This PharmGKB summary briefly discusses the very important pharmacogene GSTT1 and its variants that can influence drug responses. A fully interactive version of this short review, with links to individual paper annotations and population descriptions can be found at http://www.pharmgkb.org/vip/PA183.
The very important pharmacogenes (VIPs) were selected by Pharmacogenetic Research Network (National Institutes of Health-PGRN) owing to their significant effects on drug treatment both at the pharmacokinetic and pharmacodynamic levels. Our objective was to identify single nucleotide polymorphisms (SNPs) that potentially affected the expression of these genes or potential SNP–gene interactions involved to improve our understanding of genetic effects on drug therapy.
Gene expression was evaluated in 176 International HapMap lymphoblastoid cell lines derived from CEU (CEPH, Utah residents with ancestry from northern and western Europe; n = 87) and YRI (Yoruba in Ibadan, Nigeria; n = 89) using Affymetrix GeneChip Human Exon 1.0 ST arrays (Affymetrix Laboratory, Affymetrix Inc., Santa Clara, California, USA) with interrogation of greater than 17000 human genes. Genome-wide association was performed between over two million publicly available HapMap SNPs and gene expression.
The expression of two PGRN-VIPs (GSTT1 and GSTM1) are significantly associated with SNPs within 2.5 Mb of the genes; whereas the expression of three and ten PGRN-VIPs are significantly associated with distant-acting SNPs in CEU and YRI, respectively. In addition, three and four PGRN-VIPs harbor SNPs that are distantly associated with other gene expressions in CEU and YRI, respectively.
Using this information, one may identify genetic variants that are significantly associated with the expression of any set of genes of interest; or evaluate potential gene–gene interaction through SNP expression relationships.
exon array; expression quantitative trait loci; gene expression; glutathione-S-transferase; pharmacogenes
This PharmGKB summary briefly discusses the CYP2C19 gene and current understanding of its function, regulation, and pharmacogenomic relevance.
antidepressants; clopidogrel; CYP2C19*17; CYP2C19*2; CYP2C19; proton pump inhibitors; rs4244285
Regulatory elements play an important role in the variability of individual responses to drug treatment. This has been established through studies on three classes of elements that regulate RNA and protein abundance: promoters, enhancers and microRNAs. Each of these elements, and genetic variants within them, are being characterized at an exponential pace by next-generation sequencing (NGS) technologies. In this review, we outline examples of how each class of element affects drug response via regulation of drug targets, transporters and enzymes. We also discuss the impact of NGS technologies such as chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA sequencing (RNA-Seq), and the ramifications of new techniques such as high-throughput chromosome capture (Hi-C), chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) and massively parallel reporter assays (MPRA). NGS approaches are generating data faster than they can be analyzed, and new methods will be required to prioritize laboratory results before they are ready for the clinic. However, there is no doubt that these approaches will bring about a systems-level understanding of the interplay between genetic variants and drug response. An understanding of the importance of regulatory variants in pharmacogenomics will facilitate the identification of responders versus non-responders, the prevention of adverse effects and the optimization of therapies for individual patients.
ChIP-Seq; enhancers; miRNA; next-generation sequencing; pharmacogenomics; promoters; RNA-Seq
Human genetic variation is likely to be responsible for a substantial fraction of the variability in complex traits including drug response. Single nucleotide polymorphisms (SNPs) have been implicated in drug response using genome-wide association studies as well as candidate-gene approaches. A more comprehensive catalogue of human genetic variation should complement the current large-scale genotypic dataset from the International HapMap Project, which focuses on common genetic variants. The 1000 Genomes Project (KGP) is an international research effort that aims to provide the most comprehensive map of human genetic variation using next-generation sequencing platforms. Due to the lack of convenient tools, however, it is a challenge for the pharmacogenetic research community to take advantage of these data. We present here a new database of some pharmacogenes of particular interest to pharmacogenetic researchers. Our database provides a convenient portal for immediate utilization of the newly released KGP data in pharmacogenetic studies.
