SNPs. We examined the association between tagging SNPs and subtypes of epilepsy in two independent cohorts; the first consisted of 677 cases and 384 healthy controls, the second of 684 cases and 277 healthy controls. RESULTS: We failed to detect any variation that conferred an increased risk of disease development in both cohorts. DISCUSSION: Our results suggest that common variants of strong effect in GABRG2 do not appear to play a role in the development of common, complex forms of epilepsy. This report illustrates a number of important features of study design in genetic association studies, including the simultaneous use of map and sequence-based techniques and the necessity of replication before robust conclusions can be drawn from results.

Alleles↗
PubMed2006

A pharmacogenetic exploration of vigabatrin-induced visual field constriction.

INTRODUCTION: Use of the antiepileptic drug (AED) vigabatrin is severely limited by irreversible visual field constriction, an adverse reaction to the drug reported in approximately 40% of patients. Given the evidence suggesting an idiosyncratic drug response, we set out to detect genetic variation of strong, clinically relevant effect that might guide clinicians in the safe, controlled prescribing of this otherwise usefuldrug. METHODS: Patients with a history of at least 1-year exposure to vigabatrin were enrolled at two independent referral centers. Using Goldmann perimetry, visual fields and the extent of constriction were calculated for each patient. We examined the correlation between the extent of vigabatrin induced visual field constriction and genetic variation across six candidate genes (SLC6A1, SLC6A13, SCL6A11, ABAT, GABRR1 and GABRR2). We availed of HapMap data and used a tagging SNP technique in an effort to efficiently capture all common variation within these genes. We attempted to replicate any positive associations before drawing conclusions from our results. RESULTS: The degree of visual field constriction correlated with three SNPs and one haplotype in a cohort of 73 patients. However we were unable to replicate these findings in a second independent cohort consisting of 58 patients, suggesting the initial results were possibly false positives, or variants of weak effect. CONCLUSION: Common variants of strong, clinically relevant effect do not appear to reside in the candidate genes studied here. This does not rule out the presence of genetic variants of weak effect in these genes, nor of variants of strong effect in other genes.

4-Aminobutyrate Transaminase↗
PubMed2006

UCHL-1 is not a Parkinson's disease susceptibility gene.

OBJECTIVE: The UCHL-1 gene is widely cited as a susceptibility factor for sporadic Parkinson's disease (PD). The strongest evidence comes from a meta-analysis of small studies that reported the S18Y polymorphism as protective against PD, after pooling studies of white and Asian subjects. Here, we present data that challenge this association. METHODS: In a new large case-control study in white individuals (3,023 subjects), the S18Y variant was not protective against PD under any genetic model of inheritance. Similarly, a more powerful haplotype-tagging approach did not detect other associated variants. RESULTS: Finally, in an updated S18Y-PD meta-analysis (6,594 subjects), no significant association was observed under additive, recessive, or dominant models (odds ratio = 1.00 [95% confidence interval: 0.74-1.33]; odds ratio = 1.01 [95% confidence interval: 0.76-1.35]; and odds ratio = 0.96 [95% confidence interval: 0.86-1.08], respectively), and a cumulative meta-analysis showed a trend toward a null effect. INTERPRETATION: Based on the current evidence, the UCHL-1 gene does not exhibit a protective effect in PD.

Case-Control Studies↗
PubMed2006

No association of DYNC1H1 with sporadic ALS in a case-control study of a northern European derived population: a tagging SNP approach.

The cytoplasmic dynein-dynactin complex has been implicated in the aetiology of motor neuron degeneration in both mouse models and human forms of motor neuron disease. We have previously shown that mutations in the cytoplasmic dynein 1 heavy chain 1 gene (Dync1h1) are causal in a mouse model of late-onset motor neuron degeneration but have found no association of the homologous sites in human DYNC1H1 with human motor neuron disease. Here we extend these analyses to investigate the DYNC1H1 genomic locus to determine if it is associated with sporadic amyotrophic lateral sclerosis (ALS) in a northern European-derived population. Among the 16 single nucleotide polymorphisms (SNPs) we examined, just two SNPs (rs2251644 and rs941793) were sufficient to tag the majority of haplotypic variation (r2 > or = 0.85) and these were tested in a case-control association study with 266 North American sporadic ALS patients and 225 matched controls. We found no association between genetic variation at DYNC1H1 and sporadic ALS (rs2251644; p = 0.538, rs941793; p = 0.204, haplotype; p = 0.956). In addition we investigated patterns of diversity at DYNC1H1 in Japanese and Cameroonian populations to establish the evolutionary history for this gene and observed reduced genetic diversity in the northern Europeans suggestive of selection at this locus.

