Lapatinib is associated with a low incidence of serious liver injury. Previous investigations have identified and confirmed the Class II allele HLA-DRB1*07:01 to be strongly associated with ...lapatinib-induced liver injury; however, the moderate positive predictive value limits its clinical utility. To assess whether additional genetic variants located within the major histocompatibility complex locus or elsewhere in the genome may influence lapatinib-induced liver injury risk, and potentially lead to a genetic association with improved predictive qualities, we have taken two approaches: a genome-wide association study and a whole-genome sequencing study. This evaluation did not reveal additional associations other than the previously identified association for HLA-DRB1*07:01. The present study represents the most comprehensive genetic evaluation of drug-induced liver injury (DILI) or hypersensitivity, and suggests that investigation of possible human leukocyte antigen associations with DILI and other hypersensitivities represents an important first step in understanding the mechanism of these events.
HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and ...taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10
, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.
Technological and scientific advances, stemming in large part from the Human Genome and HapMap projects, have made large-scale, genome-wide investigations feasible and cost effective. These advances ...have the potential to dramatically impact drug discovery and development by identifying genetic factors that contribute to variation in disease risk as well as drug pharmacokinetics, treatment efficacy, and adverse drug reactions. In spite of the technological advancements, successful application in biomedical research would be limited without access to suitable sample collections. To facilitate exploratory genetics research, we have assembled a DNA resource from a large number of subjects participating in multiple studies throughout the world. This growing resource was initially genotyped with a commercially available genome-wide 500,000 single-nucleotide polymorphism panel. This project includes nearly 6,000 subjects of African-American, East Asian, South Asian, Mexican, and European origin. Seven informative axes of variation identified via principal-component analysis (PCA) of these data confirm the overall integrity of the data and highlight important features of the genetic structure of diverse populations. The potential value of such extensively genotyped collections is illustrated by selection of genetically matched population controls in a genome-wide analysis of abacavir-associated hypersensitivity reaction. We find that matching based on country of origin, identity-by-state distance, and multidimensional PCA do similarly well to control the type I error rate. The genotype and demographic data from this reference sample are freely available through the NCBI database of Genotypes and Phenotypes (dbGaP).
Xeroderma pigmentosum variant (XP-V) is an inherited disorder resulting in hypersensitivity to the cytotoxic, mutagenic, and carcinogenic effects of UV light. There is evidence suggesting that XP-V ...cells carry a defect in the replication of UV-induced DNA damage, leading to mutations in genes, e.g., proto-oncogenes and tumor suppressor genes, of exposed skin cells. Using an in vitro assay to quantitatively evaluate replication of the most prevalent UV-derived DNA lesion, the cis,syn-thymine dimer (T x T), we have recently found that a T x T located on the leading strand can be bypassed by a bona fide human replication fork but can also induce fork uncoupling with selective synthesis of the undamaged lagging strand (D. Svoboda and J-M. Vos, Proc. Natl. Acad. Sci. USA, 92: 11975-11979, 1995). We now report the application and further refinement of this sensitive assay to the replication of a T x T-containing template by XP-V cell-free extracts. In comparison to normal controls, a 10-26-fold deficiency in the bypass replication of T x T was observed in XP-V cell extracts. In contrast, the disease extracts were as competent as controls for replication of the undamaged TT plasmid and for leading T x T-induced fork uncoupling. Besides mismatch repair and nucleotide excision repair, the bypass replication defect of XP-V may represent a novel category of hereditary mutator phenotypes affecting DNA damage processing.
Leptin and Renal Disease Briley, Libbie P.; Szczech, Lynda A.
Seminars in dialysis,
01/2006, Letnik:
19, Številka:
1
Journal Article
Recenzirano
ABSTRACT
Leptin is a mediator of metabolism and disease in a variety of organ systemsmost notably as an agent of energy stores. Howeverits role in renal disease as an inflammatory agent as well as ...its potential impact on the cachexia of uremia have sparked new interest in the molecule for nephrologists. This review elucidates the complex uremic statethe historical discovery of leptin and its physiologyand the potential interactions leptin has on both the progression of kidney disease as well as the morbidity and mortality of end‐stage renal disease.
