Biomedical subjects

Guliang Wang

Publications and source records attributed to Guliang Wang.

11 recordsLinked to original sources

PubMed2006

Non-B DNA structure-induced genetic instability.

Repetitive DNA sequences are abundant in eukaryotic genomes, and many of these sequences have the potential to adopt non-B DNA conformations. Genes harboring non-B DNA structure-forming sequences increase the risk of genetic instability and thus are associated with human diseases. In this review, we discuss putative mechanisms responsible for genetic instability events occurring at these non-B DNA structures, with a focus on hairpins, left-handed Z-DNA, and intramolecular triplexes or H-DNA. Slippage and misalignment are the most common events leading to DNA structure-induced mutagenesis. However, a number of other mechanisms of genetic instability have been proposed based on the finding that these structures not only induce expansions and deletions, but can also induce DNA strand breaks and rearrangements. The available data implicate a variety of proteins, such as mismatch repair proteins, nucleotide excision repair proteins, topoisomerases, and structure specific-nucleases in the processing of these mutagenic DNA structures. The potential mechanisms of genetic instability induced by these structures and their contribution to human diseases are discussed.

Base Sequence↗

PubMed2006

Z-DNA-forming sequences generate large-scale deletions in mammalian cells.

Spontaneous chromosomal breakages frequently occur at genomic hot spots in the absence of DNA damage and can result in translocation-related human disease. Chromosomal breakpoints are often mapped near purine-pyrimidine Z-DNA-forming sequences in human tumors. However, it is not known whether Z-DNA plays a role in the generation of these chromosomal breakages. Here, we show that Z-DNA-forming sequences induce high levels of genetic instability in both bacterial and mammalian cells. In mammalian cells, the Z-DNA-forming sequences induce double-strand breaks nearby, resulting in large-scale deletions in 95% of the mutants. These Z-DNA-induced double-strand breaks in mammalian cells are not confined to a specific sequence but rather are dispersed over a 400-bp region, consistent with chromosomal breakpoints in human diseases. This observation is in contrast to the mutations generated in Escherichia coli that are predominantly small deletions within the repeats. We found that the frequency of small deletions is increased by replication in mammalian cell extracts. Surprisingly, the large-scale deletions generated in mammalian cells are, at least in part, replication-independent and are likely initiated by repair processing cleavages surrounding the Z-DNA-forming sequence. These results reveal that mammalian cells process Z-DNA-forming sequences in a strikingly different fashion from that used by bacteria. Our data suggest that Z-DNA-forming sequences may be causative factors for gene translocations found in leukemias and lymphomas and that certain cellular conditions such as active transcription may increase the risk of Z-DNA-related genetic instability.

Animals↗

PubMed2005

Are published characteristics of the ambulatory blood pressure generalizable to rural Chinese? The JingNing population study.

OBJECTIVE: We investigated the ambulatory blood pressure (BP) in rural Chinese and compared its characteristics with those reported in other population-based studies. METHODS: We enrolled inhabitants from six villages of the JingNing County, China. We recorded the ambulatory BP using 90207 SpaceLabs monitors. Trained physicians measured the conventional BP at the participants' homes. Hypertension was defined as a conventional BP of > or = 140/ > or = 90 mmHg or a condition requiring the intake of antihypertensive drugs. Using MEDLINE, we searched for population-based studies on ambulatory BP monitoring. RESULTS: The 356 participants (12-86 years) included 192 (53.9%) women and 117 (32.9%) hypertensive patients. In all participants, systolic/diastolic BP averaged 129/80 mmHg at home. The ambulatory BP means were 121/77 mmHg over 24 h, 126/81 mmHg during daytime (0800 to 1800 h) and 112/70 mmHg during night-time (2200 to 0400 h). The awake and asleep BPs averaged 126/82 and 112/70 mmHg, respectively. Using previously published definitions of daytime (1000 to 2000 h) and night-time (midnight to 0600 h) instead of those given above, inflated the BP differences with the awake and asleep BPs from 0.4/0.2 to 1.2/1.0 mmHg and from 0.3/0 to 1.4/1.6 mmHg, respectively. Compared with daytime values, conventional BP was 2.7/3.1 mmHg lower in normotensive individuals, but 14.9/1.3 mmHg higher in hypertensive patients. In our normotensive individuals, the whole-day and night-time diastolic BPs were from 1 to 4 mmHg and from 3 to 7 mmHg higher than in five other population studies in Caucasians or Japanese, whereas night-time BP in our participants was 9/5 mmHg lower than in Chinese living in Taiwan. CONCLUSIONS: We demonstrated significant differences in the characteristics of the ambulatory blood pressure across Asian and Caucasian populations. To what extent different activity patterns and genetic and environmental factors explain this context-dependency remains to be clarified.

Adolescent↗

PubMed2004

Naturally occurring H-DNA-forming sequences are mutagenic in mammalian cells.

