Tang N.L.S.,Chinese University of Hong Kong |
Tang N.L.S.,Li Ka Shing Institute of Health science |
Tang N.L.S.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases |
Liao C.D.,Chinese University of Hong Kong |
And 8 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2013
Background: Breast cancer patients regularly undergo adjuvant chemotherapies following surgery. However, these treatments are largely associated with chemotherapeutic toxicities ranging from nausea to severe myelosuppression. In this investigation, we examined the effects of four SNPs in NR1I2, CYP3A4 and CYP3A5 genes on chemotherapy-induced severe neutropenia in 311 female Chinese breast cancer patients undergoing a standard adjuvant chemotherapy regimen. Methods: Patients were monitored for adverse reactions throughout the treatment, then divided into "none or mild" (80 %) or "severe" (20 %) toxicity groups according to whether they suffered grade 4 neutropenia defined as having an absolute neutrophil counts (ANC) of less than 0.5 × 109/L anytime during the treatment. DNA was extracted from patients' peripheral blood samples, then genotyped using allele-specific Tm-shift PCR and melting analysis. Results: Logistic regression revealed that rs776746 or CYP3A53 strongly associated with grade 4 neutropenia (OR = 2.56, P = 0.023) after adjustment for covariates, one of which more significant factor was baseline ANC (OR = 0.68, P = 0.020). Although univariate analysis in all patients did not reveal any association at first, further analysis indicated that rs776746 is significantly associated with severe neutropenia in subgroup of breast cancer patients with normal baseline ANC (≥2.0 × 109/L). These carriers of A-allele have 3.14-fold increased risk of developing severe neutropenia (P = 0.004). Conclusion: Our results suggested that polymorphisms in CYP3A5 might be useful pharmacogenetic markers for the prediction of severe neutropenia during chemotherapy, however, only after screening patients by their baseline ANC in the presence of gene-environmental interaction. We demonstrate an approach of pharmacogenetic analysis, in which the genetic data should be analyzed in the perspective of other clinical parameters. © 2012 Springer-Verlag Berlin Heidelberg.
Chen H.Y.,Chinese University of Hong Kong |
Huang W.,Peking Union Medical College |
Leung V.H.K.,Chinese University of Hong Kong |
Fung S.L.M.,Chinese University of Hong Kong |
And 4 more authors.
Human Mutation | Year: 2013
A CA-repeat microsatellite in insulin-like growth factor 1 (IGF1) promoter was associated with interindividual variation of circulating IGF1 level. Previously, we reported that such association was due to variation of haplotype unit in a linkage disequilibrium block composed of microsatellite and single-nucleotide polymorphisms (SNPs), suggesting the presence of an interaction between them. In this study, reporter assays were performed to investigate the regulatory effect and interaction of genetic variants on gene expression. We used an in vitro system to compare the transcriptional activities of haplotypes (rs35767:T>C, the CA-repeat microsatellite, rs5742612:T>C, and rs2288377:T>A) in evolutionarily conserved region of IGF1 promoter. In haplotype C-T-T, a longer microsatellite had a lower transcriptional activity (17.6 ± 2.4-fold for 17 repeats and 8.3 ± 1.1-fold for 21 repeats), whereas in haplotype T-C-A, such trend could not be observed, as the microsatellite with 21 repeats had the highest transcriptional activity (17.5 ± 2.3-fold). Because the microsatellite and SNPs affected the transcriptional activity of each other, there may be an interaction between them in the regulation of IGF1 expression. For the first time, we demonstrated that a noncoding microsatellite polymorphism could act as a functional unit and interact with SNPs in the regulation of transcription in human genome. © 2013 WILEY PERIODICALS, INC.
Peng M.-S.,CAS Kunming Institute of Zoology |
Peng M.-S.,KIZ CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases |
Peng M.-S.,University of Chinese Academy of Sciences |
Zhang Y.-P.,CAS Kunming Institute of Zoology |
And 2 more authors.
