19p13.3-GADD45B common variants and 19q13.3-PPP1R13L and 19q13.3-CD3EAP in lung cancer risk among Chinese.

Lung cancer is the most common cause of cancer-related mortality worldwide. The GADD45 gene family plays important roles in a variety of the responses to cell injury including cell cycle checkpoints, apoptosis, DNA repair and anti-tumor immunity. The 19p13.3-GADD45B encoded protein product is involved in apoptosis and inhibiting tumor growth. To evaluate the association of 19p13.3-GADD45B common variants and lung cancer risk, the present study containing 544 Chinese lung cancer cases and 550 cancer-free controls was conducted. Three htSNPs (haplotype-tagging single nucleotide polymorphism) (rs7354, rs14384, and rs3783501) covering 95% of the common haplotype diversity in 19p13.3-GADD45B and interaction of 19p13.3-GADD45B and 19q13.3-PPP1R13L and 19q13.3-CD3EAP variants and smoking-duration were explored. Genotype and allele frequencies and haplotype distributions of the 19p13.3-GADD45B 3 htSNPs were not associated with lung cancer risk after adjustment for smoking status. 19p13.3-GADD45B rs7354 was associated with lung cancer risk among ≤20 (years) smokers [C/A-A/A versus CC, OR (95% CI) = 3.20 (1.11-9.20), P = 0.025] in a dominant model stratified by smoking duration. MDR (multifactor dimensionality reduction) analyses showed that smoking history as main effect and three-way models (smoking duration, 19p13.3-GADD45B rs3783501, 19q13.3-CD3EAP rs967591) (P = 0.001-0.002) indicated statistically significant association with lung cancer risk. The study identified evidence implicating DNA damage response genes on chromosome 19 in etiology of smoke-exposed lung cancer. In conclusion, our findings demonstrate that 19p13.3-GADD45B rs7354 variant and interaction between 19p13.3-GADD45B rs3783501 and 19q13.3-CD3EAP rs967591 may play a role in association with smoke-exposed lung cancer among Chinese. 19p13.3-GADD45B variants should be further evaluated in large prospective studies with molecular pathological annotations of lung cancer.

Prenatal exposure to organophosphate pesticides and neurobehavioral development of neonates: a birth cohort study in Shenyang, China.

BACKGROUND: A large amount of organophosphate pesticides (OPs) are used in agriculture in China every year, contributing to exposure of OPs through dietary consumption among the general population. However, the level of exposure to OPs in China is still uncertain. OBJECTIVE: To investigate the effect of the exposure to OPs on the neonatal neurodevelopment during pregnancy in Shenyang, China. METHODS: 249 pregnant women enrolled in the Central Hospital Affiliated to Shenyang Medical College from February 2011 to August 2012. A cohort of the mothers and their neonates participated in the study and information on each subject was obtained by questionnaire. Dialkyl phosphate (DAP) metabolites were detected in the urine of mothers during pregnancy to evaluate the exposure level to OPs. Neonate neurobehavioral developmental levels were assessed according to the standards of the Neonatal Behavioral Neurological Assessment (NBNA). Multiple linear regressions were utilized to analyze the association between pregnancy exposure to OPs and neonatal neurobehavioral development. RESULTS: The geometric means (GM) of urinary metabolites for dimethyl phosphate (DMP), dimethyl thiophosphate (DMTP), diethyl phosphate (DEP), and diethyl thiophosphate (DETP) in pregnant women were 18.03, 8.53, 7.14, and 5.64 µg/L, respectively. Results from multiple linear regressions showed that prenatal OP exposure was one of the most important factors affecting NBNA scores. Prenatal total DAP concentrations were inversely associated with scores on the NBNA scales.?Additionally, a 10-fold increase in DAP concentrations was associated with a decrease of 1.78 regarding the Summary NBNA (95% CI, -2.12 to -1.45). And there was an estimated 2.11-point difference in summary NBNA scores between neonates in the highest quintile of prenatal OP exposure and the lowest quintile group. CONCLUSION: The high exposure of pregnant women to OPs in Shenyang, China was the predominant risk factor for neonatal neurobehavioral development.

HapMap-based study identifies risk sub-region on chromosome 19q13.3 in relation to lung cancer among Chinese.

