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Background Epidemiological evidence remains conflicting regarding diet and risk of lung cancer. Objectives We sought to systematically investigate whether dietary factors are associated with the risk of incident lung cancer in the UK Biobank. Methods A total of 416,588 participants (54% women) from the UK Biobank were included in the present study. Based on baseline data from FFQs, 3 main dietary patterns were identified by using principal component analysis. Cox proportional hazards models were used to investigate the association of individual food groups and dietary patterns with lung cancer risk. Results During a median follow-up of 7.13 y, 1782 incident lung cancer cases were documented. The association analysis showed high intake of red meat and processed meat was associated with an increased risk of lung cancer (HRper 50 g/d: 1.36; 95% CI: 1.13, 1.65 for red meat; HRper 25 g/d: 1.30; 95% CI: 1.10, 1.53 for processed meat). However, the consumption of fruits (HRper 100 g/d: 0.90; 95% CI: 0.84, 0.95), vegetables (HRper 100 g/d: 0.89; 95% CI: 0.81, 0.99), breakfast cereals (HRper 50 g/d: 0.81; 95% CI: 0.74, 0.89), and dietary fiber (HRper 5 g/d: 0.76; 95% CI: 0.69, 0.84) was inversely associated with the risk of lung cancer. For the dietary pattern analysis [quartile (Q) comparison], high adherence to the Prudent pattern (HRQ4 compared with Q1: 0.84; 95% CI: 0.73, 0.96) was associated with a lower risk of lung cancer, whereas the Western pattern (HRQ4 compared with Q1: 1.27; 95% CI: 1.11, 1.46) was associated with a higher risk of lung cancer. Conclusions Our study indicated that a diet characterized by high intake of fruits, vegetables, breakfast cereals, and dietary fiber, as well as low intake of red meat and processed meat, was associated with a lower risk of lung cancer. [ABSTRACT FROM AUTHOR]

Background Many cohort studies have explored the relation between tea consumption and stroke risk; however, the conclusions have been inconsistent. In addition, evidence is lacking in China, where the patterns of tea consumption and main types of tea consumed differ substantially from those in high-income countries. Objective We aimed to systematically assess the association of tea consumption with the risk of stroke based on a Chinese large-scale cohort study. Methods A total of 487,377 participants from the China Kadoorie Biobank were included in the present study. Detailed information about tea consumption (including frequency, duration, amount, and tea type) was self-reported at baseline. After ∼4.3 million person-years of follow-up, 38,727 incident cases of stroke were recorded, mainly through linkage with mortality and morbidity registries and based on the national health insurance system. Results Overall, 128,280 adults (26.3%) reported drinking tea almost daily (41.4% men, 15.9% women), predominantly green tea (86.7%). Tea consumption had an inverse and dose–response relation with the risk of stroke (P trend < 0.001). Compared with nonconsumers, those who consumed tea occasionally, weekly, and daily had adjusted HRs and 95% CIs of 0.96 (0.94, 0.99), 0.94 (0.90, 0.98), and 0.92 (0.89, 0.95) respectively, with little difference by stroke type. Among those who consumed tea daily, the HRs for stroke decreased with the increasing duration and amount of tea consumed (all P  < 0.001). These inverse associations were significant for green tea but not for other types of tea. Among men, but not women, the inverse relations could be detected, and similar inverse associations could be found for male noncurrent alcohol-consumers and noncurrent smokers as well. Conclusions Among Chinese adults, higher consumption of tea, especially green tea, was associated with a lower risk of ischemic and hemorrhagic stroke. [ABSTRACT FROM AUTHOR]

Background Coffee consumption has been linked to lower risk of various health outcomes. However, the biological pathways mediating the associations remain poorly understood. Objectives The aim of this study was to assess the association between coffee consumption and concentrations of plasma biomarkers in key metabolic and inflammatory pathways underlying common chronic diseases. Methods We investigated the associations of total, caffeinated, and decaffeinated coffee consumption with 14 plasma biomarkers, including C-peptide, insulin-like growth factor 1 (IGF-1), IGF binding protein (IGFBP) 1, IGFBP-3, estrone, total and free estradiol, total and free testosterone, sex hormone–binding globulin (SHBG), total adiponectin, high-molecular-weight (HMW) adiponectin, leptin, C-reactive protein (CRP), interleukin 6 (IL-6), and soluble tumor necrosis factor receptor 2 (sTNFR-2). Data were derived from 2 cohorts of 15,551 women (Nurses' Health Study) and 7397 men (Health Professionals Follow-Up Study), who provided detailed dietary data before blood draw and were free of diabetes, cardiovascular disease, or cancer at the time of blood draw. Multivariable linear regression was used to calculate the percentage difference of biomarker concentrations comparing coffee drinkers with nondrinkers, after adjusting for a variety of demographic, clinical, and lifestyle factors. Results Compared with nondrinkers, participants who drank ≥4 cups of total coffee/d had lower concentrations of C-peptide (−8.7%), IGFBP-3 (−2.2%), estrone (−6.4%), total estradiol (−5.7%), free estradiol (−8.1%), leptin (−6.4%), CRP (−16.6%), IL-6 (−8.1%), and sTNFR-2 (−5.8%) and higher concentrations of SHBG (5.0%), total testosterone (7.3% in women and 5.3% in men), total adiponectin (9.3%), and HMW adiponectin (17.2%). The results were largely similar for caffeinated and decaffeinated coffee. Conclusion Our data indicate that coffee consumption is associated with favorable profiles of numerous biomarkers in key metabolic and inflammatory pathways. This trial was registered at clinicaltrials.gov as NCT03419455. [ABSTRACT FROM AUTHOR]

