An atlas of genetic effects on cellular composition of the tumor microenvironment.

Deciphering the composition of the tumor microenvironment (TME) is critical for understanding tumorigenesis and to design immunotherapies. In the present study, we mapped genetic effects on cell-type proportions using single-cell and bulk RNA sequencing data, identifying 3,494 immunity quantitative trait loci (immunQTLs) across 23 cancer types from The Cancer Genome Atlas. Functional annotation revealed regulatory potential and we further assigned 1,668 genes that regulate TME composition. We constructed a combined immunQTL map by integrating data from European and Chinese colorectal cancer (CRC) samples. A polygenic risk score that incorporates these immunQTLs and hits on a genome-wide association study outperformed in CRC risk stratification within 447,495 multiethnic individuals. Using large-scale population cohorts, we identified that the immunQTL rs1360948 is associated with CRC risk and prognosis. Mechanistically, the rs1360948-G-allele increases CCL2 expression, recruiting regulatory T cells that can exert immunosuppressive effects on CRC progression. Blocking the CCL2-CCR2 axis enhanced anti-programmed cell death protein 1 ligand therapy. Finally, we have established a database (CancerlmmunityQTL2) to serve the research community and advance our understanding of immunogenomic interactions in cancer pathogenesis.

Genetic Control of Alternative Splicing and its Distinct Role in Colorectal Cancer Mechanisms.

BACKGROUND & AIMS: Dysregulation of alternative splicing is implicated in many human diseases, and understanding the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of cancers. We aimed to provide a comprehensive functional dissection of splicing quantitative trait loci (sQTLs) in cancer and focus on elucidating its distinct role in colorectal cancer (CRC) mechanisms. METHODS: We performed a comprehensive sQTL analysis to identify genetic variants that control messenger RNA splicing across 33 cancer types from The Cancer Genome Atlas and independently validated in our 154 CRC tissues. Then, large-scale, multicenter, multi-ethnic case-control studies (34,585 cases and 76,023 controls) were conducted to examine the association of these sQTLs with CRC risk. A series of biological experiments in vitro and in vivo were performed to investigate the potential mechanisms of the candidate sQTLs and target genes. RESULTS: The molecular characterization of sQTL revealed its distinct role in cancer susceptibility. Tumor-specific sQTL further showed better response to cancer development. In addition, functionally informed polygenic risk score highlighted the potentiality of sQTLs in the CRC prediction. Complemented by large-scale population studies, we identified that the risk allele (T) of a multi-ancestry-associated sQTL rs61746794 significantly increased the risk of CRC in Chinese (odds ratio, 1.20; 95% CI, 1.12-1.29; P = 8.82 × 10-7) and European (odds ratio, 1.11; 95% CI, 1.07-1.16; P = 1.13 × 10-7) populations. rs61746794-T facilitated PRMT7 exon 16 splicing mediated by the RNA-binding protein PRPF8, thus increasing the level of canonical PRMT7 isoform (PRMT7-V2). Overexpression of PRMT7-V2 significantly enhanced the growth of CRC cells and xenograft tumors compared with PRMT7-V1. Mechanistically, PRMT7-V2 functions as an epigenetic writer that catalyzes the arginine methylation of H4R3 and H3R2, subsequently regulating diverse biological processes, including YAP, AKT, and KRAS pathway. A selective PRMT7 inhibitor, SGC3027, exhibited antitumor effects on human CRC cells. CONCLUSIONS: Our study provides an informative sQTLs resource and insights into the regulatory mechanisms linking splicing variants to cancer risk and serving as biomarkers and therapeutic targets.

Genetic architectures of the human hippocampus and those involved in neuropsychiatric traits.

