Prenatal Parental Exposure to Metals and Birth Defects: A Prospective Birth Cohort Study.

While maternal exposure to high metal levels during pregnancy is an established risk factor for birth defects, the role of paternal exposure remains largely unknown. We aimed to assess the associations of prenatal paternal and maternal metal exposure and parental coexposure with birth defects in singletons. This study conducted within the Jiangsu Birth Cohort recruited couples in early pregnancy. We measured their urinary concentrations for 25 metals. A total of 1675 parent-offspring trios were included. The prevalence of any birth defects among infants by one year of age was 7.82%. Paternal-specific gravity-corrected urinary concentrations of titanium, vanadium, chromium, manganese, cobalt, nickel, copper, and selenium and maternal vanadium, chromium, nickel, copper, selenium, and antimony were associated with a 21-91% increased risk of birth defects after adjusting for covariates. These effects persisted after mutual adjustment for the spouse's exposure. Notably, when assessing the parental mixture effect by Bayesian kernel machine regression, paternal and maternal chromium exposure ranked the highest in relative importance. Parental coexposure to metal mixture showed a pronounced joint effect on the risk of overall birth defects, as well as for some specific subtypes. Our findings suggested a couple-based prevention strategy for metal exposure to reduce birth defects in offspring.

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

Background: Lung adenocarcinoma (LUAD) among never-smokers is a public health burden especially prevalent in East Asian (EAS) women. Polygenic risk scores (PRSs), which quanefy geneec suscepebility, are promising for straefying risk, yet have mainly been developed in European (EUR) populaeons. We developed and validated single-and mule-ancestry PRSs for LUAD in EAS never-smokers, using the largest available genome-wide associaeon study (GWAS) dataset. Methods: We used GWAS summary staesecs from both EAS (8,002 cases; 20,782 controls) and EUR (2,058 cases; 5,575 controls) populaeons, as well as independent EAS individual level data. We evaluated several PRSs approaches: a single-ancestry PRS using 25 variants that reached genome-wide significance (PRS-25), a genome-wide Bayesian based approach (LDpred2), and a mule-ancestry approach that models geneec correlaeons across ancestries (CT-SLEB). PRS performance was evaluated based on the associaeon with LUAD and AUC values. We then esemated the lifeeme absolute risk of LUAD (age 30-80) and projected the AUC at different sample sizes using EAS-derived effect-size distribueon and heritability esemates. Findings: The CT-SLEB PRS showed a strong associaeon with LUAD risk (odds raeo=1.71, 95% confidence interval (CI): 1.61, 1.82) with an AUC of 0.640 (95% CI: 0.629, 0.653). Individuals in the 95 th percenele of the PRS had an esemated 6.69% lifeeme absolute risk of LUAD. Comparison of LUAD risk between individuals in the highest and lowest 20% PRS quaneles revealed a 3.92-fold increase. Projeceon analyses indicated that achieving an AUC of 0.70, which approaches the maximized prediceon poteneal of the PRS given the esemated geneec variance, would require a future study encompassing 55,000 EAS LUAD cases with a 1:10 case-control raeo. Interpretations: Our study underscores the poteneal of mule-ancestry PRS approaches to enhance LUAD risk straeficaeon in never-smokers, parecularly in EAS populaeons, and highlights the necessary scale of future research to uncover the geneec underpinnings of LUAD.

Spicy food consumption and risk of vascular disease: Evidence from a large-scale Chinese prospective cohort of 0.5 million people.

