Biomedical subjects

Daru Lu

Publications and source records attributed to Daru Lu.

At least 19 recordsLinked to original sources

PubMed2026

Engineered Transformer Base Editor with Enhanced Editing Efficiency.

Canonical cytosine base editors (CBEs) achieve precise C-to-T conversions without inducing DNA double-strand breaks (DSBs), yet their clinical potential remains hampered by substantial off-target (OT) mutations. The recently developed transformer base editor (tBE) significantly reduces both genomic and transcriptomic OT mutations by using a cleavable deoxycytidine deaminase inhibitor (dCDI) domain. However, the modest base editing efficiency limits its broader applications. Here, through rational deaminase engineering and fusion of a uracil DNA glycosylase inhibitor (UGI) domain, we developed the engineered tBE (etBE). The etBE exhibited substantially enhanced editing efficiencies compared with the parental tBE (up to 35.11-fold improvement), while maintaining high editing fidelity and background levels of OT mutations. As a therapeutic proof-of-concept, dual adeno-associated virus (AAV)-mediated delivery of etBE targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), a well-established therapeutic target for cardiovascular diseases, was evaluated in a humanized mouse model. The treatment achieved efficient in vivo base editing (up to 35.13%), resulting in substantial reductions in plasma PCSK9 protein (24%) and low-density lipoprotein cholesterol (LDL-C) levels (33%), while inducing only minimal OT mutations. Collectively, etBE represents a highly efficient and specific base editing platform with enormous potential for both basic research and clinical applications.

CRISPR‐Cas9↗

PubMed2025

Noninvasive preimplantation genetic testing for aneuploidy using blastocyst spent culture medium may serve as a backup of trophectoderm biopsy in conventional preimplantation genetic testing.

BACKGROUND: To investigate whether the noninvasive preimplantation genetic testing (niPGT) complement conventional preimplantation genetic testing (PGT) in the embryos for aneuploidy. RESULTS: 40 spent culture medium (SCM) samples from routine embryo culture were collected, and half of each SCM (10 µL) sample was used for whole genome amplification, while the other half was stored at -80 °C for 3-6 months. Thirty-six out of 40 fresh SCM samples were successfully amplified and sequenced. Thirty-six paired frozen-thawed SCM samples showed 100% concordance with the freshly amplified SCM samples. Then, SCM and trophectoderm (TE) samples from 149 blastocysts from 51 couples were collected. A 98.0% successful SCM sample amplification rate (146/149) was achieved. For the 146 paired TE biopsy and SCM samples, the overall concordance rate was 82.9% (121/146). Ten embryos with aneuploid TE results but euploid niPGT results were donated. A 70.0% (7/10) true negative rate was achieved by niPGT with respect to the inner cell mass (ICM) results (TE-positive embryos). CONCLUSIONS: These results suggested that SCM stored at -80 °C for 6 months without affecting niPGT results based on NICSInst amplification.

Humans↗

PubMed2006

Effect of mu-opioid receptor gene polymorphisms on heroin-induced subjective responses in a Chinese population.

BACKGROUND: Genetic factors that influence subjective responses to drug use (such as euphoria) contribute to the risk of addiction. mu-opioid receptor is the molecular target of heroin mediating its effects in both pain relief and euphoria. METHODS: To evaluate the association of mu-opioid receptor gene (OPRM1) variants with heroin-induced positive responses on first use, we studied 336 Chinese Han heroin addicts recruited in Shanghai and divided heroin addicts into two groups (positive vs. negative) according to the self-reporting feeling on first use. Association analyses with the genotypes and alleles in nine tagging single nucleotide polymorphisms (tSNPs) in OPRM1 with subjective responses were performed. Similar analysis with haplotypes of these tSNPs was also performed. RESULTS: Allele frequencies of three tSNPs were significantly different between the positive and negative groups. They were rs696522 (odds ratio [OR] = 3.06, p = .0013), rs1381376 (OR = 3.16, p = .0008), and rs3778151 (OR = 3.12, p = .0004). Such association remains after adjustment for demographic covariates and for multiple testing. The subjects with heroin-induced positive responses on first use consumed more drugs than the negative group (Mann-Whitney U = 224.0, Wilcoxon W = 16334.0, p <or= .0001). CONCLUSIONS: Self-reported positive responses on first use of heroin were found to be associated with OPRM1. The findings suggest that heroin-induced positive responses are likely associated with more heroin consumption.

