Recent Publications on Type 2 Diabetic Retinopathy, Grapevine Flavor, Pulminary Function, and Pharmacogenetics Testing

         November 30, 2010

Let’s kick off this month’s recognition with Audrey Papp and Wolfgang Sadee at Ohio State University for their work on “Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition” just published in PLoS ONE. (All abstracts below.)

Also in pharmacogenetics (albeit in mice) this month is Tristan Sissung at the NIH National Cancer Research. His work is in Clinical Cancer Research, distributed by the American Association for Cancer Research, and is entitled “Impact of ABCB1 allelic variants on QTc interval prolongation.”

Next up is Chao-Qiang Lai from Tufts University, et al for their work on “Genome-wide association study of copy number variations associated with pulmonary function measures in Korea Associated Resource (KARE) cohorts” featured in Genomics.

Finally, we have two new articles in BMC Plant Biology and BMC Medical Genetics, exploring grapevine flavor and diabetes, respectively. Kudos to Fielding Hejtmancik at the NIH for his work on “Association Analysis of Nine Candidate Gene Polymorphisms in Indian Patients with Type 2 Diabetic Retinopathy.”

Congrats to all!

Flavopiridol Pharmacogenetics: Clinical and Functional Evidence for the Role of SLCO1B1/OATP1B1 in Flavopiridol Disposition, PLoS ONE, Ni, W. et al
Background: Flavopiridol is a cyclin-dependent kinase inhibitor in phase II clinical development for treatment of various forms of cancer. When administered with a pharmacokinetically (PK)-directed dosing schedule, flavopiridol exhibited striking activity in patients with refractory chronic lymphocytic leukemia. This study aimed to evaluate pharmacogenetic factors associated with inter-individual variability in pharmacokinetics and outcomes associated with flavopiridol therapy.
Methodology/Principal Findings: Thirty-five patients who received single-agent flavopiridol via the PK-directed schedule were genotyped for 189 polymorphisms in genes encoding 56 drug metabolizing enzymes and transporters. Genotypes were evaluated in univariate and multivariate analyses as covariates in a population PK model. Transport of flavopiridol and its glucuronide metabolite was evaluated in uptake assays in HEK-293 and MDCK-II cells transiently transfected with SLCO1B1. Polymorphisms in ABCC2, ABCG2, UGT1A1, UGT1A9, and SLCO1B1 were found to significantly correlate with flavopiridol PK in univariate analysis. Transport assay results indicated both flavopiridol and flavopiridol-glucuronide are substrates of the SLCO1B1/OATP1B1 transporter. Covariates incorporated into the final population PK model included bilirubin, SLCO1B1 rs11045819 and ABCC2 rs8187710. Associations were also observed between genotype and response. To validate these findings, a second set of data with 51 patients was evaluated, and overall trends for associations between PK and PGx were found to be consistent.
Conclusions/Significance: Polymorphisms in transport genes were found to be associated with flavopiridol disposition and outcomes. Observed clinical associations with SLCO1B1 were functionally validated indicating for the first time its relevance as a transporter of flavopiridol and its glucuronide metabolite. A second 51-patient dataset indicated similar trends between genotype in the SLCO1B1 and other candidate genes, thus providing support for these findings. Further study in larger patient populations will be necessary to fully characterize and validate the clinical impact of polymorphisms in SLCO1B1 and other transporter and metabolizing enzyme genes on outcomes from flavopiridol therapy. Access this article

Impact of ABCB1 allelic variants on QTc interval prolongation, Clinical Cancer Research, Sissung, T. et al.
Purpose: While the ABCB1 (P-glycoprotein) drug transporter is a constituent of several blood-tissue barriers (i.e. blood-brain and blood-nerve), its participation in a putative blood-heart barrier has been poorly explored. ABCB1 could decrease the intracardiac concentrations of drugs that cause QT-prolongation and cardiotoxicity.
Experimental Design: ABCB1-related romidepsin transport kinetics were explored in LLC-PK1 cells transfected with different ABCB1 genetic variants. ABCB1 plasma and intracardiac concentrations were determined in Abcb1a/1b (-/-) mice and wild-type FVB controls. These same mice were used to evaluate romidepsin-induced QTc prolongation over time. Finally, a cohort of 83 individuals with available QTcB and ABCB1 genotyping data were used to compare allelic variation in ABCB1 versus QTc-prolongation phenotype. Results: Here, we demonstrate that mice lacking the ABCB1-type P-glycoprotein have higher intracardiac concentrations of a model ABCB1 substrate, romidepsin, that correspond to changes in QT-prolongation from baseline (ΔQTc) over time. Consistent with this observation, we also demonstrate that patients carrying genetic variants that could raise ABCB1 expression in the cardiac endothelium have lower ΔQTc following a single dose of romidepsin.
Conclusions: To our knowledge, this is the first evidence that Abcb1-type P-glycoprotein can limit intracardiac exposure to a drug that mediates QT-prolongation and suggests that certain commonly inherited polymorphisms in ABCB1 may serve as markers for QT-prolongation following the administration of ABCB1-substrate drugs. Access this article