PLoS ONE | Year: 2011
Background: Extensive studies in different fields have been performed to reconstruct the prehistory of populations in the Japanese archipelago. Estimates the ancestral population dynamics based on Japanese molecular sequences can extend our understanding about the colonization of Japan and the ethnogenesis of modern Japanese. Methodology/Principal Findings: We applied Bayesian skyline plot (BSP) with a dataset based on 952 Japanese mitochondrial DNA (mtDNA) genomes to depict the female effective population size (Nef) through time for the total Japanese and each of the major mtDNA haplogroups in Japanese. Our results revealed a rapid Nef growth since ~5 thousand years ago had left ~72% Japanese mtDNA lineages with a salient signature. The BSP for the major mtDNA haplogroups indicated some different demographic history. Conclusions/Significance: The results suggested that the rapid population expansion acted as a major force in shaping current maternal pool of Japanese. It supported a model for population dynamics in Japan in which the prehistoric population growth initiated in the Middle Jomon Period experienced a smooth and swift transition from Jomon to Yayoi, and then continued through the Yayoi Period. The confounding demographic backgrounds of different mtDNA haplogroups could also have some implications for some related studies in future. © 2011 Peng, Zhang.
Wang C.-Y.,CAS Kunming Institute of Zoology |
Li H.,CAS Kunming Institute of Zoology |
Hao X.-D.,CAS Kunming Institute of Zoology |
Hao X.-D.,University of Chinese Academy of Sciences |
And 9 more authors.
PLoS ONE | Year: 2011
In the past decade, a high incidence of somatic mitochondrial DNA (mtDNA) mutations has been observed, mostly based on a fraction of the molecule, in various cancerous tissues; nevertheless, some of them were queried due to problems in data quality. Obviously, without a comprehensive understanding of mtDNA mutational profile in the cancerous tissue of a specific patient, it is unlikely to disclose the genuine relationship between somatic mtDNA mutations and tumorigenesis. To achieve this objective, the most straightforward way is to directly compare the whole mtDNA genome variation among three tissues (namely, cancerous tissue, para-cancerous tissue, and distant normal tissue) from the same patient. Considering the fact that most of the previous studies on the role of mtDNA in colorectal tumor focused merely on the D-loop or partial segment of the molecule, in the current study we have collected three tissues (cancerous, para-cancerous and normal tissues) respectively recruited from 20 patients with colorectal tumor and completely sequenced the mitochondrial genome of each tissue. Our results reveal a relatively lower incidence of somatic mutations in these patients; intriguingly, all somatic mutations are in heteroplasmic status. Surprisingly, the observed somatic mutations are not restricted to cancer tissues, for the para-cancer tissues and distant normal tissues also harbor somatic mtDNA mutations with a lower frequency than cancerous tissues but higher than that observed in the general population. Our results suggest that somatic mtDNA mutations in cancerous tissues could not be simply explained as a consequence of tumorigenesis; meanwhile, the somatic mtDNA mutations in normal tissues might reflect an altered physiological environment in cancer patients. © 2011 Wang et al.
Ma L.,CAS Kunming Institute of Zoology |
Ma L.,University of Chinese Academy of Sciences |
Wu D.-D.,CAS Kunming Institute of Zoology |
Ma S.L.,Chinese University of Hong Kong |
And 7 more authors.
Journal of Psychiatric Research | Year: 2014
CREB1 is a cAMP responsive transcriptional factor which plays a key role in neural development. CREB1 signal pathway (CSP) has been implicated repeatedly in studies of predisposition for schizophrenia. We speculated that CSP has undergone positive selection during evolution of modern human and some genes that have undergone natural selection in the past may predispose to schizophrenia (SCZ) in modern time. Positive selection and association analysis were employed to explore the molecular evolution of CSP and association with schizophrenia. Our results showed a pan-ethnic selection event on NRG1 and CREB1, as confirmed in all 14 ethnic populations studied, which also suggested a selection process occurred before the "Out of Africa" scenario. Analysis of 62 SNPs covering 6 CSP genes in 2019 Han Chinese (976 SCZ patients and 1043 healthy individuals) showed an association of two SNPs (rs4379857, P = 0.009, OR [95% CI]: 1.200 [1.379-1.046]; rs2238751, P = 0.023, OR [95% CI]: 1.253 [1.522-1.032]) with SCZ. However, none of these significances survived after multiple testing corrections. Nonetheless, we observed an association of a rare CREB1 haplotype CCGGC (Bonferroni corrected P = 1.74 × 10-5) with SCZ. Our study showed that there was substantial population heterogeneity in genetic predisposition to SCZ, and different genes in the CSP pathway may predispose to SCZ in different populations. © 2014 Elsevier Ltd.