pharmacogenetics; pharmacogene; single nucleotide polymorphism; next generation sequencing; database
OATP2; organic anion transporter; pharmacogenomics; pharmacokinetics; SLCO1B1; statins
ACE:insertion/deletion; angiotensin-converting enzyme inhibitors; antihypertensives; pharmacogenomic; PharmGKB
acute lymphoblastic leukemia; pharmacogenetics; pharmacogenomics; polymorphism; thiopurine drugs
bupropion; cytochrome P450; CYP2B6; efavirenz; pharmacogene
HMGCR; 3-hydroxy-3-methylglutaryl coenzyme A reductase; PharmGKB; pravastatin; statin
ABC transporter; drug permeability; multidrug resistance; pharmacogenomics; PharmGKB
cyclooxygenase-2; coxibs; non-steroidal anti-inflammatory drugs; pharmacogenomics; PTGS2; rs20417; rs5275; rs689466
CYP1A2; caffeine; pharmacogene; pharmGKB
drug-induced oxidative stress; glucose-6-phosphate dehydrogenase deficiency; hemolytic anemia; pharmacodynamics; pharmacokinetics; polymorphic variants
CYP3A5; CYP3A5*2; CYP3A5*3; CYP3A5*6; CYP3A5*7; pharmacogenomics; rs10264272; rs28365083; rs76293380; rs776746
CYP2A6; inter-individual variation; pharmacokinetics; genetic polymorphisms; drug metabolism; drug efficacy
drug response; genetic variants; pharmacogenomics; vitamin D receptor
The management of premature birth still remains unsatisfactory. Since the relative lack of efficiency and/or safety of current tocolytic agents have been highlighted, it is necessary to develop new uterorelaxant drugs deprived of important maternal and foetal side effects. Our work reported in this review focuses on a potential new target for tocolytic drugs, the β3-adrenoceptor (ADRB3). This third type of ADRB is shown to be present and functional in human myometrium. We demonstrated that ADRB3 agonists are able to inhibit in-vitro spontaneous contractions of myometrial strips, via a cyclic AMP-mediated pathway. Furthermore, we established that ADRB3 is the predominant subtype over the ADRB2 in human myometrium and that its expression is increased in near-term myometrium, compared to non-pregnant myometrium. Finally, we reported that contrary to ADRB2, the human myometrial ADRB3 is resistant to long-term agonist-induced desensitisation. These compelling data confirm the clinical potential interest of ADRB3 agonists in the pharmacological management of preterm labour.
The involvement of β2-adrenergic receptor (ADRB2) and β3-adrenergic receptor (ADRB3) in both adipocyte lipolysis and thermogenic activity suggests that polymorphisms in the encoding genes might be linked with interindividual variation in obesity, an important risk factor for postmenopausal breast cancer. In order to examine the hypothesis that genetic variations in ADRB2 and ADRB3 represent interindividual susceptibility factors for obesity and breast cancer, we conducted a hospital-based, case-control study in the Aichi Cancer Center, Japan.
A self-administered questionnaire was given to 200 breast cancer patients and 182 control individuals, and pertinent information on lifestyle, family history and reproduction was collected. ADRB2 and ADRB3 genotypes were determined by polymerase chain reaction (PCR) restriction fragment length polymorphism assessment.
Twenty-five (12.4%) breast cancer patients and 32 (17.6%) control individuals were found to bear a glutamic acid (Glu) allele for the ADRB2 gene (odds ratio [OR] 0.67, 95% confidence interval [CI] 0.38-1.18), and 60 (30.0%) breast cancer patients and 61 (33.5%) control individuals were found to bear an Arg allele for the ADRB3 gene (OR 0.85, 95% CI 0.55-1.31). A significantly lower risk was observed in those who carried the Glu ADRB2 allele and who reported first childbirth when they were younger than 25 years (OR 0.35; 95% CI 0.13-0.99).
A potential association may exist between risk of breast cancer and polymorphisms in the ADRB2 and ADRB3 genes; further studies in larger samples and/or in different ethnic groups are warranted to investigate this potential association.
β2-adrenergic receptor gene; β3-adrenergic receptor gene; breast cancer risk; polymorphisms; reproductive history
The beta-2-Adrenergic receptor (ADRB2) gene on chromosome 5q33.1 is an important immunoregulatory factor. We and others have previously implicated chromosomal region 5q31-33 for contribution to the genetic susceptibility to Graves disease (GD) in East-Asian populations. Two recent studies showed associations between the single nucleotide polymorphism (SNP) rs1042714 in the ADRB2 gene and GD. In this study, we aimed to fully investigate whether the ADRB2 gene conferred susceptibility to GD in Chinese population, and to perform a meta-analysis of association between ADRB2 and GD.
Approximately 1 kb upstream the transcription start site and the entire coding regions of the ADRB2 gene were resequenced in 48 Han Chinese individuals to determine the linkage disequilibrium (LD) patterns. Tag SNPs were selected and genotyped in a case-control collection of 1,118 South Han Chinese subjects, which included 428 GD patients and 690 control subjects. A meta-analysis was performed with the data obtained in the present samples and those available from prior studies.