BACKGROUND: Chromosome 19q13.3 has been identified as one of the regions that associate with cancer risk in previous studies. METHODS: We systematically examined the 70.772kb region comprising four genes on chromosome 19q13.3 among Chinese using the haplotype-tagging SNP (htSNP) approach and the HapMap platform. The study involved 339 lung cancer cases and 358 non-cancer controls. Two htSNPs (rs1046282 and rs735482) captured most of the common haplotypes of CD3EA and the combined effects of sixteen htSNPs provided high coverage of common haplotypes of ERCC2, PPP1R13L, CD3EAP and ERCC1. RESULTS: Both carriers of variant CC genotype [adjusted OR (95% CI)=1.28 (1.02-1.60), P=0.04] and variant C-allele among >20 years' smokers [OR (95% CI)=2.13 (1.24-3.67), P=0.006] for CD3EAP rs735482 were at increased risk of lung cancer. Four haplotype blocks of strong linkage disequilibrium were identified. The haplotype ERCC2 rs3916874(G) and rs238415(C) [OR (95% CI)=1.26 (1.02-1.57), P=0.03] in block 1 and the haplotype PPP1R13L rs4803817(A), CD3EAP rs1046282(T), rs735482(C), ERCC1 rs3212980(A), rs3212964(G) [OR (95% CI)=3.56 (1.55-8.18), P=0.005] in block 3 were associated with lung cancer risk. MDR (multifactor dimensionality reduction) analysis demonstrated the best significant model of two-attributes containing smoking duration and rs2298881 in ERCC1 (P=0.004-0.005) and suggested that the effects of high-order interactions among smoking duration and ERCC2, PPP1R13, ERCC1 htSNPs could modulate lung cancer risk. CONCLUSIONS: HapMap-based study of 19q13.3 identified that genetic variation of CD3EAP and two loci were associated with lung cancer risk and interaction of smoking duration and genetic variants was the strongest predictor of lung cancer risk in a Chinese population.

Effects of PPP1R13L and CD3EAP variants on lung cancer susceptibility among nonsmoking Chinese women.

The pathogenesis of lung cancer in the never-smokers could possibly be different from the one in smokers. PPP1R13L and CD3EAP on chromosome 19q13.3 are mainly involved in apoptosis and transcription. PPP1R13L and CD3EAP variants may be associated with cancer risk. We addressed the effects of variants/haplotypes of PPP1R13L rs1970764 and CD3EAP rs967591 and rs735482 on susceptibility of lung cancer among nonsmoking Chinese women. A hospital-based case-control study consisted of 79 lung cancer cases and 108 cancer-free controls matched by age (±3years), gender, ethnicity and lifetime never-smoking. Genotyping and statistical analysis were performed by using the method of ligase detection reaction coupled with polymerase chain reaction (LDR-PCR) and SHEsis program and SPSS software. The presence of variant A-allele for CD3EAP rs967591 was associated with increased lung cancer risk [GA versus GG, OR (95% CI)=2.53 (1.16-5.48), P=0.02 and GA+AA versus GG, OR (95% CI)=2.46 (1.16-5.20), P=0.02]. Both D' values and r(2) values accorded with marker distances on chromosome 19q13.3. No associations were found for two other individual SNPs and haplotype distributions of three markers in the whole or single. In conclusion, this study suggests that CD3EAP rs967591 variant allele carriers are at increased susceptibility of lung cancer among nonsmoking Chinese women.

No evidence of association between the synonymous polymorphisms in XRCC1 and ERCC2 and breast cancer susceptibility among nonsmoking Chinese.

DNA repair proficiency has also been proposed as a potential susceptibility factor for breast cancer. Synonymous polymorphism roles of the DNA repair genes in relation to breast cancer remain largely unknown. Nonsmokers are a good model in which to investigate genetic susceptibility to cancer because they are at low-dose carcinogen exposure. To validate genetic biomarkers of the disease, we explored the effects of the two synonymous polymorphisms [Pro206Pro (rs915927) and Arg156Arg (rs238406)] in the DNA repair genes XRCC1 and ERCC2 at chromosome 19q13.2-3 on breast cancer susceptibility among nonsmoking Chinese. The study recruited 243 patients with breast cancer and 234 cancer-free controls matched to the cases by age (±3years), gender, nonsmoking status and ethnicity. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism. No associations were observed between both individual single nucleotide polymorphisms or haplotypes and breast cancer susceptibility. After stratification, no effects were detected for age-dependent effects or menopause status in relation to breast cancer occurrence. No evidence of gene-gene interaction in breast cancer susceptibility was revealed. The two loci were at weak linkage disequilibrium (D' value=0.244, P=0.07). The present data suggest that XRCC1 Pro206Pro and ERCC2 Arg156Arg do not substantially influence breast cancer susceptibility among nonsmoking Chinese.

Hapmap-based evaluation of ERCC2, PPP1R13L, and ERCC1 and lung cancer risk in a Chinese population.