A one-size-fits-all approach to colorectal cancer (CRC) screening that does not account for CRC risk factors is not conducive to personalized screening. On the basis of the principle of equal management of equal risks, we aimed to tailor and validate risk-adapted starting ages of CRC screening for individuals with different CRC risk factors. A multi-center community-based population cohort (N = 3,165,088) was used to evaluate the starting age of CRC screening with comprehensive consideration of risk factors. Age-specific 10-year cumulative risk curves were used to determine when individuals at greater risk for CRC reached the same risk level as the 50-year-old general population, which is currently the recommended starting age for CRC screening in China. During the study follow-up period (2013–2021), 4,840 incident CRCs were recorded. Family history of CRC, adverse lifestyle, and comorbidities demonstrated heterogeneous associations with CRC risk (hazard ratios, 1.05–1.55; P <.05). Men and women with CRC family history and at least 2 risk factors reached the standard benchmark risk (0.28%) for screening at the age of 40, 10 years earlier than their peers without risk factors in the general population. Proposed starting ages for CRC screening were validated in an independent community-based population cohort (N = 1,023,367). We determined a risk-adapted CRC screening starting age for individuals with various CRC risk factors. Earlier, personalized screening based on these findings could allow for scarce health resources to be dedicated to individuals who benefit most. [ABSTRACT FROM AUTHOR]

Hepatitis B (HBV) infection is the leading cause of hepatocellular carcinoma (HCC) in Asia.1 Hepatitis B surface antigen (HBsAg) seroclearance is considered to be one of the most important end points of chronic HBV infection and is associated with a reduced risk of HCC. [ABSTRACT FROM AUTHOR]

Summary: The missense variant S180L in TIRAP (Toll-interleukin-1 receptor domain-containing adaptor protein) gene is implicated in attenuating TLRs signal transaction and may affect individual response to Mycobacterium tuberculosis infection. Several studies investigated the association between TIRAP S180L and risk of tuberculosis (TB), but the results were controversial. In this study, we quantitatively synthesized nine studies relevant to the association between TIRAP S180L polymorphism and TB risk with total 6584 TB cases and 7294 controls using meta-analysis. We found that the variant allele Leu180 and heterozygous genotype Ser/Leu were not significantly associated with risk of TB (allelic OR = 0.99, 95%CI: 0.88–1.11; Ser/Leu vs Ser/Ser: OR = 0.99, 95%CI: 0.87–1.13) with heterogeneity P values > 0.05. In subgroup analysis, none of the significant associations were observed for S180L and TB risk in Africans (allelic OR = 0.58, 95%CI: 0.29–1.61; heterozygous OR = 0.65, 95%CI: 0.32–1.32) or Asians (allelic OR = 1.30, 95%CI: 0.97–1.74; heterozygous OR = 1.17, 95%CI: 0.84–1.65) or risk of pulmonary tuberculosis (PTB) (allelic OR = 0.92, 95%CI: 0.69–1.22; heterozygous OR = 0.98, 95%CI: 0.86–1.12). This meta-analysis indicates that TIRAP S180L polymorphism is unlikely to substantially contribute to TB susceptibility. [ABSTRACT FROM AUTHOR]

Mammalian cells are constantly exposed to a wide variety of genotoxic agents from both endogenous and exogenous sources. Genetic variability in DNA repair may contribute to human cancer risk. In this population-based case-control study in China, we tested the hypothesis that a C to T variant (Thr241Met) of DNA repair gene XRCC3 (X-ray repair cross-complementing group 3) is associated with risk of developing gastric cancer. We genotyped for this variant using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) in 188 histologically confirmed gastric cancer patients and 166 frequency-matched cancer-free controls. The XRCC3 genotype and allele frequencies were not significantly different between cases and controls (P=0.99 for genotype; P=0.76 for allele). The XRCC3 241Met allele frequency (4.8%) was significantly lower in healthy Chinese controls than previously reported healthy US Caucasian controls (38.9%). Compared with the XRCC3 241Thr/Thr genotype, the variant XRCC3241Thr/Met and Met/Met genotypes were not associated with an increased risk of gastric cancer (adjusted odds ratio (ORa), 1.06; 95% confidence interval (CI), 0.52–2.16). These findings suggest that polymorphisms of XRCC3 Thr241Met may not play a role in the etiology of gastric cancer. Further studies with a larger number of subjects and simultaneous measurement of different polymorphisms in DNA repair genes in the same pathway are needed to confirm these findings. [Copyright &y& Elsevier]

p53 plays an important role in cell-cycle control, as it facilitates DNA repair activities in response to DNA damage. An aberrant cell cycle impairs DNA repair and increases the probability of mutations that lead to carcinogenesis. The p53 codon 72 Arg/Pro polymorphism has been suggested to be associated with susceptibility to tobacco-related cancers, but this association remains controversial. In this hospital-based case-control study of 304 patients newly diagnosed with squamous cell carcinoma of the head and neck (SCCHN) and 333 cancer-free controls, we evaluated the association between this p53 polymorphism and the risk of SCCHN. All subjects were non-Hispanic whites, and the controls were frequency-matched to the cases by age (±5 years), sex and smoking status. Our results suggested that there was no difference in the distributions of p53 codon 72 genotypes between cases and controls (odds ratio (OR)=1.04, 95% confidence interval (CI) 0.75–1.44 for Pro/Pro vs. Arg/Arg and OR=1.01, 95% CI 0.54–1.91 for Arg/Pro vs. Arg/Arg). However, there was evidence that the Pro allele was associated with an early age of onset of SCCHN. The median ages of onset of SCCHN were 59, 56 and 53 years for Arg/Arg, Arg/Pro and Pro/Pro cases, respectively (P=0.151 among three genotypes; P=0.057 for Pro/Pro and Arg/Pro combined vs. Arg/Arg). The median ages at onset of oral cancers were 62, 57 and 51 years for Arg/Arg, Arg/Pro and Pro/Pro, respectively (P=0.091 among three genotypes; P=0.046 for Pro/Pro vs. Arg/Arg; P=0.066 for Pro/Pro and Arg/Pro combined vs. Arg/Arg). While the results suggest that the P53 codon 72 polymorphism may contribute to oral cancer susceptibility, larger studies are needed to confirm these findings. [Copyright &y& Elsevier]