BACKGROUND: The hippocampus, with its complex subfields, is linked to numerous neuropsychiatric traits. While most research has focused on its global structure or a few specific subfields, a comprehensive analysis of hippocampal substructures and their genetic correlations across a wide range of neuropsychiatric traits remains underexplored. Given the hippocampus's high heritability, considering hippocampal and subfield volumes (HASV) as endophenotypes for neuropsychiatric conditions is essential. METHODS: We analyzed MRI-derived volumetric data of hippocampal and subfield structures from 41,525 UK Biobank participants. Genome-wide association studies (GWAS) on 24 HASV traits were conducted, followed by genetic correlation, overlap, and Mendelian randomization (MR) analyses with 10 common neuropsychiatric traits. Polygenic risk scores (PRS) based on HASV traits were also evaluated for predicting these traits. RESULTS: Our analysis identified 352 independent genetic variants surpassing a significance threshold of 2.1 × 10-9 within the 24 HASV traits, located across 93 chromosomal regions. Notably, the regions 12q14.3, 17q21.31, 12q24.22, 6q21, 9q33.1, 6q25.1, and 2q24.2 were found to influence multiple HASVs. Gene set analysis revealed enrichment of neural differentiation and signaling pathways, as well as protein binding and degradation. Of 240 HASV-neuropsychiatric trait pairs, 75 demonstrated significant genetic correlations (P < 0.05/240), revealing 433 pleiotropic loci. Particularly, genes like ACBD4, ARHGAP27, KANSL1, MAPT, ARL17A, and ARL17B were involved in over 50 HASV-neuropsychiatric pairs. Leveraging Mendelian randomization analysis, we further confirmed that atrophy in the left hippocampus, right hippocampus, right hippocampal body, and right CA1-3 region were associated with an increased risk of developing Parkinson's disease (PD). Furthermore, PRS for all four HASVs were significantly linked to a higher risk of Parkinson's disease (PD), with the highest hazard ratio (HR) of 1.30 (95% CI 1.18-1.43, P = 6.15 × 10⁻8) for right hippocampal volume. CONCLUSIONS: These findings highlight the extensive distribution of pleiotropic genetic determinants between HASVs and neuropsychiatric traits. Moreover, they suggest a significant potential for effectively managing and intervening in these diseases during their early stages.

Joint exposure to multiple air pollutants, genetic risk, and incident psoriasis: a large-scale prospective cohort study.

BACKGROUND: Air pollution and genetic risk have been found to contribute to both onset and development of psoriasis. However, the extent to which genetic susceptibility modifies the effects of air pollutants on the risk of incident psoriasis remains unknown. OBJECTIVES: Our study aimed to assess the association between joint exposure to multiple air pollutants and the risk of psoriasis and the modification by the genetic susceptibility. METHODS: This prospective study included 451,064 participants with complete air pollution data and free of psoriasis at baseline from the UK Biobank. All participants were enrolled from 2006 to 2010 and followed up to 2022. The air pollution score (APS) was calculated to assess the joint exposure to multiple air pollutants, including particulate matter (PM) with diameters ≤ 2.5 µm (PM2.5), between 2.5 and 10 µm (PM2.5-10), and ≤ 10 µm (PM10), as well as nitrogen dioxide (NO2) and nitrogen oxides (NOx). To evaluate the genetic risk, the polygenic risk score (PRS) for psoriasis was constructed. The Cox proportional hazard models were used to assess the association of air pollution and genetic susceptibility with the risk of psoriasis. Stratified analyses were conducted based on the individual characteristics. RESULTS: During a median follow-up of 13.79 years, 4414 psoriasis events were recorded. The hazard ratios (HRs) [95% confidence intervals (CIs)] for psoriasis were 1.036 (0.936-1.147), 1.091 (0.987-1.206), 1.159 (1.048-1.283), and 1.163 (1.052-1.286) in higher quintile groups compared with the lowest quintile of APS (P trend <0.05). When considering genetic susceptibility, participants with high PRS and high APS had the greatest risk of incident psoriasis [HR (95% CI): 1.962 (1.630-2.362)] than those with low PRS and low APS. The HRs (95% CIs) for PM2.5-10, NOx, PM2.5 absorbance, PM2.5, NO2, and PM10 in the group with high exposure level and genetic risk were 1.831 (1.537-2.181), 1.722 (1.431-2.073), 1.698 (1.416-2.037), 1.619 (1.353-1.938), 1.504 (1.252-1.806), and 1.425 (1.192-1.704), respectively. CONCLUSIONS: Long-term exposure to various air pollutants is positively associated with an increased risk of incident psoriasis, particularly in individuals with high genetic risk. More comprehensive measures are needed to reduce the air pollution levels for better prevention of psoriasis.

Integrated systematic functional screen and fine-mapping decipher the role and genetic regulation of RPS19 in colorectal cancer development.