BACKGROUND: Spicy food consumption has been reported to be inversely associated with mortality from multiple diseases. However, the effect of spicy food intake on the incidence of vascular diseases in the Chinese population remains unclear. This study was conducted to explore this association. METHODS: This study was performed using the large-scale China Kadoorie Biobank (CKB) prospective cohort of 486,335 participants. The primary outcomes were vascular disease, ischemic heart disease (IHD), major coronary events (MCEs), cerebrovascular disease, stroke, and non-stroke cerebrovascular disease. A Cox proportional hazards regression model was used to assess the association between spicy food consumption and incident vascular diseases. Subgroup analysis was also performed to evaluate the heterogeneity of the association between spicy food consumption and the risk of vascular disease stratified by several basic characteristics. In addition, the joint effects of spicy food consumption and the healthy lifestyle score on the risk of vascular disease were also evaluated, and sensitivity analyses were performed to assess the reliability of the association results. RESULTS: During a median follow-up time of 12.1 years, a total of 136,125 patients with vascular disease, 46,689 patients with IHD, 10,097 patients with MCEs, 80,114 patients with cerebrovascular disease, 56,726 patients with stroke, and 40,098 patients with non-stroke cerebrovascular disease were identified. Participants who consumed spicy food 1-2 days/week (hazard ratio [HR] = 0.95, 95% confidence interval [95% CI] = [0.93, 0.97], P <0.001), 3-5 days/week (HR = 0.96, 95% CI = [0.94, 0.99], P = 0.003), and 6-7 days/week (HR = 0.97, 95% CI = [0.95, 0.99], P = 0.002) had a significantly lower risk of vascular disease than those who consumed spicy food less than once a week (Ptrend <0.001), especially in those who were younger and living in rural areas. Notably, the disease-based subgroup analysis indicated that the inverse associations remained in IHD (Ptrend = 0.011) and MCEs (Ptrend = 0.002) risk. Intriguingly, there was an interaction effect between spicy food consumption and the healthy lifestyle score on the risk of IHD (Pinteraction = 0.037). CONCLUSIONS: Our findings support an inverse association between spicy food consumption and vascular disease in the Chinese population, which may provide additional dietary guidance for the prevention of vascular diseases.

Development and evaluation of a risk prediction tool for risk-adapted screening of colorectal cancer in China.

Risk prediction tools for colorectal cancer (CRC) have potential to improve the efficiency of population-based screening by facilitating risk-adapted strategies. However, such an applicable tool has yet to be established in the Chinese population. In this study, a risk score was created using data from the China Kadoorie Biobank (CKB), a nationwide cohort study of 409,854 eligible participants. Diagnostic performance of the risk score was evaluated in an independent CRC screening programme, which included 91,575 participants who accepted colonoscopy at designed hospitals in Zhejiang Province, China. Over a median follow-up of 11.1 years, 3136 CRC cases were documented in the CKB. A risk score was created based on nine questionnaire-derived variables, showing moderate discrimination for 10-year CRC risk (C-statistic = 0.68, 95 % CI: 0.67-0.69). In the CRC screening programme, the detection rates of CRC were 0.25 %, 0.82 %, and 1.93 % in low-risk (score <6), intermediate-risk (score: 6-19), and high-risk (score >19) groups, respectively. The newly developed score exhibited a C-statistic of 0.65 (95 % CI: 0.63-0.66), surpassing the widely adopted tools such as the Asia-Pacific Colorectal Screening (APCS), modified APCS, and Korean Colorectal Screening scores (all C-statistics = 0.60). In conclusion, we developed a novel risk prediction tool that is useful to identify individuals at high risk of CRC. A user-friendly online calculator was also constructed to encourage broader adoption of the tool.

Association of prenatal multiple metal exposures with child neurodevelopment at 3 years of age: A prospective birth cohort study.