DNA ligases catalyze the joining of single and double-strand DNA breaks, which is an essential step in DNA replication, recombination and repair. Recently, a common single nucleotide polymorphism (A→C) in exon 6 of DNA ligase I (LIG1) was identified, but its functional relevance remains to be determined. Because LIG1 participates in DNA repair and reduced DNA repair capacity is associated with risk of lung cancer, we evaluated in a non-population-based case-control study of 530 lung cancer cases and 570 cancer-free controls the role of this polymorphism in susceptibility to lung cancer. All of the subjects were non-Hispanic whites and the controls were frequency-matched to cases on age, sex and smoking status. Using the polymerase chain reaction–restriction fragment length polymorphism method, we found that this LIGI A→C substitution was very common in healthy controls and that the A and C allele frequencies were close to 0.5. However, there was no significant difference in the frequency distributions of LIGI genotypes between lung cancer cases and controls (25.7, 49.8 and 24.5% in cases and 26.1, 49.7 and 24.2% in controls for the AA, AC and CC genotypes, respectively). Therefore, there was no evidence to support an association between this polymorphism and the risk of lung cancer (adjusted odds ratio (OR)=1.06, 95% confidence interval (CI)=0.76–1.49 for AC versus CC and OR=0.93, 95% CI=0.64–1.36 for AA versus CC) neither in all cases nor in different histopathologic types. The results of this large case-control study suggest that this LIG1 polymorphism may not play an important role in susceptibility to lung cancer. [Copyright &y& Elsevier]

Exclusive breastfeeding is advantageous for infant neurodevelopment. Nevertheless, insufficient human milk supply in exclusively breastfed infants may elevate the risk of neonatal jaundice, which can potentially result in neurological harm. Whether mothers should adhere to exclusive breastfeeding in infants with neonatal jaundice remains unclear. Data comes from the Jiangsu Birth Cohort (JBC), a prospective and longitudinal birth cohort study in China. A total of 2,577 infants born from November 2017 to March 2021 were included in the analysis. Multivariate linear regression models were used to analyze the associations between breastfeeding status, neonatal jaundice, and their interaction with infant neurodevelopment. Analysis was performed in 2022. Compared with "exclusive breastfeeding," fine motor scores of infants were lower for "mixed feeding" (β adj , −0.16; 95% CI, −0.29 to −0.03; p =0.016) and "no breastfeeding" (β adj , −0.41; 95% CI, −0.79 to −0.03; p =0.034). Compared with "no neonatal jaundice," infants with "severe neonatal jaundice" had lower scores for cognition (β adj , −0.44; 95% CI, −0.66 to −0.23; p <0.001) and fine motor (β adj , −0.19; 95% CI, −0.35 to −0.03; p =0.024). In infants with severe neonatal jaundice, the termination of exclusive breastfeeding before 6 months was associated with worse cognition (β adj , −0.28; 95% CI, −0.57 to 0.01), while this association was not observed in those without neonatal jaundice (β adj , 0.09; 95% CI, −0.26 to 0.43). Exclusive breastfeeding for the first 6 months is beneficial to the neurodevelopment of infants, especially in those with severe neonatal jaundice. [ABSTRACT FROM AUTHOR]

Background: Mosaic chromosomal alterations (mCAs) detected from blood-derived DNA are large structural alterations of clonal haematopoietic origin and are associated with various diseases, such as haematological malignancies, infections, and solid cancers. We aimed to investigate whether mCAs contribute to the risk of lung cancer and modify the effect of polygenic risk score (PRS) on lung cancer risk prediction.Methods: The blood-derived DNA of patients with lung cancer and cancer-free controls with Chinese ancestry from the Nanjing Lung Cancer Cohort (NJLCC) study were genotyped with a Global Screening Array, and mCAs were detected with the Mosaic Chromosomal Alterations (MoChA) pipeline. mCA call sets of individuals with European ancestry were obtained from the prospective cohort UK Biobank (UKB) study, including documented incident lung cancer. All patients with lung cancer from the NJLCC study (aged 15 years or older at diagnosis) were histopathologically confirmed as new lung cancer cases by at least two pathologists and were free of chemotherapy or radiotherapy before diagnosis. Participants with incident lung cancer (aged 37-73 years at assessment) diagnosed after recruitment to the UKB were identified through linkage to national cancer registries. Logistic regression and Cox proportional hazard models were applied to evaluate associations between mCAs and risk of lung cancer in the NJLCC (logistic regression) and UKB (Cox proportional hazard model) studies.Findings: The NJLCC study included 10 248 individuals (6445 [62·89%] men and 3803 [37·11%] women; median age 60·0 years [IQR 53·0-66·0]) with lung cancer and 9298 individuals (5871 [63·14%] men and 3427 [36·86%] women; median age 60·0 years [52·0-65·0]) without lung cancer recruited from three sub-regions (north, central, and south) across China between April 15, 2003, and Aug 18, 2017. The UKB included 450 821 individuals recruited from 22 centres across the UK between March 13, 2006, and Nov 1, 2010, including 2088 individuals with lung cancer (1075 [51·48%] men and 1013 [48·52%] women; median age 63·0 years [IQR 59·0-66·0]), and 448 733 participants were free of lung cancer (204 713 [45·62%] men and 244 020 [54·38%] women; median age 58·0 years [IQR 50·0-63·0]). Compared with non-carriers of mosaic losses, carriers had a significantly increased risk of lung cancer in the NJLCC (odds ratio [OR] 1·81, 95% CI 1·43-2·28; p=6·69 × 10-7) and UKB (hazard ratio [HR] 1·40, 95% CI 1·00-1·95; p=0·048) studies. This increased risk was even higher in patients with expanded cell fractions of mCAs (ie, cell fractions ≥10% vs cell fractions <10%) in the NJLCC (OR 1·61 [95% CI 1·26-2·08] vs 1·03 [0·83-1·26]; p for heterogeneity test=6·41 × 10-3). A significant multiplicative interaction was observed between PRS and mosaic losses on the risk of lung cancer in both the NJLCC (interaction p value=0·030) and UKB (p=0·043). Compared with non-carriers of mosaic loss abnormalities with low genetic risk, participants with expanded mosaic losses (cell fractions ≥10%) and high genetic risk had around a six-times increased risk of lung cancer in the NJLCC study (OR 6·40 [95% CI 3·22-12·69]), and an almost four-times increased risk of lung cancer (HR 3·75 [95% CI 1·86-7·55]) in the UKB study. The additive interaction also contributed a 3·67 (95% CI 0·49-6·85) relative excess risk of developing lung cancer in the NJLCC study, and a 2·15 (0·12-4·19) relative excess risk in the UKB study.Interpretation: mCAs act as a new endogenous indicator for the risk of lung cancer and might be jointly used with PRS to optimise personalised risk stratification for lung cancer.Funding: National Natural Science Foundation of China, Outstanding Youth Foundation of Jiangsu Province, Natural Science Foundation of Jiangsu Province, and Postdoctoral Science Foundation of China.Translation: For the Chinese translation of the abstract see Supplementary Materials section. [ABSTRACT FROM AUTHOR]

