David B Goldstein

Publications of David B Goldstein

• Clinical application of exome sequencing in undiagnosed genetic conditions.

  Authors: Anna C Need, Vandana Shashi, Yuki Hitomi, Kelly Schoch, Kevin V Shianna, Marie T McDonald, Miriam H Meisler, David B Goldstein

  Journal of medical genetics. 05/2012;

  BackgroundThere is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinicalBackgroundThere is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations.MethodsThe authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met.ResultsThis undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features).ConclusionsThis study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.

• Genetic basis of susceptibility to drug-induced liver injury: what have we learned and where do we go from here?

  Authors: Thomas J Urban, David B Goldstein, Paul B Watkins

  Pharmacogenomics. 05/2012; 13(7):735-8.

• The Association of Genetic Variants with Hepatic Steatosis in Patients with Genotype 1 Chronic Hepatitis C Infection.

  Authors: Paul J Clark, Alexander J Thompson, Qianqian Zhu, David M Vock, Mingfu Zhu, Keyur Patel, Stephen A Harrison, Susanna Naggie, Dongliang Ge, Hans L Tillmann [......] Jacques Fellay, Zachary Goodman, Stephanie Noviello, Lisa D Pedicone, Nezam Afdhal, Mark Sulkowski, Janice K Albrecht, David B Goldstein, John G McHutchison, Andrew J Muir

  Digestive diseases and sciences. 04/2012;

  BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impactsBACKGROUND: Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined. AIM: We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy. METHODS: A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0-3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR). RESULTS: IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10(-7); rs2896019, p = 7.56 × 10(-4)); clinically significant steatosis (rs12979860, p = 1.82 × 10(-3); rs2896019, p = 1.27 × 10(-4)); and steatosis severity (rs12979860, p = 2.05 × 10(-8); rs2896019, p = 2.62 × 10(-6)). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR. CONCLUSIONS: IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.

• Modifier genetics in neuropsychiatric disease: challenges and opportunities.

  Authors: Elizabeth K Ruzzo, Andrea L Pappas, David B Goldstein

  Genome biology. 03/2012; 13(3):150.

  ABSTRACT: A new study focuses attention on multigenic interactions influencing the risk of autism spectrum disorders.

• Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1.

  Authors: Charles D Howell, Alexis Gorden, Kathleen A Ryan, Alexander J Thompson, Chadi Ibrahim, Michael Fried, Nezam H Afdhal, John G McHutchison, Kevin V Shianna, David B Goldstein, Alan R Shuldiner, Braxton D Mitchell

  Journal of hepatology. 03/2012; 56(3):557-63.

  We studied the relationship between IL28B gene-related SNP rs12979860 and early viral kinetics (day 0-28) during peginterferon and ribavirin treatment, in 173 African Americans (AA) and 188 CaucasianWe studied the relationship between IL28B gene-related SNP rs12979860 and early viral kinetics (day 0-28) during peginterferon and ribavirin treatment, in 173 African Americans (AA) and 188 Caucasian Americans (CA) with HCV genotype 1. We studied the relationship between IL28B 16 gene-related SNP rs12979860 and early viral kinetics (day 0-28) 17 during peginterferon and ribavirin treatment, in 171 African 18 Americans (AA) and 188 Caucasian Americans (CA) with HCV 19 genotype 1. Compared to non-C/C genotypes, C/C was associated with greater declines in serum HCV RNA during phase 1 (day 0-2), phase 2 (day 7-28), and day 0-28 and higher response (undetected HCV RNA) rates at weeks 4 and 12 in AA and CA. A static phase and increases in HCV RNA from day 2 to 7 were more common in patients with non-C/C genotypes. C/C was also associated with higher week 24, 48, and 72 response rates in CA (p<0.01) but not in AA. At baseline, SNP genotype was the only independent predictor of phase 1; SNP genotype and phase 1 were independent predictors of phase 2 (p<0.001). There were no racial differences in HCV RNA declines during phase 1, day 2-7, phase 2, and day 0-28 with the same SNP genotype. AA with C/C and C/T genotypes had lower week 24, 48, and 72 (SVR) rates than did CA (p=0.03). SNP C/C predicted higher SVR rates in AA and CA with high baseline HCV RNA (⩾600,000IU/ml), and in CA with ⩾1log(10)IU/ml decrease in HCV RNA from day 0 to 28. SNP rs12979860 is strongly associated with both phase 1 and phase 2 HCV RNA kinetics in AA and CA with HCV genotype 1.

• Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.

  Authors: Michael J Ombrello, Elaine F Remmers, Guangping Sun, Alexandra F Freeman, Shrimati Datta, Parizad Torabi-Parizi, Naeha Subramanian, Tom D Bunney, Rhona W Baxendale, Marta S Martins [......] Elizabeth T Cirulli, David B Goldstein, Eric O Long, Susan Moir, Eric Meffre, Steven M Holland, Daniel L Kastner, Matilda Katan, Hal M Hoffman, Joshua D Milner

  The New England journal of medicine. 01/2012; 366(4):330-8.

  Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. We identified three families with a dominantlyMendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing. Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class-switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease-associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase Cγ(2) (PLCγ(2)), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in-frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures. Genomic deletions in PLCG2 cause gain of PLCγ(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.).

• Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia in HIV/HCV-coinfected patients with all HCV genotypes.

  Authors: Susanna Naggie, Norma I Rallon, José M Benito, Judith Morello, Sonia Rodriguez-Novoa, Paul J Clark, Alexander J Thompson, Kevin V Shianna, Eugenia Vispo, John G McHutchison, David B Goldstein, Vincent Soriano

  The Journal of infectious diseases. 12/2011; 205(3):376-83.

  A recent genome-wide association study reported a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate (ITPA) gene and hemolytic anemia in patients infected withA recent genome-wide association study reported a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate (ITPA) gene and hemolytic anemia in patients infected with hepatitis C virus (HCV) receiving pegylated interferon and ribavirin. We investigate these polymorphisms in a cohort of human immunodeficiency virus (HIV)/HCV-coinfected patients. DNA was available for 161 patients with validated outcomes. We analyzed the association between the variants and week 4 hemoglobin reduction. Anemia over the course of therapy, ribavirin (RBV) dose reduction, serum RBV level, and rapid virological response (RVR) and sustained virological response (SVR) were also investigated. Using a candidate gene approach, ITPA variants rs1127354 and rs7270101 were tested using the ABI TaqMan kit. Multivariable models were used to identify predictors of anemia. A significant minority (33%) of patients were predicted to have reduced ITPase activity. The minor allele of each variant was associated with protection against week 4 anemia. In multivariable models only the genetic variants, creatinine, and zidovudine exposure remained significant. ITPase deficiency was not associated with RBV-dose reduction, RVR, or SVR. This study confirms that polymorphisms in the ITPA gene are associated with protection from RBV-induced anemia in HIV/HCV-coinfected patients but not improved clinical outcomes.

• Correction: Copy Number Variation of KIR Genes Influences HIV-1 Control.

  Authors: Kimberly Pelak, Anna C Need, Jacques Fellay, Kevin V Shianna, Sheng Feng, Thomas J Urban, Dongliang Ge, Andrea De Luca, Javier Martinez-Picado, Steven M Wolinsky [......] Jay H Bream, Maureen P Martin, Persephone Borrow, Norman L Letvin, Andrew J McMichael, Barton F Haynes, Amalio Telenti, Mary Carrington, David B Goldstein, Galit Alter

  PLoS biology. 12/2011; 9(12).

  [This corrects the article on p. e1001208 in vol. 9.].

• Genetic and environmental correlates of topiramate-induced cognitive impairment.

  Authors: Elizabeth T Cirulli, Thomas J Urban, Susan E Marino, Kristen N Linney, Angela K Birnbaum, Chantal Depondt, Deborah K Attix, Rodney A Radtke, David B Goldstein

  Epilepsia. 11/2011; 53(1):e5-8.