Prenatal exposures to toxic metals and trace elements have been linked to childhood neurodevelopment. However, existing evidence remains inconclusive, and further research is needed to investigate the mixture effects of multiple metal exposures on childhood neurodevelopment. We aimed to examine the associations between prenatal exposure to specific metals and metal mixtures and neurodevelopment in children. In this prospective cohort study, we used the multivariable linear regressions and the robust modified Poisson regressions to explore the associations of prenatal exposure to 25 specific metals with neurodevelopment among children at 3 years of age in 854 mother-child pairs from the Jiangsu Birth Cohort (JBC) Study. The Bayesian kernel machine regression (BKMR) was employed to assess the joint effects of multiple metals on neurodevelopment. Prenatal manganese (Mn) exposure was negatively associated with the risk of non-optimal cognition development of children, while vanadium (V), copper (Cu), zinc (Zn), antimony (Sb), cerium (Ce) and uranium (U) exposures were positively associated with the risk of non-optimal gross motor development. BKMR identified an interaction effect between Sb and Ce on non-optimal gross motor development. Additionally, an element risk score (ERS), representing the mixture effect of multiple metal exposures including V, Cu, Zn, Sb, Ce and U was constructed based on weights from a Poisson regression model. Children with ERS in the highest tertile had higher probability of non-optimal gross motor development (RR = 2.37, 95 % CI: 1.15, 4.86) versus those at the lowest tertile. Notably, Sb [conditional-posterior inclusion probabilities (cPIP) = 0.511] and U (cPIP = 0.386) mainly contributed to the increased risk of non-optimal gross motor development. The findings highlight the importance of paying attention to the joint effects of multiple metals on children's neurodevelopment. The ERS score may serve as an indicator of comprehensive metal exposure risk for children's neurodevelopment.

Associations of combined phenotypic aging and genetic risk with incident cancer: A prospective cohort study.

Background: Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer. Methods: Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs). Results: Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18-1.27) in men, and 1.26 (1.22-1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10-2.51) for men and 1.94 (1.78-2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = -1.01 in men, p<0.001; Beta = -0.98 in women, p<0.001). Conclusions: Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle. Funding: This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).

Age is a major risk factor for cancer. Other factors, such as lifestyle or environmental exposures, may increase or mitigate cancer risks. Biological age, which considers accelerated aging processes, may, however, better predict cancer risk than chronological age. Some scientists propose using biological aging measures as an alternative for assessing cancer and other age-related disease risks, as these markers may provide a more accurate assessment of the various factors contributing to cancer risk. PhenoAge, a measure of biological aging processes in the body, could provide an alternative way to assessing aging-related cancer risks. This tool utilizes an individual's chronological age and nine biomarkers of aging processes. It has the potential to identify individuals whose aging process is accelerated compared to their peers, potentially indicating an increased cancer risk. This information may empower them to make lifestyle changes that could significantly reduce their risk. To assess the suitability of PhenoAge, Bian, Ma et al. used nine clinical chemistry biomarkers and chronological age to calculate PhenoAge in 374,463 participants from the UK Biobank. Their findings revealed that people with older PhenoAges ­ regardless of their genetic risk profiles ­ have an increased risk of cancer. Individuals with higher PhenoAge scores, indicating accelerated biological aging, had a roughly 25 percent higher risk of developing cancer. Individuals with both a high genetic risk and higher PhenoAge score had roughly double the risk of cancer. People with lower PhenoAges were more likely to have healthier lifestyles. These results suggest that adopting healthier lifestyles may slow the aging process and reduce cancer risk. While the analyses conducted by Bian, Ma et al. provide promising insights, they also underscore the need for further research. PhenoAge may offer a way to assess biological aging and identify individuals at higher risk of cancer. Those with higher PhenoAge scores may benefit from earlier cancer screening, and adopting a healthier lifestyle could potentially slow down the aging process and reduce their cancer risk. However, more studies in more diverse cohorts of people are needed to confirm that PhenoAge is a reliable marker for cancer risk and to test interventions to slow aging and reduce cancer risks in individuals with accelerated aging.

Inter- and trans-generational impacts of real-world PM2.5 exposure on male-specific primary hypogonadism.