CpG-SNPs in gene promoter regions are proposed to be associated with multiple diseases. To date, few studies have focused on the associations between CpG-SNPs in miRNA promoters and the risk of breast cancer. In this study, 138 miRNAs differentially expressed between breast cancer and non-cancer tissues (fold change >2, P  < 0.05) were identified using The Cancer Genome Atlas (TCGA) Research database. In total, 13 SNPs were selected in the promoters of the miRNAs and were evaluated in a case-control study of Chinese women including 1486 cases and 1519 controls. After multivariate logistic regression analysis, we found that three CpG-SNPs: rs1190983, rs155247, and rs62382272, were significantly associated with breast-cancer susceptibility in the population (Additive model: rs1190983: adjusted OR = 0.88, 95% CI: 0.79–0.99, P  = 0.034; rs155247: adjusted OR = 0.83, 95% CI: 0.74–0.93, P  = 0.002; rs62382272: adjusted OR = 1.24, 95% CI: 1.04–1.47, P  = 0.016). eQTL analysis showed that these three SNPs were correlated with the expression of the related miRNAs in TCGA breast cancer tissues ( P  = 0.006,0.009,0.001 for rs1190983, rs155247, and rs62382272). Furthermore, rs1190983 was found to be associated with CpG site (cg20488673) methylation (meQTL) ( P  = 0.004), which was in turn correlated with miR-342 expression ( P  = 0.016). These findings indicated that the three CpG-SNPs in the promoters of miRNAs were likely to possess important biological functions to breast cancer in the Han Chinese population. [ABSTRACT FROM AUTHOR]

Objectives The polymorphic major histocompatibility complex (MHC) plays a vital role in the immune system and drives predisposition to multiple cancers. A number of lung cancer-related genetic variants in the MHC have been identified in recent genome-wide association studies; however, the causal variants remain unclear. Materials and methods In the present study, we conducted a large-scale fine-mapping study of lung cancer in the MHC region of 13,945 unrelated Asian individuals to search for potential causal variants. We used the recently constructed Pan-Asian panel as the reference and imputed eight HLA genes ( HLA-A , HLC-B , HLA-C , HLA-DRB1 , HLA-DQA1 , HLA-DQB1 , HLA-DPA1 , and HLA-DPB1 ) using SNP2HLA software. Results We identified one single nucleotide polymorphism, rs12333226 (OR = 1.41, P = 3.97 × 10 −7 ), five HLA amino acid polymorphisms in HLA-DRB1 (OR = 0.89, P = 7.51 × 10 −6 –8.57 × 10 −6 ), and one two-digit classic HLA allele HLA-A*11 (OR = 0.87, P = 9.68 × 10 −6 ) that were strongly associated with the risk of lung cancer. Rs12333226 was an expression quantitative trait locus of HLA-A and HLA-H in circulating monocytes, and exerted effect on lung cancer risk especially in the younger. HLA-DRβ1 positions 10, 16, and 25 drove the effect of one reported SNP rs2395185. The peptide position analysis identified additional lung cancer susceptibility amino acid positions, including HLA-DRβ1 position 30 and 11 ( P omnibus = 6.11 × 10 −5 and 6.91 × 10 −5 ), HLA-DQa1 47 and 76 ( P omnibus = 3.96 × 10 −4 and 1.41 × 10 −2 ) and HLA-A 152 ( P omnibus = 4.86 × 10 −4 ). Most of the peptide positions were located in the peptide-binding grooves and seemed to affect antigen presentation. All the existing and novel variants explained approximately 2.37% of the phenotypic variances, while 21.10% was attributed to the variants identified in this study. Conclusion We identified seven novel bi-allelic variants and five polymorphic amino acid positions in HLA-DRβ1, HLA-DQα1, and HLA-A that confer a risk of lung cancer. This finding provides evidence for the substantial contributions of HLA class I and II molecules to lung cancer susceptibility. [ABSTRACT FROM AUTHOR]