Adult↗

PubMed2006

Promoter hypermethylation-mediated down-regulation of LATS1 and LATS2 in human astrocytoma.

LATS1 and LATS2 are tumor suppressor genes implicated in the regulation of cell cycle, but their methylation statuses are still unknown in human astrocytoma. Here, we found that the promoter hypermethylation frequencies of LATS1 and LATS1 were 63.66% (56/88) and 71.5% (63/88) in 88 astrocytomas by methylation-specific PCR. But no methylation of LATS1 and LATS2 promoter was detected in the 10 normal brain tissues. There was an increased methylation frequency of LATS1 and LATS2 with the malignant development of astrcytoma. By real-time PCR, the mRNA expression of LATS1 or LATS2 was detected significantly decreased in different pathological grade astrocytomas (P<0.05). And the mRNA levels of LATS1 and LATS2 in astrocytomas with hypermethylation were both significantly (P<0.01) lower than those without methylation. The methylation of LATS1 and LATS2 was detected in U251 and SHG-44 cell lines, and 5-aza-deoxycytidine could restore their expression to induce cell apoptosis. Our results suggested that LATS1 and LATS2 mRNA was down-regulated in astrocytoma by hypermethylation of the promoter. The methylation and mRNA expression of LATS1 and LATS2 may provide useful clues to the development of the diagnostic assays for astrocytoma. Our results also suggested that LATS1 and LATS2 may be a useful target for astrocytoma therapy.

Adult↗

PubMed2006

Expression analyses of 27 DNA repair genes in astrocytoma by TaqMan low-density array.

DNA repair systems act to maintain genome integrity in the face of replication errors, environmental insults, and the cumulative effects of age. The mRNA expressions of 27 genes of the DNA repair system as well as their correlation with the clinical characteristics were studied in human astrocytoma. We applied TaqMan low-density array to investigate the mRNA expressions of 27 DNA repair genes in 40 astrocytoma tissues (10 of grade II, 10 of grade III, and 20 of grade IV, according to the WHO Grading System). And the normal brain tissues from 10 non-astrocytoma patients were collected as the control. In addition, correlation of their mRNA levels with clinical characteristics was also analyzed. We found that the expression of the 13 genes were significantly (P<0.01) down-regulated in grade II, III, IV of astrocytoma compared to normal brain tissues, including ERCC1, ERCC2, ERCC3, ERCC4, MGMT, MLH1, MLH3, NTHL1, OGG1, RAD50, SMUG1, XRCC4 and XRCC5. Meanwhile, we found that the expression of MSH2, MSH6, NUDT1 and XRCC3 were only significantly lower in grade II and III of astrocytoma, and the expression of MRE11A and MUS81 were only significantly lower in grade III and IV. But the expression of MPG, MSH3, MUTHY and RAD51 were not changed in any grade of astrocytoma. Furthermore, we found that the decrease expression of eight genes was significantly (P<0.05) associated with a poor prognosis, including ERCC3, ERCC4, MLH3, MRE11A, NTHL1, RAD50, XRCC4 and XRCC5. We suggest that TaqMan low-density array is an effective multivariate technique to examine the expression of DNA repair genes in astrocytomas, which can be applied to identify tumor-specific genes. We also suggest that the down-regulation of some DNA repair genes may be associated with pathogenesis and poor prognosis of astrocytoma.

Adolescent↗

PubMed2006

A novel type of PTD, common helix-loop-helix motif, could efficiently mediate protein transduction into mammalian cells.