A genomic region on chromosome 19q13.3 has been associated with cancer susceptibility. A Chinese case-control study including 339 lung cancer cases and 358 controls was conducted using haplotype-tagging SNP (htSNP) approach and HapMap database to evaluate the role of this locus. Four htSNPs (rs6966, rs2070830, rs4802252, and rs4803817) representing 95% of the common variations in PPP1R13L, as well as fourteen htSNPs encompassing ERCC2, PPP1R13L, and ERCC1 on chromosome 19q13.3 were explored. Three haplotype blocks of strong linkage disequilibrium were identified. Overall, no single htSNP or haplotype associations were found for PPP1R13L. Highly significant differential distributions of haplotypes defined by both nine htSNPs covering ERCC2 and PPP1R13L and fourteen htSNPs covering ERCC2, PPP1R13L, and ERCC1 were found (global test P = 8.12e-005 and P = 4.82e-006, respectively). The results indicate that the biologically relevant genetic variation may be located at or near the subregion spanning from ERCC2 inton19 rs1799787 to PPP1R13L intron8 rs2070830.

A specific diplotype defined by PPP1R13L rs1970764, CD3EAP rs967591 and ERCC1 rs11615 and lung cancer risk in a Chinese population.

Haplotypes defined by multiple loci may be more precise and useful than genotypes in providing risk estimates for particular cancers. Diplotype is defined as a specific combination of two haplotypes. A Chinese case-control analysis comprising 370 cases and 388 controls was conducted to evaluate the effects of the high-risk diplotype predefined as PPP1R13L rs1970764(AA)-CD3EAP rs967591(GG)-ERCC1 rs11615(AA) among Caucasians and three SNPs alone or other haplotypes combined for lung cancer risk. Both the variant G-allele of PPP1R13L rs1970764 and the variant A-allele of CD3EAP rs967591 were significantly over-represented among cases (P=0.03 and P=0.002, respectively). The variant GG-homozygotes of PPP1R13L rs1970764 had increased risk [GG versus AA: adjusted OR (95% CI)=1.30 (1.04-1.62), P=0.02]. The carriers of variant A-allele of CD3EAP rs967591 also presented increased risk [AA versus GG: adjusted OR (95% CI)=1.40 (1.12-1.75), P=0.004; AG versus GG: adjusted OR (95% CI)=1.47 (1.05-2.07), P=0.03 and AG+AA versus GG: adjusted OR (95% CI)=1.26 (1.07-1.48), P=0.005]. Interaction between CD3EAP rs967591 and smoking duration was observed (P=0.003). Only haplotype 1 (the common haplotype) defined as PPP1R13L rs1970764(G)-CD3EAP rs967591(A)-ERCC1 rs11615(G) showed marginally increased risk [OR (95% CI)=1.38 (1.09-1.75), P=0.009] after Bonferroni correction. The frequency of the high-risk diplotype predefined among Caucasians was 1% in controls and no significant evidence of the diplotype distribution between cases and controls was detected in present study. In conclusion, we found that variant alleles of PPP1R13L rs1970764 and CD3EAP rs967591 may contribute to risk factors of lung cancer, but the high-risk diplotype predefined among Caucasians was rare and the diplotype is unlikely to confer lung cancer risk in a Chinese population.

HapMap-based study of a region encompassing ERCC1 and ERCC2 related to lung cancer susceptibility in a Chinese population.

DNA repair genes play a crucial role in carcinogenesis. The paper aims to explore if common variants in ERCC1 are involved in lung cancer susceptibility. A Chinese case-control study included 339 lung cancer cases and 358 controls using five haplotype-tagging SNPs (htSNPs) (rs3212980, rs3212964, rs3212961, rs11615 and rs2298881) from the HapMap database, capturing 95% of the common haplotypic diversity of ERCC1. A combined analysis of eleven htSNPs covering ERCC2 and ERCC1 was performed. No significant association between individual htSNPs and lung cancer susceptibility was observed. There were interactions between rs3212961 and rs2298881and smoking duration (P=0.03 and P=0.01, respectively). Thus, the variant alleles of rs3212961 [OR (95% CI)=1.81(1.03-3.17), P=0.04] and rs2298881 [OR (95% CI)=2.16(1.26-3.70), P=0.005] were associated with risk of lung cancer among long-term smokers (>20 years) but not among never smokers and short-term smokers. No significant associations with lung cancer susceptibility were observed for global or individual haplotypes defined by five htSNPs of ERCC1. A highly differential distribution of haplotypes based on eleven htSNPs covering ERCC2 and ERCC1 were found (global test P=4.3×10(-5)). After Bonferroni correction, haplotypeER2+1-1 [OR (95% CI)=3.63 (1.39-9.47), P=0.005, marginally] and haplotypeER2+1-8 [OR (95% CI)=4.46 (2.03-9.79), P=5.6×10(-5), strongly] were associated with increased risk of lung cancer. The diplotype analysis with haplotypeER2+1-8 was also statistically significant (P<0.001). Haplotype analysis of pathological subtypes revealed that htSNPs of both genes may mainly influence the risk of lung adenocarcinoma. Strong linkage disequilibrium exist in two regions encompassing ERCC2 and ERCC1. These data suggest that common genetic variations in ERCC1 may influence increased risk of smoking-related lung cancer and one of the causative effectors may locate around or within ERCC2.