Autophagy associated genes (ATGs) played an important role in the repair process of DNA damage and decreased autophagy may weaken the repair process and aggravate DNA damage. Based on this, we hypothesized that DNA damage levels might be modified by genetic variants in autophagy associated genes. In order to validate our hypothesis, 307 subjects were recruited from three different cities (Zhuhai, Wuhan and Tianjin) in China. Demographic data, individual 24-h PM 2.5 exposure and peripheral blood DNA damage levels were also detected. Seven potentially functional polymorphisms in four essential autophagy associated genes ( ATG5 , ATG7 , ATG8 and ATG13 ) were screened to evaluate the relationship between the polymorphisms of autophagy associated genes and DNA damage levels. This association was assessed by using multivariable linear regression model, age, sex, smoke and PM 2.5 exposure levels were adjusted in each city. We found that rs12599322 in ATG8 (A > G, β = 0.263, 95% CI: 0.108–0.419, P = 8.98 × 10 − 4 ) and rs7484002 in ATG13 (A > G, β = 0.396, 95% CI: 0.085–0.708, P = 0.013) were significantly associated with higher DNA damage levels. Furthermore, functional annotations showed that both rs12599322 and rs7484002 located at transcription factor binding sites (TFBS), indicating that they could regulate the expression of related genes through TF regulation. Following allelic trend analysis revealed that the DNA damage levels were significantly aggravated with the increasing number of risk variants in autophagy associated genes ( P for trend: 8.09 × 10 − 5 ). Our findings suggested that the polymorphisms in ATGs may influence DNA damage levels in one of the Chinese population. [ABSTRACT FROM AUTHOR]

Background: Few studies have been conducted in China to investigate the association between diet and the risk of head-and-neck cancer (HNC). The aim of this study was to determine the relationship between diet and HNC risk in the Chinese population and to examine whether smoking status has any effect on the risk.Methods: Our multicenter case-control study included 921 HNC cases and 806 controls. We obtained information on the frequency of both animal- and plant-based food consumption. Unconditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals (95%CIs).Results: The risk of HNC increased with more frequent consumption of processed meat and fermented foods but decreased with frequent consumption of fruits and vegetables. There was a significant increasing P for trend of 0.006 among smokers who consumed meat and an increased OR among smokers who consumed processed meat (OR 2.95, 95%CI 1.12-7.75). Protective odds ratios for vegetable consumption were observed among smokers only. We also observed protective odds ratios for higher egg consumption among never-smokers (P for trend=0.0.003).Conclusions: Reduced HNC risks were observed for high fruit and vegetable intake, a finding consistent with the results of previous studies. Processed meat intake was associated with an increased risk. The role of dietary factors in HNC in the East Asian population is similar to that in European populations. [ABSTRACT FROM AUTHOR]

Chromatin remodeling complexes utilize the energy of ATP hydrolysis to remodel nucleosomes and have essential roles in transcriptional modulation. Increasing evidences indicate that these complexes directly interact with numerous proteins and regulate the formation of cancer. However, few studies reported the association of polymorphisms in chromatin remodeling genes and lung cancer. We hypothesized that variants in critical genes of chromatin remodeling pathway might contribute to the susceptibility of lung cancer. To validate this hypothesis, we systematically screened 40 polymorphisms in six key chromatin remodeling genes ( SMARCA5 , SMARCC2 , SMARCD2 , ARID1A , NR3C1 and SATB1 ) and evaluated them with a case-control study including 1341 cases and 1982 controls. Logistic regression revealed that four variants in NR3C1 and SATB1 were significantly associated with lung cancer risk after false discovery rate (FDR) correction [For NR3C1 , rs9324921: odds ratio (OR) = 1.23, P for FDR = 0.029; rs12521436: OR = 0.85, P for FDR = 0.040; rs4912913: OR = 1.17, P for FDR = 0.040; For SATB1 , rs6808523: OR = 1.33, P for FDR = 0.040]. Combing analysis presented a significant allele-dosage tendency for the number of risk alleles and lung cancer risk ( P trend < 0.001). Moreover, expression quantitative trait loci (eQTL) analysis revealed that these two genes were differently expressed between lung tumor and adjacent normal tissues in the database of The Cancer Genome Atlas (TCGA) ( P = 0.009 for rs6808523). These findings suggested that genetic variants in key chromatin remodeling genes may contribute to lung cancer risk in Chinese population. Further large and well-designed studies are warranted to validate our results. [ABSTRACT FROM AUTHOR]

Aminoacyl-tRNA synthetases (ARSs) and ARS-interacting multi-functional proteins (AIMPs) form a multisynthetase complex (MSC) and play an important role in the process of DNA damage repair. We hypothesized that genetic variants in key ARSs and AIMPs might regulate the DNA damage response. Therefore, we systematically screened 23 potentially functional polymorphisms in MSC genes and evaluated the association between the genetic variants and DNA damage levels in 307 subjects from three cities in southern, central and northern China (Zhuhai, Wuhan and Tianjin, respectively). We examined personal 24-h PM 2.5 exposure levels and DNA damage levels in peripheral blood lymphocytes for each subject. We found that the variant allele of rs12199241 in AIMP3 was significantly associated with DNA damage levels ( β = 0.343, 95%CI: 0.133–0.554, P = 0.001). Meanwhile, the results of rs5030754 in EPRS and rs3784929 in KARS indicated their suggestive roles in DNA damage processes ( β = 0.331, 95%CI: 0.062–0.599, P = 0.016 for rs5030754; β = 0.192, 95%CI: 0.016–0.368, P = 0.033 for rs3784929, respectively). After multiple testing, rs12199241 was still significantly associated with DNA damage levels. Combined analysis of these three polymorphisms showed a significant allele-dosage association between the number of risk alleles and higher DNA damage levels ( P trend < 0.001). These findings indicate that genetic variants in MSC genes may account for PM 2.5 -modulated DNA damage levels in Chinese populations. [ABSTRACT FROM AUTHOR]