Protein transduction domains (PTDs), such as HIV TAT PTD, have been widely used as delivery tools into living cells. Here we reported for the first time that the helix-loop-helix (HLH) domain of basic helix-loop-helix (bHLH) family was a novel type of PTD. Efficient internalization has been obtained with HLH domains derived from bHLH proteins, NeuroD/BETA2, Neurogenin3, and Mitf, in various cell types including stable cell lines and primary cells. Cellular uptake of HLH PTD was barely or slightly inhibited by the metabolic, phagocytosis, clathrin- or caveolar-endocytosis formation inhibitors, but significantly and substantially reduced by heparin and macropinocytosis inhibitor, which suggested important roles of cell surface glycosaminoglycans and macropinocytosis during the protein transduction. Furthermore, NeuroD proteins still preserved transcription activation after internalized into cells. Our results demonstrated a new motif of PTD different from previous models as cationic residues cluster or amphipathic helix. The HLH domain is also the characteristic of the bHLH family, which implied a large number of PTDs could be discovered in this family to fit different purposes, and some of them could be directly recruited to penetrate cell membrane according to their crucial roles in development such as NeuroD and Ngn3.

Animals↗

PubMed2006

Complete sequence data support lack of balancing selection on PRNP in a natural Chinese population.

The M129V mutation in the human prion protein gene (PRNP) is the primary site linked to susceptibility to prion diseases in humans. The heterozygous state of this allele has been proven to be more resistant to prion-related diseases such as Creutzfeldt-Jakob disease. Based on a study of the common genetic variations, it has been proposed that balancing selection has played a critical role in shaping the distribution of 129V in worldwide populations. Kreitman and Di-Rienzo [Kreitman and Di-Rienzo (2004)Trend Genet 20:300-304] challenged this hypothesis by pointing out that the exclusion of polymorphisms with low frequency may introduce an ascertainment bias and, in turn, lead to a wrong conclusion. By studying sequence variations in samples from the Human Genome Diversity Project, Soldevila et al. [Soldevila et al. (2005) Trends Genet 21:389-391] showed that this ascertainment bias does exist. We argue that the evidence presented by Soldevila et al. may be compromised by the samples tested since they were selected from a population that may be substructured. In this study, we re-evaluated the hypothesis of balancing selection in a natural Chinese population using a much longer segment encompassing the entire genomic region of the PRNP gene (15 kb). We showed that the pattern of genetic variation in PRNP is not consistent with the presence of balancing selection in this gene.

Asian People↗

PubMed2006

Polymorphisms in DNA damage binding protein 2 (DDB2) and susceptibility of primary lung cancer in the Chinese: a case-control study.

DNA damage binding protein 2 (DDB2) is one of the major DNA repair proteins involved in the nucleotide excision repair (NER) pathway. Mutations in the DDB2 gene can cause a repair-deficiency syndrome xeroderma pigmentosum group E. Because tobacco carcinogens can cause DNA damage that is repaired by NER and suboptimal NER capacity is reported to be associated with lung cancer risk, we hypothesized that common variants in the DDB2 gene are associated with lung cancer risk. To test this hypothesis, we conducted a case-control study of 1010 patients with incident lung cancer and 1011 cancer-free controls and genotyped two DDB2 single nucleotide polymorphisms (SNPs) (rs830083 and rs3781620) that are in linkage disequilibrium with other untyped SNPs. We found that compared with the rs830083CC, subjects carrying the heterozygous rs830083CG genotype had a significantly 1.31-fold increased risk of lung cancer [95% confidence interval (CI) 1.08-1.60] and those carrying the homozygous rs830083GG genotype had a non-significantly 1.22-fold elevated risk (95% CI 0.89-1.67). In addition, effects of the combined rs830083CG/GG variant genotypes were more evident in young subjects, heavy smokers and subjects with a positive family history of cancer. These findings indicate, for the first time, that the DDB2 rs830083 polymorphism may contribute to the etiology of lung cancer. Further functional studies on this SNP and/or related variants are warranted to elucidate the underlying molecular mechanisms of the association.

Aged↗

PubMed2006

Genetic variants in the MDM2 promoter and lung cancer risk in a Chinese population.