Amyotrophic Lateral Sclerosis↗
PubMed2006

A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose.

OBJECTIVES: A broad range of phenytoin doses is used in clinical practice, with the final 'maintenance' dose normally determined by trial and error. A common functional polymorphism in the SCN1A gene (one of the genes encoding the drug target) has been previously associated with maximum dose of phenytoin used clinically, and also maximum dose of carbamazepine, another antiepileptic drug with the same drug target. METHODS: We have related variation at the SCN1A IVS5-91 G>A polymorphism to maximum dose and to maintenance dose of phenytoin in 168 patients with epilepsy treated with phenytoin. We also related genotype to phenytoin serum levels at maximum dose and at maintenance dose of phenytoin. We genotyped the polymorphism using an Applied Biosystems Taqman assay. RESULTS: The polymorphism is associated with phenytoin serum concentration at maintenance dose (P=0.03). In a reduced cohort of 71 patients receiving phenytoin monotherapy this association is also significant (P=0.03). Neither association remains significant after Bonferroni correction for multiple testing. CONCLUSIONS: These results are not a replication of the original study. They do, however, support the hypothesis that this polymorphism influences the clinical use of phenytoin. They also demonstrate the utility of using multiple phenotypes in pharmacogenetics studies, particularly when attempting to separate pharmacokinetic and pharmacodynamic effects. As the SCN1A polymorphism affects phenytoin pharmacodynamics, it is particularly useful to obtain data on serum levels in addition to dose because association of a pharmacodynamic variant may be stronger with serum levels than dose as the serum level may eliminate or reduce pharmacokinetic variability.

Anticonvulsants↗
PubMed2005

The genetics of human drug response.

The genetics of variable drug response appears to be a more tractable complex trait than common disease predisposition. This has implications for prioritizing research and for experimental design, and in particular argues for extensive use of candidate gene based approaches in pharmacogenetic association studies. Eventually, when whole genome scanning becomes feasible, it may be appropriate to consider weighting schemes that assign higher prior probabilities of variants in genes related to the mode of action of metabolism of medicines.

Genes↗
PubMed2005

Positive selection on a high-sensitivity allele of the human bitter-taste receptor TAS2R16.

BACKGROUND: During periods of human expansion into new environments, recognition of bitter natural toxins through taste may have conferred an important selective advantage. The G protein-coupled receptor encoded by TAS2R16 mediates response to salicin, amygdalin, and many bitter beta-glucopyranosides. beta-glucopyranosides are ubiquitous in nature, with many having a highly toxic cyanogenic activity. RESULTS: We examined evidence for natural selection on the human receptor TAS2R16 by sequencing the entire coding region, as well as part of the 5' and 3' UTRs, in 997 individuals from 60 human populations. We detected signatures of positive selection, indicated by an excess of evolutionarily derived alleles at the nonsynonymous site K172N and two linked sites and significant values of Fay and Wu's H statistics in 19 populations. The estimated age range for the common ancestor of the derived N172 variant is 78,700-791,000 years, placing it in the Middle Pleistocene and before the expansion of early humans out of Africa. Using calcium imaging in cells expressing different receptor variants, we showed that N172 is associated with an increased sensitivity to salicin, arbutin, and five different cyanogenic glycosides. CONCLUSION: We have detected a clear signal of positive selection at the bitter-taste receptor gene TAS2R16. We speculate that the increased sensitivity that is shown toward harmful cyanogenic glycosides and conferred by the N172 allele may have driven the signal of selection at an early stage of human evolution.

Alleles↗
PubMed2005

Failure to replicate previously reported genetic associations with sporadic temporal lobe epilepsy: where to from here?