The polymorphism of DNA repair gene ERCC2/XPD Arg156Arg and susceptibility to breast cancer in a Chinese population.

Polymorphisms in DNA repair genes are good candidates for modifying cancer risk. ERCC2/XPD, a gene involved in nucleotide excision repair and basal transcription, may influence individual DNA repair capacity, particularly of bulky adducts. This is implicated in cancer susceptibility. To detect the association between ERCC2/XPD Arg156Arg and susceptibility to breast cancer in a Chinese population, we conducted a hospital-based case-control study consisting of 129 patients with breast cancer and 205 controls matched by age, gender, and ethnicity. PCR-RFLP was used for genotyping. No associations were found between ERCC2/XPD Arg156Arg and risk of breast cancer (AA/AC versus CC: OR = 0.79, 95% CI = 0.49-1.28, P = 0.33; AA versus CC: OR = 0.89, 95% CI = 0.49-1.63, P = 0.72; AC versus CC: OR = 0.74, 95% CI = 0.44-1.24, P = 0.25). Breast cancer cases with the variant AA genotype were marginally younger (mean age 45 years) than cases with the wild CC genotype (mean age 50 years) (P = 0.05). There were no differences in risk estimates in relation to menopause and occurrence of breast cancer. Our findings do not suggest that ERCC2/XPD Arg156Arg contributes to breast cancer susceptibility in a Chinese population.

Driver sleepiness and risk of car crashes in Shenyang, a Chinese northeastern city: population-based case-control study.

OBJECTIVE: To estimate the association of driver sleepiness with the risk of car crashes. METHODS: A population-based case-control study was conducted in Shenyang, a northeastern city in China, between November 2001 and July 2002. The case group comprised 406 car drivers involved in crashes, and 438 car drivers recruited at randomly selected sites, and on the day of week, and the time of day when they were driving on highways in the study region during the study period were used as control groups. Face-to-face interviews with drivers were conducted according to a well-structured questionnaire covering the circumstances of their current trip and their background information. Stanford sleepiness scale and Epworth sleepiness scale were used to quantify acute sleepiness and chronic sleepiness respectively. RESULTS: There was a strong association between chronic sleepiness and the risk of car crash. Significantly increased risk of crash was associated with drivers who identified themselves as sleepy (Epworth sleepiness score > or = 10 vs < 10; adjusted odds ratio 2.07, 95% confidence interval 1.30 to 3.29), but no increased risk was associated with measures of acute sleepiness. CONCLUSIONS: Chronic sleepiness in car drivers significantly increases the risk of car crash. Reductions in road traffic injuries may be achieved if fewer people drive when they are sleepy.

[A case-control study on the risk factors for road injury].

OBJECTIVE: To investigate the risk factors of road injury. METHODS: Case-control study was used. From November 2001 to August 2002, 406 drivers who had 438 drivers who had not experienced a motor vehicle crash in Huanggu district, Shenyang city were recruited by randomly selection on time of day, day of week and site in the same period at same district. Face to face interviews with drivers were conducted according to a highly structured questionnaire covering the circumstances of the current trip, usual behavior and background characteristics of the drivers and the condition of motor vehicles. Stanford sleepiness scale and Epworth sleepiness scale were used to quantify acute and chronic sleepiness respectively. RESULTS: Increased risk was associated with drivers who identified themselves as having chronic doziness (OR = 1.98, 95% CI: 1.26 - 3.12). Increase in risk was associated with measures of acute tiredness, but without statistical significance (OR = 2.38, 95% CI: 0.89 - 6.31). Comparing to permanent daytime work pattern, rotating shifts or permanent night-work pattern increased the risk of crash (OR = 2.09, 95% CI: 1.48 - 2.94). The risk of motor vehicle crash among the drivers who drank alcohol in the previous 6 hours was 3.59 times (95% CI: 1.13 - 11.39) of those drivers who did not drink. Driving violations also contributed to the increased risk of crash (OR = 1.73, 95% CI: 1.22 - 2.46). CONCLUSION: Factors as chronic doziness, rotating shifts or permanent night-work pattern, driving under alcohol impairment, violation of motor vehicle regulation all significantly increased the risk of road injury. Acute sleepiness might serve as a potential risk factor for road injury.