Overexpression of MDM2 may attenuate the P53 stress response pathway through direct blocking of P53 transcriptional activity and mediating P53 degradation. Two promoter polymorphisms (one is a T to G substitution at the intronic P53-response promoter, and the other is a 40-bp insertion/deletion polymorphism in the constitutive promoter) were identified, and recently the T/G substitution (SNP309) has been demonstrated to alter the levels of MDM2 gene products. In this molecular epidemiological study with 717 incident lung cancer cases and 1,083 cancer-free controls, we genotyped these 2 promoter polymorphisms of MDM2 and evaluated their associations with risk of lung cancer. We found that there were no significant associations between MDM2 SNP309 variant genotypes and lung cancer risk (adjusted OR = 1.20, 95% CI = 0.95-1.53 for TG and adjusted OR = 1.12, 95% CI = 0.85-1.48 for GG, respectively). Similarly, we did not find evidence for any association between risk of lung cancer and MDM2 insertion/deletion polymorphism. The findings suggest that these two MDM2 promoter polymorphisms may not play a major role in lung cancer susceptibility in this Chinese population.

Alleles↗

PubMed2006

Mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys polymorphism contributes to the variation in efficacy of sublingual nitroglycerin.

Glyceryl trinitrate (GTN), also known as nitroglycerin, has been used to treat angina and heart failure for more than 130 years. Recently, it was shown that mitochondrial aldehyde dehydrogenase-2 (ALDH2) is responsible for formation of NO, the metabolite needed for GTN efficacy. In the present study, we show that the common G-to-A polymorphism in exon 12 of ALDH2--resulting in a Glu504Lys replacement that virtually eliminates ALDH2 activity in both heterozygotes and homozygotes--is associated with a lack of efficacy of sublingual GTN in Chinese subjects. We also show that the catalytic efficiency (Vmax/Km) of GTN metabolism of the Glu504 protein is approximately 10-fold higher than that of the Lys504 enzyme. We conclude that the presence of the Lys504 allele contributes in large part to the lack of an efficacious clinical response to nitroglycerin; we recommend that this genetic factor be considered when administering nitroglycerin to patients, especially Asians, 30-50% of whom possess the inactive ALDH2*2 mutant allele.

Administration, Sublingual↗

PubMed2006

Transplantation of rat islets transduced with human heme oxygenase-1 gene using adenovirus vector.

OBJECTIVE: To investigate whether human heme oxygenase-1 (HO-1) gene has protective action on islets cultured in vitro, and to explore whether transduction of HO-1 gene to donor islets could enhance engrafted islets survival and suppress local lymphocytic infiltration in islet grafts. METHODS: Newly isolated rat islets were isolated from the Sprague-Dawley rats and were divided into 3 groups in vitro study as follows: enhanced green fluorescent protein (EGFP) group, islets transduced with adenovirus vectors containing EGFP gene using multiplicities of infection (MOI) = 2, 5, 10, and 20 to determine the transduction efficacy; HO-1 group, islets transduced with adenovirus vectors containing human HO-1 gene using MOI = 20; and control group, mock transduced islets. Flow cytometry was used to detect apoptotic cells after induction by recombinant human tumor necrosis factor-alpha (rTNF-alpha) and cycloheximide (CHX) for 48 hours. Diabetic recipients were randomly divided into the following groups: HO-1 group (n = 9), receiving islets transduced with recombinant adenovirus-HO-1; control group (n = 9), receiving mock transduced islets; and phosphate buffer solution (PBS) group (n = 6), receiving only 0.8 mL PBS. About 1200 rat islet equivalents were transplanted into each recipient rendered by streptozotocin using the portal vein as transplant site. Allograft survival, apoptosis, and the state of lymphocytic infiltration were analyzed. RESULTS: After treatment with rTNF-alpha and CHX, the apoptotic ratio of islet cells was 4.22% +/- 2.38% in the HO-1 group (MOI = 20), significantly lower than 23.81% +/- 8.51% in the control group (P < 0.05), and 28.76% +/- 14.76% in the EGFP group (MOI = 20; P < 0.05). Maintenance of normoglycemia was prolonged in the HO-1 group, indicated by results that islet survival time was 10.56 +/- 4.33 days significantly longer than that of untreated islets which was 5.33 +/- 4.18 days (P < 0.05). The lymphocytic infiltration degree in engrafted islets treated with HO-1 gene was lower than that in the control group. CONCLUSIONS: HO-1 gene overexpression in rat islets by adenovirus transduction can protect cultured islets against rTNF-alpha and CHX-mediated cytotoxicity. HO-1 gene has cytoprotective effects on engrafted islets, which could prolong engrafted islets survival in allogenic transplantation model, and diminish the degree of lymphocytic infiltration in islet grafts. These findings suggest a potential therapeutic application for HO-1 gene in improving islet survival/function in human islet transplantation.