Temporal lobe epilepsy (TLE), traditionally thought to develop largely due to environmental factors, has recently become the focus of association studies in an effort to determine genetic risk factors. Here we examine all previous claims of association of genetic polymorphisms with TLE by attempting replication in a cohort of 339 TLE patients of European origin. We also examine if these variants contribute to other types of epilepsy by examination in a larger cohort of 752 patients representing a range of different epilepsies. We fail to clearly replicate any of the previously reported associations and also fail to show a role for these variants in the development of other forms of epilepsy. Although our results cannot definitively rule out a role for these genes, they do suggest that most and perhaps all of the previous associations are false positives. As has been the experience with other diseases, these results highlight the importance of larger sample sizes and replication. In TLE, it appears that collaboration before publication is the best option to increase sample size sufficiently in the short term. These general principles are applicable to other studies undertaken for common complex diseases.

Amyloid↗
PubMed2005

Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin.

Phenytoin and carbamazepine are effective and inexpensive anti-epileptic drugs (AEDs). As with many AEDs, a broad range of doses is used, with the final "maintenance" dose normally determined by trial and error. Although many genes could influence response to these medicines, there are obvious candidates. Both drugs target the alpha-subunit of the sodium channel, encoded by the SCN family of genes. Phenytoin is principally metabolized by CYP2C9, and both are probable substrates of the drug transporter P-glycoprotein. We therefore assessed whether variation in these genes associates with the clinical use of carbamazepine and phenytoin in cohorts of 425 and 281 patients, respectively. We report that a known functional polymorphism in CYP2C9 is highly associated with the maximum dose of phenytoin (P = 0.0066). We also show that an intronic polymorphism in the SCN1A gene shows significant association with maximum doses in regular usage of both carbamazepine and phenytoin (P = 0.0051 and P = 0.014, respectively). This polymorphism disrupts the consensus sequence of the 5' splice donor site of a highly conserved alternative exon (5N), and it significantly affects the proportions of the alternative transcripts in individuals with a history of epilepsy. These results provide evidence of a drug target polymorphism associated with the clinical use of AEDs and set the stage for a prospective evaluation of how pharmacogenetic diagnostics can be used to improve dosing decisions in the use of phenytoin and carbamazepine. Although the case made here is compelling, our results cannot be considered definitive or ready for clinical application until they are confirmed by independent replication.

Adolescent↗
PubMed2005

UCHL-1 gene in multiple system atrophy: a haplotype tagging approach.

To date, the etiology of multiple system atrophy (MSA) has proved impenetrable. We investigated the role of genetic variation in the UCHL-1 gene in MSA and looked for the presence of disease susceptibility alleles. We determined the linkage disequilibrium structure of the gene and employed a haplotype tagging strategy with power to represent 95% of the haplotype diversity. This approach was performed using a set of tagging single nucleotide polymorphisms (SNPs) that can infer the allelic state of all the common SNPs in UCHL-1 with a high coefficient of determination. This strategy enabled us to scan across the gene and maintain the power to detect signal(s) from any potential functional variant(s). In 257 Gilman-probable or -definite MSA subjects and 1,536 controls, we did not detect a case-control frequency difference for either the tagged haplotypes or for individual tagging SNPs. This search included the S18Y variant of UCHL-1, which has been reported to be protective in Parkinson's disease.

Adult↗
PubMed2005

Priorities and standards in pharmacogenetic research.

The current enthusiasm for pharmacogenetics draws much of its inspiration from the relatively few examples of polymorphisms that have marked and seemingly clinically relevant effects on drug response. In this regard, pharmacogenetic research has paralleled the study of human disease, which has enjoyed success in identifying mutations underlying mendelian conditions. Progress in deciphering the genetics of complex diseases, involving the interaction of multiple genes with each other and with the environment has been considerably less successful. In most instances, drug responses will probably also prove to be complex, influenced by both the environment and multiple genetic factors. For pharmacogenetics to deliver on its potential, this complexity will need to be recognized and accommodated, both in basic research and in clinical application of pharmacogenetics. As the attention of researchers begins to shift toward more systematic pharmacogenetic investigations, we suggest some priorities and standards for pharmacogenetic research.

Drug Design↗