Objectives: The aim of our study is to explore the role of the history of oral lesions and chronic diseases on the risk of head and neck cancer in a Chinese population.Materials and Methods: Our case-control study included 921 head and neck cancer cases and 806 controls. We obtained medical history information by administering questionnaires to both cases and controls. We used unconditional logistic regression to estimate odds ratios for oral lesions and chronic conditions.Results: Oral submucous fibrosis (OR=24.24, 95% CI=7.39-79.52), oral leukoplakia (OR=4.05, 95% CI=2.44-6.71) and repetitive dental ulcers (OR=5.12, 95% CI=3.17-8.28) increased the risk of HNC. Depression was associated with HNC risk when adjusted for several covariates (OR=2.10, 95% CI=1.06-4.15), but the association was not statistically significant after adjusting for smoking and alcohol drinking (OR=1.53, 95% CI=0.72-3.25). Also, the crude OR suggested an association between diabetes and HNC risk (OR=1.51, 95% CI=1.09-2.11), but it was not significant after adjusting for confounders.Conclusion: Our study reported on strong associations between HNC risk and oral leukoplakia, oral submucous fibrosis, which is consistent with prior research. We also observed repetitive dental ulcer to be associated with HNC risk. Future studies may focus on studying the association between depression and HNC, using medical records or psychological evaluation results to get more accurate information about depression, with careful assessment of tobacco and alcohol history. [ABSTRACT FROM AUTHOR]

• Co-exposure to trace elements impacts children's early neurodevelopment. • Lithium, aluminum and iron contributed most to an increase in cognitive composite score. • Zinc, silver, and antimony mainly contributed to motor composite score. • An inverted U-shaped relationship between Sb and motor function was identified. • We found antagonistic interaction effect between Ba and Sb on motor function. Prenatal exposures to neurotoxic metals and trace elements are associated with early childhood neurodevelopmental outcomes. However, consequences of simultaneous exposure to mixtures of elements remain unclear. To examine individual and joint effects of prenatal trace element exposure on early childhood neurodevelopment. Using a well-established Bangladesh prospective birth cohort (2008–2011), we measured concentrations of 52 trace elements in umbilical cord serum of 569 mother–infant pairs using inductively coupled plasma mass spectrometry. Neurodevelopment was evaluated at 20–40 months of age using Bayley Scales of Infant and Toddler Development, Third Edition. Stability elastic net (ENET) was used to screen elements individually associated with the outcome; candidate exposures were combined by weighted linear combination to form a risk score representing their mixture effect on early childhood neurodevelopment. Stability ENET identified 15 trace elements associated with cognitive composite score and 14 associated with motor composite score, which were linearly combined to form the element risk score (ERS). Children with higher ERS cognitive had lower probability of cognitive developmental delay (OR highest vs lowest : 0.21; 95 %CI: 0.10, 0.40; P < 0.001; P trend < 0.001). Children with ERS motor in the top quintile had a significantly lower risk of motor developmental delay (OR: 0.16; 95 %CI: 0.09, 0.31; P < 0.001; P trend < 0.001) versus the lowest quintile. In Bayesian kernel machine regression analyses, lithium [conditional posterior inclusion probability (cPIP) = 0.68], aluminum (cPIP = 0.83) and iron (cPIP = 1.00) contributed most to the lower cognitive composite score; zinc (cPIP = 1.00), silver (cPIP = 0.81), and antimony (cPIP = 0.65) mainly contributed to the change of motor composite score. Co-exposure to lithium/aluminum/iron or zinc/silver/antimony appears to impact children's neurodevelopment. ERS score reflecting maternal exposure could indicate children's risk of neurodevelopmental delay, warranting further studies to explore the underlying mechanism. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA) is believed to be both the source and target of reactive oxygen species (ROS), and mtDNA genetic alterations have been reported to be associated with molecular defects in the oxidative phosphorylation (OXPHOS) system. In order to investigate the potentially susceptible mtDNA genetic variants to oligoasthenospermia, we conducted a two-stage study in 921 idiopathic infertile men with oligoasthenospermia and 766 healthy controls using comprehensive molecular analysis. In the screen stage, we used next generation sequencing (NGS) in 233 cases and 233 controls to screen oligoasthenospermia susceptible mitochondrial genetic variants. In total, seven variants (C5601T, T12338C, A12361G, G13928C, A15235G, C16179T and G16291A) were screened to be potentially associated with idiopathic oligoasthenospermia. In the validation stage, we replicated these variants in 688 cases and 533 healthy controls using SNPscan. Our results demonstrated that the genetic alteration of C16179T was associated with idiopathic male infertility (odds ratio (OR) 3.10, 95% CI 1.41–6.79) ( p = 3.10 × 10 − 3 ). To elucidate the exact role of the genetic variants in spermatogenesis, two main sperm parameters (sperm count and motility) were taken into account. We found that C16179T was associated with both low sperm count and motility, with ORs of 4.18 (95% CI 1.86–9.40) ( p = 1.90 × 10 − 4 ) and 3.17 (95% CI 1.40–7.16) ( p = 3.50 × 10 − 3 ), respectively. Additionally, A12361G was found to be associated with low sperm count, with an OR of 3.30 (95% CI 1.36–8.04) ( p = 5.50 × 10 − 3 ). These results indicated that C16179T influenced both the process of spermatogenesis and sperm motility, while A12361G may just only participate in the process of spermatogenesis. Further investigation in larger populations and functional characterizations are needed to validate our findings. [ABSTRACT FROM AUTHOR]

Background Alternative splicing is an important biological step during mRNA processing. Misregulation of alternative splicing can produce aberrant protein isoforms, thus contributing to cancer. We hypothesized that variants in 5 critical splicing factor-associated genes might play an important role in carcinogenesis of lung cancer. Materials and methods A case-control study including 1,341 non-small cell lung cancer (NSCLC) cases and 1,982 cancer-free controls were conducted to evaluate the associations of 16 tagging/functional polymorphisms in 5 splicing factor-associated genes with lung cancer risk. Results We found altogether 8 SNPs were associated with lung cancer risk with adjustment of age, gender, and smoking status after multiple corrections (FDR). Among these, six SNPs were related with SRSF7 (rs10197412, OR(95%CI) = 1.23(1.06–1.43), P for FDR = 0.018; rs12621103, OR(95%CI) = 1.25(1.08–1.46), P for FDR = 0.016; rs13024811, OR(95%CI) = 1.25(1.07–1.46), P for FDR = 0.016; rs2037875, OR(95%CI) = 1.23(1.06–1.42), P for FDR = 0.018; rs3134628, OR(95%CI) = 1.25(1.07–1.45), P for FDR = 0.016 and rs6715866, OR(95%CI) = 1.23(1.07–1.43), P for FDR = 0.016); one SNP was near PTBP2 (rs12566237: OR(95%CI) = 1.16(1.05–1.28), P for FDR = 0.016) and one SNP in HNRNPQ (rs16876385: OR(95%CI) = 1.17(1.04–1.32), P for FDR = 0.022). Conclusions Our findings indicated that genetic variants in these splicing-associated genes might modify individual susceptibility to lung cancer in Chinese population. Further large-scale well-formed population studies and functional researches are warranted to confirm our findings. [ABSTRACT FROM AUTHOR]