Genome-wide association study of copy number variations associated with pulmonary function measures in Korea Associated Resource (KARE) next term cohorts, Genomics, Lee, B. et al
Copy number variation (CNV) is an attractive emerging approach to study the association with various diseases. We performed a CNV-based genome-wide association study of pulmonary function measures (FEV1, FVC, and FEV1/FVC) in KARE cohorts. Affymetrix Genome-wide Human SNP Array 5.0 was used to measure genome-wide variation and CNV segmentation was performed using Golden Helix SVS 7.0. Single and multivariate regressions were used for the association study using the R statistical package and the Dabatase for Annotation, Visualization and Integrated (DAVID v6.7b) tool for the functional annotation. We identified significantly associated 1260 CNVs with pulmonary function measures of FEV1 and FVC. Functional gene classification and annotation analysis found 5 highly enriched clusters, the BPI/LBP/Plunc superfamily, myosin, serpin peptidase inhibitor, protein tyrosine phosphatase, and olfactory receptors. According to the functional annotation, gene-based CNVs are likely to be involved in the pathogenesis and inflammatory responsiveness of pulmonary diseases. Access this article

A candidate gene association study on muscat flavor in grapevine (Vitis vinifera L.), BMC Plant Biology, Emanuelli, E. et al.
Background: The sweet, floral flavor typical of Muscat varieties (Muscats), due to high levels of monoterpenoids (geraniol, linalool and nerol), is highly distinct and has been greatly appreciated both in table grapes and in wine since ancient times. Muscat flavor determination in grape (Vitis vinifera L.) has up to now been studied by evaluating monoterpenoid levels through QTL analysis. These studies have revealed co-localization of 1-deoxy-D-xylulose 5-phosphate synthase (VvDXS) with the major QTL positioned on chromosome 5.
Results: We resequenced VvDXS in an ad hoc association population of 148 grape varieties, which included muscat-flavored, aromatic and neutral accessions as well as muscat-like aromatic mutants and non-aromatic offsprings of Muscats. Gene nucleotide diversity and intragenic linkage disequilibrium (LD) were evaluated. Structured association analysis revealed three SNPs in moderate LD to be significantly associated with muscat-flavored varieties. We identified a putative causal SNP responsible for a predicted non-neutral substitution and we discuss its possible implications for flavor metabolism. Network analysis revealed a major star-shaped cluster of reconstructed haplotypes unique to muscat-flavored varieties. Moreover, muscat-like aromatic mutants displayed unique non-synonymous mutations near the mutated site of Muscat genotypes.
Conclusions: This study is a crucial step forward in understanding the genetic regulation of muscat flavor in grapevine and it also sheds light on the domestication history of Muscats. VvDXS appears to be a possible human-selected locus in grapevine domestication and post-domestication. The putative causal SNP identified in Muscat varieties as well as the unique mutations identifying the muscat-like aromatic mutants under study may be immediately applied in marker-assisted breeding programs aimed at enhancing fragrance and aroma complexity respectively in table grape and wine cultivars. Access this article

Association Analysis of Nine Candidate Gene Polymorphisms in Indian Patients with Type 2 Diabetic Retinopathy, BMC Medical Genetics, Balasubbu, S. et al.
Background: Diabetic retinopathy (DR) is classically defined as a microvasculopathy that primarily affects the small blood vessels of the inner retina as a complication of diabetes mellitus (DM).It is a multifactorial disease with a strong genetic component. The aim of this study is to investigate the association of a set of nine candidate genes with the development of diabetic retinopathy in a South Indian cohort who have type 2 diabetes mellitus (T2DM).
Methods: Seven candidate genes (RAGE, PEDF, AKR1B1, EPO, HTRA1, ICAM and HFE) were chosen based on reported association with DR in the literature. Two more, CFH and ARMS2, were chosen based on their roles in biological pathways previously implicated in DR. Fourteen single nucleotide polymorphisms (SNPs) and one dinucleotide repeat polymorphism, previously reported to show association with DR or other related diseases, were genotyped in 345 DR and 356 diabetic patients without retinopathy (DNR). The genes which showed positive association in this screening set were tested further in additional sets of 100 DR and 90 DNR additional patients from the Aravind Eye Hospital. Those which showed association in the secondary screen were subjected to a combined analysis with the 100 DR and 100 DNR subjects previously recruited and genotyped through the Sankara Nethralaya Hospital, India. Genotypes were evaluated using a combination of direct sequencing, TaqMan SNP genotyping, RFLP analysis, and SNaPshot PCR assays. Chi-square and Fisher exact tests were used to analyze the genotype and allele frequencies.
Results: Among the nine loci (15 polymorphisms) screened, SNP rs2070600 (G82S) in the RAGE gene, showed significant association with DR (allelic P = 0.016, dominant model P = 0.012), compared to DNR. SNP rs2070600 further showed significant association with DR in the confirmation cohort (P=0.035, dominant model P = 0.032). Combining the two cohorts gave an allelic P < 0.003 and dominant P = 0.0013). Combined analysis with the Sankara Nethralaya cohort gave an allelic P = 0.0003 and dominant P = 0.00011 with an OR = 0.49 (0.34 – 0.70) for the minor allele. In HTRA1, rs11200638 (G>A), showed marginal significance with DR (P=0.055) while rs10490924 in LOC387715 gave a P = 0.07. No statistical significance was observed for SNPs in the other 7 genes studied.
Conclusions: This study confirms significant association of one polymorphism only (rs2070600 in RAGE) with DR in an Indian population which had T2DM. Access this article

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