  Topiramate is an antiepileptic drug that has marked treatment-limiting side effects on specific aspects of cognitive performance in both patients and healthy volunteers. Because these severe sideTopiramate is an antiepileptic drug that has marked treatment-limiting side effects on specific aspects of cognitive performance in both patients and healthy volunteers. Because these severe side effects occur only in certain individuals, identifying genetic or environmental variables that influence cognitive response would be of great utility in determining whether to administer this drug to a patient. We gave an acute 100 mg oral dose of topiramate to 158 healthy volunteers and measured how the drug changed their performance on a diverse battery of cognitive tests. We found a wide range of responses to topiramate, and we demonstrated that not all tests in the battery were equally affected. There was no correlation between the effect of topiramate and either education level or baseline cognitive performance. Of interest, there was an up to 55-fold variation in the topiramate plasma levels of the participants. Our genome-wide association study (GWAS) of cognitive response did not reveal any genome-wide significant associations; the study was powered to find variants explaining at least 25% of the variation in cognitive response. Combining the results of this GWAS with a retrospective study of cognitive complaints in 290 epilepsy patients who received topiramate as part of their treatment also did not result in a significant association. Our results support the need for additional genetic studies of topiramate that use larger sample sizes.

• Copy number variation of KIR genes influences HIV-1 control.

  Authors: Kimberly Pelak, Anna C Need, Jacques Fellay, Kevin V Shianna, Sheng Feng, Thomas J Urban, Dongliang Ge, Andrea De Luca, Javier Martinez-Picado, Steven M Wolinsky [......] Jay H Bream, Maureen P Martin, Persephone Borrow, Norman L Letvin, Andrew J McMichael, Barton F Haynes, Amalio Telenti, Mary Carrington, David B Goldstein, Galit Alter

  PLoS biology. 11/2011; 9(11):e1001208.

  A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control asA genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.

• The state of genome-wide association studies in pulmonary disease: a new perspective.

  Authors: Jamie L Todd, David B Goldstein, Dongliang Ge, Jason Christie, Scott M Palmer

  American journal of respiratory and critical care medicine. 07/2011; 184(8):873-80.

  With rapid advances in our knowledge of the human genome and increasing availability of high-throughput investigative technology, genome-wide association (GWA) studies have recently gained markedWith rapid advances in our knowledge of the human genome and increasing availability of high-throughput investigative technology, genome-wide association (GWA) studies have recently gained marked popularity. As an unbiased approach to identifying genomic regions of importance in complex human disease, the results of such studies have the potential to illuminate novel causal pathways, guide mechanistic research, and aid in prediction of disease risk. The use of a genome-wide approach presents considerable methodological and statistical challenges, and properly conducted studies are essential to avoid false-positive results. A total of 22 GWA studies have been published in pulmonary medicine thus far, implicating several intriguing genomic regions in the determination of pulmonary function measures, onset of asthma, and susceptibility to chronic obstructive pulmonary disease. Many questions remain, however, as most identified genetic variants contribute only nominally to overall disease risk, genetic disease mechanisms remain uncertain, and disease-associated variants are not consistent across studies. Perhaps most fundamentally, the association signals identified have not yet been traced to causal variants. This perspective will review the current state of GWA studies in pulmonary disease. We begin with an introduction to the hypothesis, principles, and limitations of this type of genome-wide approach, highlight key points from available studies, and conclude by addressing future approaches to better understand the genetics of complex pulmonary disease.

• A whole-genome analysis of premature termination codons.

  Authors: Elizabeth T Cirulli, Erin L Heinzen, Fred S Dietrich, Kevin V Shianna, Abanish Singh, Jessica M Maia, James J Goedert, David B Goldstein

  Genomics. 07/2011; 98(5):337-42.