Exposure to PM2.5, a harmful type of air pollution, has been associated with compromised male reproductive health; however, it remains unclear whether such exposure can elicit transgenerational effects on male fertility. Here, we aim to examine the effect of paternal exposure to real-world PM2.5 on the reproductive health of male offspring. We have observed that paternal exposure to real-world PM2.5 can lead to transgenerational primary hypogonadism in a sex-selective manner, and we have also confirmed this phenotype by using an external model. Mechanically, we have identified small RNAs (sRNAs) that play a critical role in mediating these transgenerational effects. Specifically, miR6240 and piR016061, which are present in F0 PM sperm, regulate intergenerational transmission by targeting Lhcgr and Nsd1, respectively. We have also uncovered that piR033435 and piR006695 indirectly regulate F1 PM sperm methylation by binding to the 3'-untranslated region of Tet1 mRNA. The reduced expression of Tet1 resulted in hypermethylation of several testosterone synthesis genes, including Lhcgr and Gnas, impaired Leydig cell function and ultimately led to transgenerational primary hypogonadism. Our findings provide insights into the mechanisms underlying the transgenerational effects of paternal PM2.5 exposure on reproductive health, highlighting the crucial role played by sRNAs in mediating these effects. The findings underscore the significance of paternal pre-conception interventions in alleviating the adverse effects of environmental pollutants on reproductive health.

Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment.

The development of an effective survival prediction tool is key for reducing colorectal cancer mortality. Here, we apply a three-stage study to devise a polygenic prognostic score (PPS) for stratifying colorectal cancer overall survival. Leveraging two cohorts of 3703 patients, we first perform a genome-wide survival association analysis to develop eight candidate PPSs. Further using an independent cohort with 470 patients, we identify the 287 variants-derived PPS (i.e., PPS287) achieving an optimal prediction performance [hazard ratio (HR) per SD = 1.99, P = 1.76 × 10-8], accompanied by additional tests in two external cohorts, with HRs per SD of 1.90 (P = 3.21 × 10-14; 543 patients) and 1.80 (P = 1.11 × 10-9; 713 patients). Notably, the detrimental impact of pathologic characteristics and genetic risk could be attenuated by a healthy lifestyle, yielding a 7.62% improvement in the 5-year overall survival rate. Therefore, our findings demonstrate the integrated contribution of pathologic characteristics, germline variants, and lifestyle exposure to the prognosis of colorectal cancer patients.

Relative effectiveness of a heterologous booster dose with adenovirus type 5 vectored COVID-19 vaccine versus three doses of inactivated COVID-19 vaccine in adults during a nationwide outbreak of omicron predominance, in China: a retrospective, individually matched cohort-control study.

Effectiveness of heterologous booster regimes with ad5 vectored COVID-19 vaccine in a large, diverse population during the national-scale outbreak of SARS-CoV-2 omicron predominance in China has not been reported, yet. We conducted a large-scale cohort-control study in six provinces in China, and did a retrospective survey on the COVID-19 attack risk during this outbreak. Participant aged ≥18 years in five previous trials who were primed with 1 to 3 doses of ICV received heterologous booster with either intramuscular or orally inhaled ad5 vectored COVID-19 vaccine were included in the heterologous-trial cohort. We performed propensity score-matching at a ratio of 1:4 to match participants in the heterologous-trial cohort individually with the community individuals who received three-dose of ICV as a control (ICV-community cohort). From February 4 to April 10, 2023, 41504 (74.5%) of 55710 individuals completed the survey. The median time since the most recent vaccination to the onset of the symptoms of COVID-19 was 303.0 days (IQR 293.0-322.0). The attack rate of COVID-19 in the heterologous-trial cohort was 55.8%, while that in the ICV-community cohort was 64.6%, resulting in a relative effectiveness of 13.7% (95% CI 11.9 to 15.3). In addition, a higher relative effectiveness against COVID-19 associated outpatient visits, and admission to hospital was demonstrated, which was 25.1% (95% CI 18.9 to 30.9), and 48.9% (95% CI 27.0 to 64.2), respectively. The heterologous booster with ad5 vectored COVID-19 vaccine still offered some additional protection in preventing COVID-19 breakthrough infection versus homologous three-dose regimen with ICV, 10 months after vaccination.