Exposure to particulate matter 2.5 (PM 2.5 ) may result in DNA damage. Histone variant H2AX phosphorylation plays a central role in the response to damaged chromatin. In the current study, we investigated whether H2AX gene polymorphisms account for PM 2.5 -modulated DNA damage levels. A total of 307 healthy urban residents were collected from three cities in southern, central, and northern China, Zhuhai, Wuhan, and Tianjin, respectively. The dust mass concentrations of PM 2.5 were detected by Gilian 5000 pumps, and the DNA damage levels were measured using comet assay. Seven potentially functional single nucleotide polymorphisms (SNPs) of H2AX gene were selected and genotyped by Illumina Infinium ® BeadChip. We found that three SNPs (rs10790283 G > A, rs604714 C > A and rs7759 A > G) were significantly associated with DNA damage levels (adjusted P = 0.002, 0.018 and 0.027, respectively). Significant interactions ( P < 0.05) were observed between certain genetic polymorphisms and PM 2.5 -modulated DNA damage levels. These results suggested that genetic variations of H2AX might be associated with the DNA damage levels in urban residents with different exposure to PM 2.5 . Further studies with large sample size in independent populations merit validating these findings. [ABSTRACT FROM AUTHOR]

Exposure to particulate matter (e.g., PM2.5) may result in DNA damage, a major culprit in mutagenesis and environmental toxicity. DNA damage levels may vary among individuals simultaneously exposed to PM2.5, however, the genetic determinants are still unclear. To explore whether PM2.5 exposure and genetic variants contribute to the alteration in DNA damage, we recruited 328 subjects from three independent cohorts (119 from Zhuhai, 123 from Wuhan and 86 from Tianjin) in southern, central and northern China with different PM2.5 exposure levels. Personal 24-h PM2.5 exposure levels and DNA damage levels of peripheral blood lymphocytes were evaluated. Genotyping were performed using Illumina Human Exome BeadChip with 241,305 single nucleotide variants (SNVs). The DNA damage levels are consistent with the PM2.5 exposure levels of each cohort. A total of 35 SNVs were consistently associated with DNA damage levels among the three cohorts with pooled P values less than 1.00 × 10 −3 after adjustment for age, gender, smoking status and PM2.5 exposure levels, of which, 18 SNVs together with gender and PM2.5 exposure levels were independent factors contributing to DNA damage. Gene-based test revealed 3 genes significantly associated with DNA damage levels ( P = 5.11 × 10 −3 for POLH , P = 2.88 × 10 −3 for RIT2 and P = 2.29 × 10 −2 for CNTN4 ). Gene ontology (GO) analyses indicated that the identified variants were significantly enriched in DNA damage response pathway. Our findings highlight the importance of genetic variation as well as personal PM2.5 exposure in modulating individual DNA damage levels. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) in populations of European ancestry have identified nine single nuclear polymorphisms (SNP) on chromosome 11 related to type 2 diabetes (T2D) susceptibility. Herein, we further evaluate the association of these SNPs and T2D in a Chinese Han population. We performed a case-control study of 2925 T2D cases and 3281 controls to evaluate the association of five SNPs of KCNJ11 , MTNR1B , CENTD2 and LOC387761 and T2D in addition to the previously reported four SNPs of KCNQ1 . Multiple logistic regression was used to evaluate SNP's effect by adjustment for confounding factor age, sex and BMI. In the first stage, SNPs rs1552224 at CENTD2 were significantly associated with T2D and the association was statistically significant in the whole study population (P = 0.001) although it was not replicated in the second stage. rs1552224 and rs2237897 of KCNQ1 showed significant joint effect on T2D and there was a significant decreased risk of T2D with the number increase of risk alleles (P for trend = 3.81 × 10 −17 ). Compared to those without carrying any risk allele, individuals carrying one, two, and three or four risk alleles had a 30.7%, 44.8% and 62.0% decreased risk for developing T2D, respectively. Our finding suggests that genetic variant rs1552224 of CENTD2 on chromosome 11 contributes to an independent effect as well as joint cumulative effect with rs2237897 of KCNQ1 on the risk of T2D in Chinese Han population, and further functional research would be warranted. [ABSTRACT FROM AUTHOR]

Background Left ventricular noncompaction (LVNC) is a genetic cardiomyopathy results from the failure of myocardial development during embryogenesis. Previous reports show that defects in TAZ , SCN5A , TPM1 , YWHAE , MYH7 , ACTC1 and TNNT2 are associated with LVNC. Sequencing of individuals using family-based design is a powerful approach for hereditary disease. In this study, we used whole-exome sequencing to screen potentially novel causal mutations in a Chinese Han family with LVNC. Methods DNA from 3 individuals belonging to the same family was extracted and sequenced based on standard whole-exome sequencing protocol. The exome sequence data was analyzed using BWA, PICARD and Genome Analysis Toolkit (GATK v2.8). Non-silent single nucleotide variants (SNVs) were further selected if they exist in both LVNC patients and not in the health control. A web-based software Snv Prioritization via the INtegration of Genomic data (SPRING), was used to prioritize the causal SNV by calculating a q-value which indicates the statistical significance that a variant is causative for a query disease. Results From the LVNC family in which the mother and son were affected, a novel single nucleotide variant c.C1492G in exon 15 of MYH7 was identified probably to be the causal SNV of the family with P -value of 3.45E− 05 and q-value of 4.65E− 03 by SPRING. The SNV was predicted as deleterious in SIFT, PolyPhe2 and MutatioTaster database. Another 12 SNVs were also identified with P -value less than 0.05 by SPRING. Conclusions A novel genetic variant in the coding regions of MYH7 gene was identified in a Chinese LVNC-family. The results support the previous evidence that MYH7 is a pathogenic gene for LVNC. [ABSTRACT FROM AUTHOR]