  We sequenced the genomes of ten unrelated individuals and identified heterozygous stop codon-gain variants in protein-coding genes: we then sequenced their transcriptomes and assessed the expressionWe sequenced the genomes of ten unrelated individuals and identified heterozygous stop codon-gain variants in protein-coding genes: we then sequenced their transcriptomes and assessed the expression levels of the stop codon-gain alleles. An ANOVA showed statistically significant differences between their expression levels (p=4×10(-16)). This difference was almost entirely accounted for by whether the stop codon-gain variant had a second, non-protein-truncating function in or near an alternate transcript: stop codon-gains without alternate functions were generally not found in the cDNA (p=3×10(-5)). Additionally, stop codon-gain variants in two intronless genes were not expressed, an unexpected outcome given previous studies. In this study, stop codon-gain variants were either well expressed in all individuals or were never expressed. Our finding that stop codon-gain variants were generally expressed only when they had an alternate function suggests that most naturally occurring stop codon-gain variants in protein-coding genes are either not transcribed or have their transcripts destroyed.

• Contribution of pastimes and testing strategies to the performance of healthy volunteers on cognitive tests.

  Authors: Elizabeth T Cirulli, Deborah K Attix, Patrick J Smith, Ornit Chiba-Falek, Tracy O'Connor Pennuto, Kristen N Linney, David B Goldstein

  The Clinical neuropsychologist. 07/2011; 25(5):778-98.

  Clinicians routinely query factors known to impact cognitive test scores, including age and education. However, without data delineating the impact of less-frequently tracked variables, cliniciansClinicians routinely query factors known to impact cognitive test scores, including age and education. However, without data delineating the impact of less-frequently tracked variables, clinicians are limited to educated inferences about their effect. We explored the relationship of demographics, pastimes, and strategies with cognitive scores in a sample of 499 healthy young volunteers. As expected, age, education, ethnicity, and native language were strongly associated with most tests, while gender and dysphoria were associated with only some. Interestingly, pastimes such as playing number games and word games, and doing activities similar to the tests, were strongly associated with many measures, and testing strategies with almost all. Importantly, at least an additional 50% of the variation in Digit Span Backward and Animals scores was explained by adding covariates about pastimes and strategies to demographic covariates. These results support the utility of querying these elements.

• Genomic microdeletions associated with epilepsy: not a contraindication to resective surgery.

  Authors: Claudia B Catarino, Dalia Kasperavičiūtė, Maria Thom, Gianpiero L Cavalleri, Lillian Martinian, Erin L Heinzen, Thomas Dorn, Thomas Grunwald, Elijah Chaila, Chantal Depondt, Günter Krämer, Norman Delanty, David B Goldstein, Sanjay M Sisodiya

  Epilepsia. 06/2011; 52(8):1388-92.

  Several recent reports of genomic microdeletions in epilepsy will generate further research; discovery of more microdeletions and other important classes of variants may follow. Detection of suchSeveral recent reports of genomic microdeletions in epilepsy will generate further research; discovery of more microdeletions and other important classes of variants may follow. Detection of such genetic abnormalities in patients being evaluated for surgical treatment might raise concern that a genetic defect, possibly widely expressed in the brain, will affect surgical outcome. A reevaluation was undertaken of clinical presurgical data, histopathology of surgical specimen, and postsurgical outcome in patients with mesial temporal lobe epilepsy (MTLE) who have had surgical treatment for their drug-resistant seizures, and who have been found to have particular genomic microdeletions. Three thousand eight hundred twelve patients with epilepsy were genotyped and had a genome-wide screen to identify copy number variation. Ten patients with MTLE, who had resective epilepsy surgery, were found to have 16p13.11 microdeletions or other microdeletions >1 Mb. On histopathology, eight had classical hippocampal sclerosis (HS), one had nonspecific findings, and one had a hamartoma. Median postsurgical follow-up time was 48 months (range 10-156 months). All patients with HS were seizure-free after surgery, International League Against Epilepsy (ILAE) outcome class 1, at last follow-up; the patient with nonspecific pathology had recurrence of infrequent seizures after 7 years of seizure freedom. The patient with a hamartoma never became seizure-free.   Large microdeletions can be found in patients with "typical" MTLE. In this small series, patients with MTLE who meet criteria for resective surgery and harbor large microdeletions, at least those we have detected, can have a good postsurgical outcome. Our findings add to the spectrum of causal heterogeneity of MTLE + HS.