Naturally occurring DNA sequences can form noncanonical structures such as H-DNA, which are abundant and regulate the expression of several disease-linked genes. Here, we show that H-DNA-forming sequences are intrinsically mutagenic in mammalian cells. This finding suggests that DNA is a causative factor in mutagenesis and not just the end product. By using the endogenous H-DNA-forming sequence found in the human c-myc promoter, mutation frequencies in a reporter gene were increased approximately 20-fold over background in COS-7 cells. H-DNA-induced double-strand breaks (DSBs) were detected near the H-DNA locus. The structures of the mutants revealed microhomologies at the breakpoints, consistent with a nonhomologous end-joining repair of the DSBs. These results implicate H-DNA-induced DSBs in c-myc gene translocations in diseases such as Burkitt's lymphoma and t(12;15) BALB/c plasmacytomas, where most breakpoints are found near the H-DNA-forming site. Thus, our findings suggest that H-DNA is a source of genetic instability resulting from DSBs and demonstrate that naturally occurring DNA sequences are mutagenic in mammals, perhaps contributing to genetic evolution and disease.

Animals↗

PubMed2003

Activation of protein kinase A and clustering of cell surface receptors by N-methyl-N'-nitro-N-nitrosoguanidine are independent of genomic DNA damage.

Alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) induces cellular stress leading to chromosomal aberrations, mutations and cell death. Previous reports from our laboratory have shown that low concentration of MNNG induces untargeted mutation (UTM), which occurs on intact DNA in mammalian cells through changes in gene expression profile. It also causes the activation of cAMP-protein kinase A (PKA) and up-regulation of POL-beta, which is demonstrated to play a role in DNA repair system. In order to find out the possible initial signal involved in UTM, we try to investigate whether the activation of PKA-CREB signal pathway is closely related to DNA damage. Our data shows that the treatment of low concentration MNNG (0.2 microM) activates PKA-CREB pathway in a comparable level both in a nuclear and enucleated cell system. And similar to the cell response caused by UV, the clustering of cell surface receptors of epidermal growth factor (EGF) and tumor necrosis factor alpha (TNFalpha) was also observed in cells exposed to MNNG. It was further demonstrated that the clustering of the surface receptors is independent of the genomic DNA damage, as this phenomenon was also observed in enucleated cells. These observations indicate that the initiation of signal cascades induced by low concentration of MNNG might be associated with its interaction with cell surface receptors and/or direct activation of related signal proteins but not its DNA damaging property.

Animals↗

PubMed2003

Linkage analysis of five candidate genes and essential hypertension in 106 Chinese nuclear families.

Five candidate genes including the lipoprotein lipase, leptin, leptin receptor, alpha-adducin and beta3 adrenergic receptor were selected to examine their possible contribution to essential hypertension (EH) in a Chinese population. On each side of the candidate gene loci, one to two highly polymorphic microsatellite markers were genotyped in 474 subjects recruited from 106 hypertension nuclear families in Shanghai. Both parametric and nonparametric linkage analyses were carried out using GENEHUNTER (version 2.0) after genotyping. Extended transmission disequilibrium testing (ETDT) was also conducted to detect preferential transmission of alleles to affected offspring. We failed to find the linkage between all these loci and EH by either parametric or nonparametric analysis, nor did we detect any significant transmission disequilibrium by ETDT. Our findings provide no support for a significant contribution of these five genes to the pathogenesis of EH among Shanghai people.

Asian People↗

PubMed2002

[Heritability of serum leptin levels: a twin study].

OBJECTIVE: To study the contribution of genetic factors to the variance of serum leptin concentration in healthy, normotensive twins. METHODS: A total of 57 pairs of twins were investigated: 28 female and 19 male pairs of monozygotic(MZ) twins, and 6 female and 4 male pairs of dizygotic(DZ) twins. The zygosity of twins was determined by comparing the concordance of the genotype of nine fluorescence-labeled microsatellite markers. The genetic analysis was performed using the variance-based method. Serum leptin levels were determined in duplicate by a radioimmunoassay Kit (Linco Research, Inc., St. Charles, Missouri) as previously described. RESULTS: The test of genetic variance revealed a significantly larger within-pair variance of serum leptin in the DZ twins, in comparison with the MZ twins. The corresponding heritability for serum leptin was 8%. Adjusted for BMI, gender, and uric acid (UA), the heritability for serum leptin was 0.18%. Log leptin correlated significantly with blood pressure (SBp r=0.355 P<0.001; DBp r=0.339 P<0.001). Stepwise multiple linear regression analysis revealed that only BMI, gender and UA were linked independently to serum leptin levels(R(2)=0.788, P<0.001). CONCLUSION: The above data indicate that environmental factors other than genetic factors are important determinants of leptinemia in normal subjects.

Adolescent↗

PubMed2002

[Linkage analysis of cytokine and cytokine-related receptor gene loci and essential hypertension in Chinese].