Adenoviridae↗

PubMed2006

Polymorphisms in the two helicases ERCC2/XPD and ERCC3/XPB of the transcription factor IIH complex and risk of lung cancer: a case-control analysis in a Chinese population.

The transcription factor IIH (TFIIH) helicases ERCC2/XPD and ERCC3/XPB are responsible for opening the DNA strand around the lesion site during nucleotide excision repair process. Genetic variants in these two genes may be markers for interindividual variability in DNA repair capacity and thus predisposition to cancer risk. In this case-control study of 1,010 incident lung cancer cases and 1,011 age and sex frequency-matched cancer-free controls in a Chinese population, we genotyped eight tagging polymorphisms of ERCC2 and ERCC3 using the high-throughput Taqman platform to determine their associations with risk of lung cancer. Although none of the eight polymorphisms was individually associated with lung cancer risk, we found that genetic variants in ERCC2 and ERCC3 jointly contributed to lung cancer risk in a dose-response manner. Compared with those with 0 to 1 "at-risk" locus, subjects carrying >1 at-risk loci were at increased risk for lung cancer [adjusted odds ratio (OR), 1.29; 95% confidence interval (95% CI), 0.98-1.70 for 2 at-risk loci; adjusted OR, 1.38; 95% CI, 1.02-1.85 for 3 at-risk loci; and adjusted OR, 1.51; 95% CI, 1.09-2.10 for > or =4 at-risk loci, respectively; P(trend) = 0.015]. This combined effect was slightly more evident in young subjects (<60 years), males, current smokers, and those with family history of cancer, particularly for histologic type of adenocarcinomas. No evidence for interaction was found. These findings indicate that these tagSNPs of the ERCC2 and ERCC3 along with their surrounding regions may serve as biomarkers of susceptibility to lung cancer, which warrant further validation by other population-based and phenotypic studies to determine the biological relevance of these tagSNPs.

Adenocarcinoma↗

PubMed2005

Beta-2 adrenergic receptor gene (ADRB2) polymorphism and risk for lung adenocarcinoma: a case-control study in a Chinese population.

The incidence of lung adenocarcinoma (AC) has been increasing over recent decades. The tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the most potent carcinogens and reproducibly induces a high incidence of lung AC in laboratory animals. In addition to its genotoxic effects, NNK has also epigenetic effects on lung cells by functioning as an agonist for beta adrenergic receptors and stimulating the signal pathways that lead to lung AC. Beta-2 adrenergic receptor (ADRB2) expressed on bronchial smooth muscle is a well-defined target for asthma treatment that has epidemiological implications in lung cancer development. And biochemical effect and pharmacogenetic relevance of regulatory and coding variants of ADRB2 have been well documented. Aiming to test whether the genetic variants of ADRB2 modify risk of lung AC, we compared the manifestation of three common single nucleotide polymorphisms (SNPs) of ADRB2 (G-1023A, G-654A, and A46G (Gly16Arg)) between 313 patients with lung AC and 321 controls. Overall association was not observed between risk and either individual of the three SNPs or their combined haplotypes. However, in the subgroup of young subjects < or =50 years old, significant association was observed for G-1023A (allele based OR, 1.82; 95% CI, 1.12-2.95), A46G (Gly16Arg) (allele based OR, 0.64; 95% CI, 0.40-1.03), and the haplotype A(-1023)A(46) (OR 2.62; 95% CI 1.30-5.27). Our results do not support a major independent role of ADRB2 polymorphisms in lung AC risk, suggesting that functional variants of other genes involved in the NNK epigenetic pathway of carcinogenesis should be investigated.

Asian People↗

PubMed2005

Functional polymorphisms of matrix metalloproteinase-9 are associated with risk of occurrence and metastasis of lung cancer.