• Impact of phenotype definition on genome-wide association signals: empirical evaluation in human immunodeficiency virus type 1 infection.

  Authors: Evangelos Evangelou, Jacques Fellay, Sara Colombo, Javier Martinez-Picado, Niels Obel, David B Goldstein, Amalio Telenti, John P A Ioannidis

  American journal of epidemiology. 06/2011; 173(11):1336-42.

  Discussion on improving the power of genome-wide association studies to identify candidate variants and genes is generally centered on issues of maximizing sample size; less attention is given to theDiscussion on improving the power of genome-wide association studies to identify candidate variants and genes is generally centered on issues of maximizing sample size; less attention is given to the role of phenotype definition and ascertainment. The authors used genome-wide data from patients infected with human immunodeficiency virus type 1 (HIV-1) to assess whether differences in type of population (622 seroconverters vs. 636 seroprevalent subjects) or the number of measurements available for defining the phenotype resulted in differences in the effect sizes of associations between single nucleotide polymorphisms and the phenotype, HIV-1 viral load at set point. The effect estimate for the top 100 single nucleotide polymorphisms was 0.092 (95% confidence interval: 0.074, 0.110) log(10) viral load (log(10) copies of HIV-1 per mL of blood) greater in seroconverters than in seroprevalent subjects. The difference was even larger when the authors focused on chromosome 6 variants (0.153 log(10) viral load) or on variants that achieved genome-wide significance (0.232 log(10) viral load). The estimates of the genetic effects tended to be slightly larger when more viral load measurements were available, particularly among seroconverters and for variants that achieved genome-wide significance. Differences in phenotype definition and ascertainment may affect the estimated magnitude of genetic effects and should be considered in optimizing power for discovering new associations.

• SVA: software for annotating and visualizing sequenced human genomes.

  Authors: Dongliang Ge, Elizabeth K Ruzzo, Kevin V Shianna, Min He, Kimberly Pelak, Erin L Heinzen, Anna C Need, Elizabeth T Cirulli, Jessica M Maia, Samuel P Dickson, Mingfu Zhu, Abanish Singh, Andrew S Allen, David B Goldstein

  Bioinformatics (Oxford, England). 05/2011; 27(14):1998-2000.

  SUMMARY: Here we present Sequence Variant Analyzer (SVA), a software tool that assigns a predicted biological function to variants identified in next-generation sequencing studies and provides aSUMMARY: Here we present Sequence Variant Analyzer (SVA), a software tool that assigns a predicted biological function to variants identified in next-generation sequencing studies and provides a browser to visualize the variants in their genomic contexts. SVA also provides for flexible interaction with software implementing variant association tests allowing users to consider both the bioinformatic annotation of identified variants and the strength of their associations with studied traits. We illustrate the annotation features of SVA using two simple examples of sequenced genomes that harbor Mendelian mutations. Availability and implementation: Freely available on the web at http://www.svaproject.org.

• Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients.

  Authors: Alexander J Thompson, Paul J Clark, Abanish Singh, Dongliang Ge, Jacques Fellay, Mingfu Zhu, Qianqian Zhu, Thomas J Urban, Keyur Patel, Hans L Tillmann [......] Paul Y Kwo, Kevin V Shianna, Stephanie Noviello, Lisa D Pedicone, Clifford A Brass, Janice K Albrecht, Mark S Sulkowski, David B Goldstein, John G McHutchison, Andrew J Muir

  Journal of hepatology. 05/2011; 56(2):313-9.

  Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify geneticInterferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia. 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ≥80×10(9)/L and an absolute neutrophil count (ANC) ≥1500/mm(3). Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294). 6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p=10(-10)). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p=10(-12), p=10(-7)) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=-0.28, p=10(-17)) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia. Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.

• Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA class I and II alleles.

  Authors: M Isabel Lucena, Mariam Molokhia, Yufeng Shen, Thomas J Urban, Guruprasad P Aithal, Raúl J Andrade, Christopher P Day, Francisco Ruiz-Cabello, Peter T Donaldson, Camilla Stephens [......] Qun-Ying Yue, Michel Eichelbaum, Aris Floratos, Itsik Pe'er, Mark J Daly, David B Goldstein, John F Dillon, Matthew R Nelson, Paul B Watkins, Ann K Daly

  Gastroenterology. 04/2011; 141(1):338-47.