OBJECTIVE: To investigate the genetic linkage between several cytokine and cytokine-related receptor gene loci and essential hypertension (EH) in Chinese. METHODS: Linkage between seven genetic markers and EH in 95 Chinese nuclear families with EH (including 477 subjects) was analyzed using a technique of fluorescence-based gene scan with DNA short tandem repeat loci. These markers were selected from the chromosomal regions nearby eight cytokines and their receptor genes. The two-point non-parametric linkage analysis (NPL), maximum Lod score and transmission/disequilibrium test (TDT) with GENEHUNTER software package were used in this study. RESULTS: Result of TDT showed significant transmission disequilibrium between D14S61 and EH (Chi square 14.29,P=0.00016) although NPL and Lod score revealed no significant linkage (Z=0.78, P>0.05 and Lod score =0.72 respectively) at this locus. No linkage between other loci typed and EH was found by the three genetic analysis methods (P>0.05 or Lod score<-1). CONCLUSION: Alleles at D14S61 were of significant transmission disequilibrium in affected siblings. Transforming growth factor beta 3 is 0.1 cM away from D14S61, which suggests that the relationship between genes at or near this regions and EH needs to be further explored.

Adult↗

PubMed2002

[Linkage analysis of 13 vasoactivity-regulating short tandem genes loci in essential hypertension in Chinese].

OBJECTIVE: To investigate whether linkage between essential hypertension (EH) and genetic loci near renin-angiotensin system, endothelin system, nitric oxide synthase, adrenergic receptor genes in Chinese. METHODS: Linkage analysis of thirteen candidate gene loci and EH was performed in 95 Chinese nuclear families including 477 subjects using a technique of fluorescence-based gene scan with DNA short tandem repeat. The markers were selected on the chromosomal regions containing candidate genes regulating vasoactivity. GENEHUNTER package were used for two-point, non-parametric linkage analysis (NPL), maximum Lod score and transmission/disequilibrium test (TDT) in this study. RESULTS: The results of TDT indicated relatively small P values at D1S1678, D3S1744, D4S1604, D13S800, D7S483 and D8S255 (0.01 < P < 0.05). No significant linkages was found at any locus by Lod score and NPL analysis (Lod </= -1, P >/= 0.05). CONCLUSIONS: TDT is considered as a sensitive test for detecting linkage disequilibrium. Significant linkage was found at 6 of the 13 loci typed in Chinese nuclear families with hypertension by using TDT, but no evidence suggested linkage of any locus to EH by NPL and Lod score. It is worthwhile to pay attention to chromosomal regions near the loci with small P values.

Asian People↗

PubMed2002

Linkage analysis of a region on chromosome 2 with essential hypertension in Chinese families.

OBJECTIVE: To verify the linkage of the candidate regions identified in a previous study (markers D2S168, D2S151, D2S142 on chromosome 2) with hypertension in Chinese families. METHODS: A genetic linkage study focused on chromosome 2 was performed on 240 Chinese families containing 856 patients with essential hypertension. A total of 1080 individuals were genotyped using 9 highly polymorphic microsatellite markers around the candidate regions on chromosome 2 with an average spacing of 5 cM. Non-parametric linkage (NPL), parametric linkage analysis and transmission-disequilibrium test (TDT) with the GENEHUNTER software were used to assess evidence for linkage. RESULTS: Linkage of a region on chromosome 2 around D2S151 and D2S142 with hypertension was confirmed by different statistical methods (NPL, LOD score and TDT). However, the linkage of D2S168 could not be replicated in this extension study. CONCLUSIONS: The data suggest that a region on chromosome 2 at or near the loci of D2S142 and D2S151 may harbor genes responsible for the development of essential hypertension in Chinese.

Alleles↗

PubMed2002

[The relation between overload and variability of blood pressure and overweight or obesity in patients with essential hypertension].

OBJECTIVE: To investigate the relationship between blood pressure variability, overweight or obesity in patients with essential hypertensive. METHODS: A hundred ninety-one patients with essential hypertension were divided into three groups: normal, overweight and obese according to body mass index (BMI). The characteristics of the variability of 24-hour ambulatory blood pressure monitoring (ABPM) in three groups were compared. RESULTS: Blood pressure overload and variability increased parallel with the increase of BMI. In overweight group, the variabilities of systolic blood pressure at night (nSBPSD) increased 14.10%, the variabilities of diastolic blood pressure at night (nDBPSD) increased 13.15% and the variabilities of mean arterial pressure at night (nMAPSD) increased 15.92% respectively. In the obese group, the above three variabilities increased more significantly (compared to normal group P < 0.05-0.01). However, increases of the three blood pressure variabilities were observed only in the male patients. CONCLUSIONS: The overweight or obesity increased the blood pressure overload and variabilities in patients with essential hypertension. The increases of blood pressure variabilities were observed only in male patients and at night.

Adult↗