Fifteen SNPs in the ADRB2 gene were identified by resequencing and one SNP was novel. Ten tag SNPs were investigated further to assess association of ADRB2 in the case-control collection. Neither individual tag SNP nor haplotypes showed association with GD in Han Chinese population (P > 0.05). Our meta-analysis of the ADRB2 SNP rs1042714 measured heterogeneity between the ethnic groups (I2 = 53.1%) and no association to GD was observed in the overall three studies with a random effects model (OR = 1.13, 95% CI, 0.95 to 1.36; P = 0.18). However, significant association was found from the combined data of Caucasian population with a fixed effects model (OR = 1.18, 95% CI, 1.06 to 1.32; P = 0.002; I2 = 5.9%).
Our study indicated that the ADRB2 gene did not exert a substantial influence on GD susceptibility in Han Chinese population, but contributed to a detectable GD risk in Caucasian population. This inconsistency resulted largely from between-ethnicity heterogeneity.
Recent studies have suggested that the Arg allele of β3-adrenergic receptor (ADRB3) gene is associated with body mass index (BMI), which is an important predictor of bone mineral density (BMD) and fracture risk. However, whether the ADRB3 gene polymorphism is associated with fracture risk has not been investigated. The aim of study was to examine the inter-relationships between ADRB3 gene polymorphisms, BMI, BMD and fracture risk in elderly Caucasians.
Genotypes of the ADRB3 gene were determined in 265 men and 446 women aged 60+ in 1989 at entry into the study, whose BMD were measured by DXA (GE Lunar, WI USA) at baseline. During the follow-up period (between 1989 and 2004), fractures were ascertained by reviewing radiography reports and personal interviews.
The allelic frequencies of the Trp and the Arg alleles were 0.925 and 0.075 respectively, and the relative frequencies of genotypes Trp/Trp, Trp/Arg and Arg/Arg 0.857, 0.138 and 0.006 respectively. There was no significant association between BMI and ADRB3 genotypes (p = 0.10 in women and p = 0.68 in men). There was also no significant association between ADRB3 genotypes and lumbar spine or femoral neck BMD in either men and women. Furthermore, there were no significant association between ADRB3 genotypes and fracture risk in both women and men, either before or after adjusting for and, BMD and BMI.
The present data suggested that in Caucasian population the contribution of ADRB3 genotypes to the prediction of BMI, BMD and fracture risk is limited.
Genes involved in the regulation of catecholamine function may be important in obesity because of the role catecholamines play in energy expenditure and lipolysis. To determine if common single nucleotide polymorphisms (SNPs) in β1 (ADRB1), β2 (ADRB2), β3 (ADRB3) and α2a adrenergic receptor (ADRA2A) genes associate with obesity and metabolic alterations, we recruited 74 healthy African American and 161 Caucasian males and females (age: 18–49y) to participate in this case-control genetic association study. Genotypes were determined by PCR and RFLP. Associations between genotype and body mass index (BMI), percent body fat (by measuring skin fold thickness in 7 different sites), fasting (12-hour) plasma glucose, insulin, potassium concentrations, glycated hemoglobin (Hgb AIC) and insulin resistance (homeostasis model assessment score (HOMA-IR)) were performed. Among Caucasians, the ADRB1 Arg389→Gly variant associated with insulin concentrations and HOMAIR: mean ± SD values for insulin and HOMAIR in Arg389 homozygotes and carriers of the Gly were 10 ± 7.0 and 12 ± 9.4 μIU/ml (p=0.02) and 2.1 ± 1.7 and 2.6 ± 2.2 (p=0.057), respectively. Systolic blood pressure was higher in Caucasian for carriers of the ADBR1 Ser49 compared to Gly49 homozygotes 124 ± 12.6 vs. 119 ± 11.3 mm Hg, respectively (p = 0.02). Subsequent analysis revealed that these associations were attributable to a higher BMI among obese participants. The ADRA2A G1780A SNP associated with BMI and percent body fat in African Americans (p=0.05). Interactions were detected between ADRA2A C-1291G and ADRB2 Gln27→Glu variants for obesity in African Americans; and between ADRA2A C-1291G SNP and ADBR1 haplotype for obesity in Caucasians. We conclude that common SNPs in adrenergic receptor genes may be important susceptibility loci for obesity and related alterations. Because of the limited size of our populations, our results should be interpreted with caution and should be replicated in larger populations.
association study; obesity; adrenergic receptor polymorphisms; insulin resistance; gene-gene interactions
Exercise elicits a number of physiologic responses to increase oxygen delivery to working muscles. The β2-adrenergic receptors (ADRB2) play a role in the cardiopulmonary response to exercise. This review is focused on how the gene that encodes the ADRB2 influences the cardiopulmonary response to exercise. In addition, we discuss possible interactions between ADRB2 and other genes important in exercise performance.
ADRB2; ADRB1; cardiac output; stroke volume; pulmonary; airway