  Drug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, butDrug-induced liver injury (DILI), especially from antimicrobial agents, is an important cause of serious liver disease. Amoxicillin-clavulanate (AC) is a leading cause of idiosyncratic DILI, but little is understood about genetic susceptibility to this adverse reaction. We performed a genome-wide association study using 822,927 single nucleotide polymorphism (SNP) markers from 201 White European and US cases of DILI following AC administration (AC-DILI) and 532 population controls, matched for genetic background. AC-DILI was associated with many loci in the major histocompatibility complex. The strongest effect was with an HLA class II SNP (rs9274407, P=4.8×10(-14)), which correlated with rs3135388, a tag SNP of HLA-DRB1*1501-DQB1*0602 that was previously associated with AC-DILI. Conditioned on rs3135388, rs9274407 is still significant (P=1.1×10(-4)). An independent association was observed in the class I region (rs2523822, P=1.8×10(-10)), related to HLA-A*0201. The most significant class I and II SNPs showed statistical interaction (P=.0015). High-resolution HLA genotyping (177 cases and 219 controls) confirmed associations of HLA-A*0201 (P=2×10(-6)) and HLA-DQB1*0602 (P=5×10(-10)) and their interaction (P=.005). Additional, population-dependent effects were observed in HLA alleles with nominal significance. In an analysis of autoimmune-related genes, rs2476601 in the gene PTPN22 was associated (P=1.3×10(-4)). Class I and II HLA genotypes affect susceptibility to AC-DILI, indicating the importance of the adaptive immune response in pathogenesis. The HLA genotypes identified will be useful in studies of the pathogenesis of AC-DILI but have limited utility as predictive or diagnostic biomarkers because of the low positive predictive values.

• Host genetic determinants of T cell responses to the MRKAd5 HIV-1 gag/pol/nef vaccine in the step trial.

  Authors: Jacques Fellay, Nicole Frahm, Kevin V Shianna, Elizabeth T Cirulli, Danilo R Casimiro, Michael N Robertson, Barton F Haynes, Daniel E Geraghty, M Juliana McElrath, David B Goldstein

  The Journal of infectious diseases. 03/2011; 203(6):773-9.

  Understanding how human genetic variation impacts individual response to immunogens is fundamental for rational vaccine development. To explore host mechanisms involved in cellular immune responsesUnderstanding how human genetic variation impacts individual response to immunogens is fundamental for rational vaccine development. To explore host mechanisms involved in cellular immune responses to the MRKAd5 human immunodeficiency virus type 1 (HIV-1) gag/pol/nef vaccine tested in the Step trial, we performed a genome-wide association study of determinants of HIV-specific T cell responses, measured by interferon γ enzyme-linked immunospot assays. No human genetic variant reached genome-wide significance, but polymorphisms located in the major histocompatibility complex (MHC) region showed the strongest association with response to the HIV-1 Gag protein: HLA-B alleles known to be associated with differences in HIV-1 control were responsible for these associations. The implication of the same HLA alleles in vaccine-induced cellular immunity and in natural immune control is of relevance for vaccine design. Furthermore, our results demonstrate the importance of considering the host immunogenetic background in the analysis of immune responses to T cell vaccines.

• HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.

  Authors: Mark McCormack, Ana Alfirevic, Stephane Bourgeois, John J Farrell, Dalia Kasperavičiūtė, Mary Carrington, Graeme J Sills, Tony Marson, Xiaoming Jia, Paul I W de Bakker [......] Massimo Pandolfo, Werner Pichler, B Kevin Park, Chantal Depondt, Sanjay M Sisodiya, David B Goldstein, Panos Deloukas, Norman Delanty, Gianpiero L Cavalleri, Munir Pirmohamed

  The New England journal of medicine. 03/2011; 364(12):1134-43.

  Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlatedCarbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).