Reports have associated non‐HLA antibodies, specifically those against angiotensin II type‐1 receptor (AT1R), with antibody‐mediated kidney graft rejection. However, association of anti‐AT1R with ...graft failure had not been demonstrated. We tested anti‐AT1R and donor‐specific HLA antibodies (DSA) in pre‐ and posttransplant sera from 351 consecutive kidney recipients: 134 with biopsy‐proven rejection and/or lesions (abnormal biopsy group ABG) and 217 control group (CG) patients. The ABG's rate of anti‐AT1R was significantly higher than the CG's (18% vs. 6%, p < 0.001). Moreover, 79% of ABG patients with anti‐AT1R lost their grafts (vs. 0%, CG), anti‐AT1R levels in 58% of those failed grafts increasing posttransplant. With anti‐AT1R detectable before DSA, time to graft failure was 31 months—but 63 months with DSA detectable before anti‐AT1R. Patients with both anti‐AT1R and DSA had lower graft survival than those with DSA alone (log‐rank p = 0.007). Multivariate analysis showed that de novo anti‐AT1R was an independent predictor of graft failure in the ABG, alone (HR: 6.6), and in the entire population (HR: 5.4). In conclusion, this study found significant association of anti‐AT1R with graft failure. Further study is needed to establish causality between anti‐AT1R and graft failure and, thus, the importance of routine anti‐AT1R monitoring and therapeutic targeting.
This study examines the association of non‐HLA antibodies against angiotensin II type 1 receptor with kidney allograft failure, showing the higher frequency of those antibodies in biopsy‐abnormal patients and also showing the independent association of de novo antibodies with graft failure. See related paper by Giral et al (page 2567) and editorial by Tinckam and Campbell (page 2515).
To date, limited information is available describing the incidence and impact of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSA) in the primary renal transplant patient. ...This report details the dnDSA incidence and actual 3-year post-dnDSA graft outcomes.
The study includes 189 consecutive nonsensitized, non-HLA-identical patients who received a primary kidney transplant between March 1999 and March 2006. Protocol testing for DSA via LABScreen single antigen beads (One Lambda) was done before transplantation and at 1, 3, 6, 9, and 12 months after transplantation then annually and when clinically indicated.
Of 189 patients, 47 (25%) developed dnDSA within 10 years. The 5-year posttransplantation cumulative incidence was 20%, with the largest proportion of patients developing dnDSA in the first posttransplantation year (11%). Young patients (18-35 years old at transplantation), deceased-donor transplant recipients, pretransplantation HLA (non-DSA)-positive patients, and patients with a DQ mismatch were the most likely to develop dnDSA. From DSA appearance, 9% of patients lost their graft at 1 year. Actual 3-year death-censored post-dnDSA graft loss was 24%.
We conclude that 11% of the patients without detectable DSA at transplantation will have detectable DSA at 1 year, and over the next 4 years, the incidence of dnDSA will increase to 20%. After dnDSA development, 24% of the patients will fail within 3 years. Given these findings, future trials are warranted to determine if treatment of dnDSA-positive patients can prevent allograft failure.
Background. Cardiac interventions are underutilized in patients with chronic kidney disease (CKD) following acute coronary syndrome (ACS) partly due to nephrotoxicity concerns. Methods. We analyzed ...outcomes of 4631 subjects with ACS enrolled in the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion trial, including time to death, time to reduced renal function (50% reduction in estimated glomerular filtration rate (eGFR) or development of end-stage renal disease (ESRD)) and percent change in eGFR from baseline. Results. Subjects with a lower baseline eGFR were more likely to be older, female and have diabetes, hypertension, congestive heart failure or peripheral vascular disease (all P < 0.0001); they were less likely to be taking aspirin ≥162 mg or to have undergone a percutaneous coronary intervention (PCI) prior to enrollment (P < 0.0001). As eGFR declined, the proportion of subjects experiencing death versus reduced eGFR or ESRD qualitatively increased. In adjusted analyses, every 10 ml/min/1.73 m2 decrease in eGFR ≤ 90 was associated with a 15% increased hazard of death (HR 1.15, P = 0.01). In adjusted analyses of predictors of percent change in eGFR, catheterization (cath) with or without PCI compared to medical therapy during follow-up was not associated with significant differences in long-term eGFR (P = 0.09). Conclusions. Among CKD subjects in this study, the risk of death greatly outweighed the risk of reduced eGFR or development of ESRD following ACS and the occurrence of cath ± PCI was not associated with significant differences in long-term renal function. The presence of CKD should not preclude potentially beneficial interventions and research should focus on reducing the high cardiovascular burden in this population.
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