Combining fecal immunochemical testing and questionnaire-based risk assessment in selecting participants for colonoscopy screening in the Chinese National Colorectal Cancer Screening Programs: A population-based cohort study.

BACKGROUND: Screening reduces colorectal cancer (CRC) burden by allowing early resection of precancerous and cancerous lesions. An adequate selection of high-risk individuals and a high uptake rate for colonoscopy screening are critical to identifying people more likely to benefit from screening and allocating healthcare resources properly. We evaluated whether combining a questionnaire-based interview for risk factors with fecal immunochemical test (FIT) outcomes for high-risk assessment is more efficient and economical than a questionnaire-based interview-only strategy. METHODS AND FINDINGS: In this multicenter, population-based, prospective cohort study, we enrolled community residents aged 40 to 74 years in 29 provinces across China. From 2016 to 2020, a total of 1,526,824 eligible participants were consecutively enrolled in the Cancer Screening Program in Urban China (CanSPUC) cohort, and 940,605 were enrolled in the Whole Life Cycle of Cancer Screening Program (WHOLE) cohort, with follow-up to December 31, 2022. The mean ages were 56.89 and 58.61 years in CanSPUC and WHOLE, respectively. In the WHOLE cohort, high-risk individuals were identified by combining questionnaire-based interviews to collect data on risk factors (demographics, diet history, family history of CRC, etc.) with FIT outcomes (RF-FIT strategy), whereas in the CanSPUC cohort, high-risk individuals were identified using only interview-based data on risk factors (RF strategy). The primary outcomes were participation rate and yield (detection rate of advanced neoplasm, early-stage detection rate of CRCs [stage I/II], screening yield per 10,000 invitees), which were reported for the entire population and for different gender and age groups. The secondary outcome was the cost per case detected. In total, 71,967 (7.65%) and 281,985 (18.47%) individuals were identified as high-risk and were invited to undergo colonoscopy in the RF-FIT group and RF group, respectively. The colonoscopy participation rate in the RF-FIT group was 26.50% (19,071 of 71,967) and in the RF group was 19.54% (55,106 of 281,985; chi-squared test, p < 0.001). A total of 102 (0.53%) CRCs and 2,074 (10.88%) advanced adenomas were detected by the RF-FIT, versus 90 (0.16%) and 3,593 (6.52%) by the RF strategy (chi-squared test, both p < 0.001). The early-stage detection rate using the RF-FIT strategy was significantly higher than that by the RF strategy (67.05% versus 47.95%, Fisher's exact test, p = 0.016). The cost per CRC detected was $24,849 by the RF-FIT strategy versus $55,846 by the RF strategy. A limitation of the study was lack of balance between groups with regard to family history of CRC (3.5% versus 0.7%). CONCLUSIONS: Colonoscopy participation and screening yield were better with the RF-FIT strategy. The association with CRC incidence and mortality reduction should be evaluated after long-term follow-up.

Comprehensive functional interrogation of susceptibility loci in GWASs identified KIAA0391 as a novel oncogenic driver via regulating pyroptosis in NSCLC.

Approximately 51 non-small-cell lung cancer (NSCLC) risk loci have been identified by genome-wide association studies (GWASs). We conducted a high throughput RNA-interference (RNAi) screening to identify the candidate causal genes in NSCLC risk loci. KIAA0391 at 14q13.1 had the highest score and could promote proliferation and metastasis of NSCLC in vitro and in vivo. We next prioritized rs3783313 as a causal variant at 14q13.1, by integrating a large-scale population study consisting of 27,120 lung cancer cases and 27,355 controls, functional annotation, and expression quantitative trait locus (eQTL) analysis. Then we found that rs3783313 could facilitate a promoter-enhancer interaction to upregulate KIAA0391 expression by affecting the affinity of transcription factor NFYA. Mechanistically, KIAA0391 knockdown dramatically influenced pyroptosis-related pathways and increased the expression of CASP1. And KIAA0391 transcriptionally repressed CASP1 by binding to SMAD2 and induced an anti-pyroptosis phenotype, promoting tumorigenesis of NSCLC, which provides new insights and potential target for NSCLC.