PURPOSE: Matrix metalloproteinase 9 (MMP-9) plays critical roles in cancer development and aggression. Nonsynonymous single-nucleotide polymorphisms (SNP) in the functional domain of the MMP-9 gene may influence substrate and inhibitor binding and contribute to cancer predisposition and aggression. PATIENTS AND METHODS: To test our hypothesis that common nonsynonymous SNPs, R279Q, P574R, and R668Q, in MMP-9 are associated with lung cancer development and metastasis, we conducted a case-control study of 744 patients with incident lung cancer and 747 cancer-free controls in Southeast China. Multivariate logistic regression analysis was used to calculate adjusted odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: We found that compared with the 279QQ genotype, the 279RR genotype was associated with significant elevated risk of lung cancer with metastasis (adjusted OR, 1.79; 95% CI, 1.03-3.08), whereas the 574PR heterozygote and 574PP homozygote had 1.46-fold (95% CI, 0.94-2.26) and 1.69-fold elevated risk (95% CI, 1.10-2.60), respectively, compared with the 574RR genotype. When we examined the combined effect of R279Q and P574R and used the 279R and 574P as the risk alleles, a significantly increased risk of lung cancer was associated with both the genotypes containing "1 to 2 risk alleles" (adjusted OR, 2.16; 95% CI, 1.30-3.59) and containing ">2 risk alleles" (adjusted OR, 2.44; 95% CI, 1.48-4.03), and it was more pronounced in 290 lung cancer cases with metastasis [adjusted OR, 2.30 (95% CI, 1.09-4.85) for the 1 to 2 risk alleles subgroup and adjusted OR, 2.82 (95% CI, 1.35-5.88) for the >2 risk alleles subgroup], compared with those without any risk alleles. However, no overall significant associations were observed between R668Q and lung cancer risk in this study population. CONCLUSION: These findings indicate that the potentially functional polymorphisms, MMP-9 P574R and R279Q, may confer the biomarker in the occurrence and metastasis of primary lung cancer. Further functional studies including these two genetic variants are warranted to confirm our findings.

Adult↗

PubMed2005

Allele 2 of the interleukin-1 receptor antagonist gene (IL1RN*2) is associated with a decreased risk of primary lung cancer.

IL-1 receptor antagonist (IL-1ra), a structural variant of IL-1, binds to the same IL-1 receptor and acts as a competitive inhibitor of IL-1 bioactivity. IL-1ra protein has been widely investigated and found to be associated with different human malignancies. In the second intron of the IL-1RN gene, there is a functional polymorphism of a variable number of tandem repeats (VNTR), which is characterized as having an importance role in regulating the serum IL-1ra levels, human immune response and cancer risk. We genotyped this VNTR of IL-1RN in a case-control study of 885 histologically confirmed lung cancer patients and 1024 cancer-free controls frequency-matched to the cases on age and sex in a Chinese population to evaluate the association of this variant and lung cancer risk. We found that the presence of the allele 2 of IL-1RN (IL-RN*2) was associated with a 32% significantly decreased risk of lung cancer (adjusted OR, 0.68; 95% CI, 0.52-0.89). Stratified analyses revealed that the reduced risks associated with the genotypes with IL-RN*2allele (I/II and II/II) were more evident in non-smokers (adjusted OR, 0.53; 95% CI, 0.35-0.79) and in subjects with squamous cell carcinoma (adjusted OR, 0.49; 95% CI, 0.31-0.76). These findings support our priori hypothesis that the IL1RN*2 allele may contribute to lung cancer risk in the Chinese population. More functional data for this IL1RN polymorphism are warranted to explore its role in lung carcinogenesis.

Adenocarcinoma↗

PubMed2005

Association study of four activity SNPs of CYP3A4 with the precocious puberty in Chinese girls.