Objective The aim of this investigation was to identify pathways involved in pneumoconiosis susceptibility, clarify their potential mechanisms, and generate SNP-to-gene to pathway hypotheses using an analytical pathway-based approach. Methods The identify candidate causal SNPs and pathways (ICSNPathway) was used to perform pathway analysis of a GWAS dataset for pneumoconiosis, which, after quality control filtering, harbored genotypes of 710,999 SNPs in 202 pneumoconiosis cases and 198 exposed controls. The first stage involved the pre-selection of candidate SNPs by linkage disequilibrium analysis and functional annotation of the most significant SNPs; the second stage involved annotation of biological mechanisms for the selected candidate SNPs using improved-gene set enrichment analysis. Results ICSNPathway analysis identified 18 candidate SNPs, involving 13 genes and 30 candidate pathways and revealed 13 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was that rs8120 and rs2292151 alters the role of TICAM1 , a gene involved in various pathways and processes, including positive regulation of tumor necrosis factor (TNF) production, innate immune response-activating signal transduction, positive regulation of the innate immune response, and the biosynthesis of type I interferon (0.001 < p < 0.008; 0.001< false discovery rate (FDR) <0.035). The second strongest mechanism was that rs2230656 modulates HIST3H3 to affect its role in chromatin assembly processes ( p < 0.001; FDR <0.001). The third mechanism was that rs11592462 modulates CDH23 , which regulates organization of the inner ear stereocilia, auditory receptor cell morphogenesis, ear morphogenesis, and cellular homeostasis (0.001 < p < 0.006; 0.001 < FDR < 0.044). Of 13 candidate genes, TICAM1 , HIST3H3 , CA1 , CA3 , PTPRZ1 , and IL27RA are associated with fibrosis. Some of the 30 candidate pathways, which include positive regulation of TNF production, innate immune response-activating signal transduction, and regulation of innate immune response, may be associated with susceptibility to pneumoconiosis. Other candidate genes and pathways were novel or lacking fibrosis-related research. Conclusion By applying ICSNPathway analysis to the pneumoconiosis GWAS data, we identified candidate SNPs, genes such as TICAM1 and HIST3H3, and pathways involved in the positive regulation of TNF production that may contribute to pneumoconiosis susceptibility. Further analyses are needed to validate the results. [ABSTRACT FROM AUTHOR]

Highlights: [•] This is the first transcriptomic study in China evaluating the use of microarray technology to elucidate the cellular response to PM2.5. [•] We observed that different concentrations of PM2.5 had a distinct effect on the gene expression in HBE cells. [•] We identified many genes and pathways that altered significantly in HBE cells after PM2.5 exposures. [ABSTRACT FROM AUTHOR]

Abstract: Autophagy is a cellular process directed at recycling of cellular proteins and removal of intracellular microorganisms, which is important for balancing sources of energy at critical times in development and in response to nutrient stress. It has been reported to be a critical process in cancer initiation and progression. We hypothesized that genetic variants in critical genes of autophagy may be involve in the development of breast cancer. Thus, we systematically screened 14 potentially functional polymorphisms in six autophagy-related genes (ATG3, ATG5, ATG7, ATG10, and ATG12 and LC3) that are core components in autophagosome formation. We conducted a case-control study including 1064 breast cancer cases and 1073 cancer-free controls to evaluate the associations of these variants with breast cancer risk. We found that rs1864182 and rs10514231 in ATG10 were significantly associated with a decreased risk of breast cancer [odds ratios (OR)=0.77, 95% confidence interval (CI): 0.61–0.96, P =0.023; and OR=0.75, 95% CI: 0.59–0.93, P =0.010, respectively]. Similar protective effects for both loci were observed between subgroups stratified by ages at diagnosis/recruitment, menarche and first live birth, and status of menopause, estrogen receptor (ER) and progesterone receptor (PR). These results suggest that genetic variants in ATG10 may implicate with breast cancer susceptibility in Chinese population. Further large and functional studies are needed to confirm our findings. [Copyright &y& Elsevier]

Summary: Background: A recent genome-wide association study (GWAS) focused on esophageal squamous cell carcinoma (ESCC) has identified several susceptible regions (5q11, 21q22, 6p21 10q23, and 12q24) in Chinese population. We hypothesized that single nucleotide polymorphisms (SNPs) identified in these regions for ESCC were also associated with the risk of head and neck cancer (HNC) which share similar risk factors with ESCC. Methods: To test this hypothesis, we genotyped three SNPs (rs2274223, rs2014300 and rs10484761) in a case–control study with 503 HNC cases and 900 cancer-free controls in a Chinese population. Results: We found that rs2274223 was associated with a significantly increased risk of HNC in our population [GG vs. AA: adjusted odds ratio (OR)=1.86, 95% confidence interval (CI)=1.09–3.16; GG vs. (AG/AA): adjusted OR=1.85, 95% CI=1.09–3.12], and the effect appeared to be more prominent among drinkers (P =0.024) and patients with oral cavity cancer (P =0.019). In contrast, rs2014300 and rs10484761 variant were not observed any significantly association with risk of HNC. Conclusions: These results indicate that rs2274223 may be a marker SNP for HNC susceptibility in Chinese population. [ABSTRACT FROM AUTHOR]