Association of Breastfeeding and Neonatal Jaundice With Infant Neurodevelopment.

INTRODUCTION: 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. METHODS: 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. RESULTS: Compared with "exclusive breastfeeding," fine motor scores of infants were lower for "mixed feeding" (ßadj, -0.16; 95% CI, -0.29 to -0.03; p=0.016) and "no breastfeeding" (ßadj, -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 (ßadj, -0.44; 95% CI, -0.66 to -0.23; p<0.001) and fine motor (ßadj, -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 (ßadj, -0.28; 95% CI, -0.57 to 0.01), while this association was not observed in those without neonatal jaundice (ßadj, 0.09; 95% CI, -0.26 to 0.43). CONCLUSIONS: Exclusive breastfeeding for the first 6 months is beneficial to the neurodevelopment of infants, especially in those with severe neonatal jaundice.

Identification of genetically predicted DNA methylation markers associated with non-small cell lung cancer risk among 34,964 cases and 448,579 controls.

BACKGROUND: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non-small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated. METHODS: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways. RESULTS: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10-6 ) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10-3 ), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified. CONCLUSIONS: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby. PLAIN LANGUAGE SUMMARY: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non-small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.

Development and evaluation of a polygenic risk score for lung cancer in never-smoking women: A large-scale prospective Chinese cohort study.

The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never-smoking women. We first performed a large GWAS meta-analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never-smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta-analysis identified eight known loci and a novel locus (5q11.2) at the genome-wide statistical significance level of P < 5 × 10-8 . Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS-21) for lung cancer in never-smoking women. Furthermore, PRS-21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18-1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00-1.72) and high (HR = 2.09, 95% CI: 1.56-2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS-21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS-derived PRS-21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never-smoking Asian women, demonstrating the potential for identification of high-risk individuals and early screening.

CYP2A6 Activity and Cigarette Consumption Interact in Smoking-Related Lung Cancer Susceptibility.

Cigarette smoke, containing both nicotine and carcinogens, causes lung cancer. However, not all smokers develop lung cancer, highlighting the importance of the interaction between host susceptibility and environmental exposure in tumorigenesis. Here, we aimed to delineate the interaction between metabolizing ability of tobacco carcinogens and smoking intensity in mediating genetic susceptibility to smoking-related lung tumorigenesis. Single-variant and gene-based associations of 43 tobacco carcinogen-metabolizing genes with lung cancer were analyzed using summary statistics and individual-level genetic data, followed by causal inference of Mendelian randomization, mediation analysis, and structural equation modeling. Cigarette smoke-exposed cell models were used to detect gene expression patterns in relation to specific alleles. Data from the International Lung Cancer Consortium (29,266 cases and 56,450 controls) and UK Biobank (2,155 cases and 376,329 controls) indicated that the genetic variant rs56113850 C>T located in intron 4 of CYP2A6 was significantly associated with decreased lung cancer risk among smokers (OR = 0.88, 95% confidence interval = 0.85-0.91, P = 2.18 × 10-16), which might interact (Pinteraction = 0.028) with and partially be mediated (ORindirect = 0.987) by smoking status. Smoking intensity accounted for 82.3% of the effect of CYP2A6 activity on lung cancer risk but entirely mediated the genetic effect of rs56113850. Mechanistically, the rs56113850 T allele rescued the downregulation of CYP2A6 caused by cigarette smoke exposure, potentially through preferential recruitment of transcription factor helicase-like transcription factor. Together, this study provides additional insights into the interplay between host susceptibility and carcinogen exposure in smoking-related lung tumorigenesis. SIGNIFICANCE: The causal pathway connecting CYP2A6 genetic variability and activity, cigarette consumption, and lung cancer susceptibility in smokers highlights the need for behavior modification interventions based on host susceptibility for cancer prevention.