CYP3A4 plays an important role in the metabolism of a variety of endogenous and exogenous compounds. Earlier studies revealed that a high-activity variation of the CYP3A4 gene, CYP3A4*1B is significantly associated with the precocious puberty in girls. Other three variations, CYP3A4*4, CYP3A4*5 and CYP3A4*6, which were found in a study carried out in a Chinese population in Taiwan, were reported to down-regulate the enzymatic activity of CYP3A4. The four activity SNPs were typed in our study in two groups of Chinese girls: 176 girls with precocious puberty as the case group, and 192 normal girls as the control group. No variations of CYP3A4*1B and CYP3A4*4 were found in all the cases and controls. Heterozygous of CYP3A4*5 was found in five subjects of the 192 controls but none in the cases, heterozygous of CYP3A4*6 was found in two subjects of the controls but none in the cases. Fisher's exact test showed that the variation of CYP3A4*5 was associated with the onset of puberty in Chinese girls (P-trend=0.038), while the variation of CYP3A4*6 was not associated with the onset of puberty in Chinese girls (P-trend=0.272). The result suggests that these mutations in the CYP3A4 gene have no contribution to the early onset of puberty in Chinese girls, but are related in some way with the puberty development in Chinese girls.

Alleles↗

PubMed2005

Dinucleotide polymorphism of p73 gene is associated with a reduced risk of lung cancer in a Chinese population.

p73, a structural and functional homologue of p53, shares some p53-like tumor suppressor activity but also possesses oncogenic activity. Therefore, p73 plays an important role in modulating cell-cycle control and apoptosis. A potentially functional dinucleotide polymorphism, G4C14-to-A4T14, has been identified in the 5' untranslated region (UTR) of exon 2 of the p73 gene, which may theoretically form a stem-loop structure and affect gene expression. To test the hypothesis that these 2 common variants play a role in lung cancer susceptibility, we conducted a case-control study of 425 lung cancer patients and 588 cancer-free controls frequency-matched to the cases on age and sex in a Chinese population. The results showed that these 2 polymorphisms were in complete linkage disequilibrium and the frequencies of variant p73 AT haplotype (A4T14) were less common in the cases (0.225) than in the controls (0.287) (p = 0.0018), suggesting that this AT haplotype was protective against lung cancer. Compared to the p73 GC/GC homozygotes, both the AT/AT variant homozygotes and GC/AT heterozygotes were associated with a significantly decreased risk (adjusted OR: 0.45, 95% CI: 0.26-0.80 and OR: 0.70, 95% CI: 0.53-0.92, respectively). These results suggest that this p73 dinucleotide polymorphism may have a role in lung cancer susceptibility in our study population. Further studies are needed to elucidate potential functional relevance of the p73 AT variant allele.

Aged↗

PubMed2005

A promoter polymorphism (-77T>C) of DNA repair gene XRCC1 is associated with risk of lung cancer in relation to tobacco smoking.

X-ray repair cross complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the base-excision repair pathway. Functional Polymorphisms in the XRCC1 gene may lead to decreased DNA repair capacity and thus confer inherited predisposition to cancer risk. In this case-control study of 710 patients with incident lung cancer and 710 cancer-free controls who were frequency matched on age, sex and residential area, we genotyped a novel T>C transition at the promoter region (-77T>C) of XRCC1 and other two common non-synonymous polymorphisms (Arg194Trp and Arg399Gln) to determine their associations with risk of lung cancer. We found that compared with the -77TT wild-type homozygote, the variant genotypes were associated with significantly increased risk of lung cancer [adjusted odds ratio (OR)=1.51; 95% confidence interval (CI)=1.17-1.94 for -77TC; OR=2.98; 95% CI=0.93-9.59 for -77CC; and OR=1.55; 95% CI=1.21-1.98 for -77TC/CC]. By contrast, no significant associations were observed between the other two exonic variants (Arg194Trp and Arg399Gln) and lung cancer risk. Furthermore, we observed a 9.82-fold increased risk (95% CI=5.66-17.02) for heavy smokers carrying the -77C variant (-77TC/CC) and a 4.07-fold increased risk (95% CI=2.85-5.81) for heavy smokers not carrying the variant. However, the interaction between the -77T>C variant and cumulative smoking was not statistically significant (P=0.1560). These findings indicate that the new XRCC1 -77T>C polymorphism may contribute to the aetiology of lung cancer. Further functional studies are warranted to elucidate the underlying molecular mechanisms of the association.

Adenocarcinoma↗