Despite genome-wide association studies (GWAS) have identified more than 200 risk loci associated with colorectal cancer (CRC), the causal genes or risk variants within these loci and their biological functions remain not fully revealed. Recently, the genomic locus 19q13.2, with the lead SNP rs1800469 was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here we employed an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk locus 19q13.2. Notably, we found that RPS19 exhibited the most significant effect among the identified genes and acted as a critical oncogene facilitating CRC cell proliferation. Subsequently, combining integrative fine-mapping analysis and a large-scale population study consisting of 6027 cases and 6099 controls, we prioritized rs1025497 as a potential causal candidate for CRC risk, demonstrating that rs1025497[A] allele significantly reduced the risk of CRC (OR 0.70, 95% confidence interval = 0.56-0.83, P = 1.12 × 10-6), which was further validated in UK Biobank cohort comprising 5,313 cases and 21,252 controls. Mechanistically, we experimentally elucidated that variant rs1025497 might acted as an allele-specific silencer, inhibiting the expression level of oncogene RPS19 mediated by the transcription suppressive factor HBP1. Taken together, our sturdy unveils the significant role of RPS19 during CRC pathogenesis and delineates its distal regulatory mechanism mediated by rs1025497, advancing our understanding of the etiology of CRC and provided new insights into the personalized medicine of human cancer.

In Utero and Childhood/Adolescence Exposure to Tobacco Smoke, Genetic Risk, and Lung Cancer Incidence and Mortality in Adulthood.

Rationale: The individual effects of early-life tobacco smoke exposure and its interactions with genetic factors on lung cancer in adulthood remain unclear. Objectives: To investigate the associations of early-life tobacco exposures as well as their interactions with polygenic risk scores (PRSs) with lung cancer incidence and mortality. Methods: A total of 432,831 participants from the UK Biobank study were included. We estimated the associations of in utero exposure to tobacco smoke, the age of smoking initiation and their interactions with PRSs with lung cancer incidence and mortality in adulthood using Cox proportional hazard models. Measurements and Main Results: Lung cancer incidence (hazard ratio [HR]: 1.59, 95% confidence interval [CI], 1.44-1.76) increased among participants with in utero tobacco exposure. Multivariable-adjusted HRs (with 95% CIs) of lung cancer incidence for smoking initiation in adulthood, adolescence, and childhood (versus never-smokers) were 6.10 (5.25-7.09), 9.56 (8.31-11.00), and 15.15 (12.90-17.79) (Ptrend < 0.001). Similar findings were observed in lung cancer mortality. Participants with high PRSs and in utero tobacco exposure (versus low PRSs participants without in utero exposure) had an HR of 2.35 for lung cancer incidence (95% CI, 1.97-2.80, Pinteraction = 0.089) and 2.43 for mortality (95% CI, 2.05-2.88, Pinteraction = 0.032). High PRSs with smoking initiation in childhood (versus never-smokers with low PRSs) had HRs of 18.71 for incidence (95% CI, 14.21-24.63, Pinteraction = 0.004) and 19.74 for mortality (95% CI, 14.98-26.01, Pinteraction = 0.033). Conclusions: In utero and childhood/adolescence exposure to tobacco smoke and its interaction with genetic factors may substantially increase the risks of lung cancer incidence and mortality in adulthood.

Saturated fatty acid intake, genetic risk and colorectal cancer incidence: A large-scale prospective cohort study.

Previous investigations mainly focused on the associations of dietary fatty acids with colorectal cancer (CRC) risk, which ignored gene-environment interaction and mechanisms interpretation. We conducted a case-control study (751 cases and 3058 controls) and a prospective cohort study (125 021 participants) to explore the associations between dietary fatty acids, genetic risks, and CRC. Results showed that high intake of saturated fatty acid (SFA) was associated with a higher risk of CRC than low SFA intake (HR =1.22, 95% CI:1.02-1.46). Participants at high genetic risk had a greater risk of CRC with the HR of 2.48 (2.11-2.91) than those at low genetic risk. A multiplicative interaction of genetic risk and SFA intake with incident CRC risk was found (PInteraction = 7.59 × 10-20 ), demonstrating that participants with high genetic risk and high SFA intake had a 3.75-fold greater risk of CRC than those with low genetic risk and low SFA intake. Furthermore, incorporating PRS and SFA into traditional clinical risk factors improved the discriminatory accuracy for CRC risk stratification (AUC from 0.706 to 0.731). Multi-omics data showed that exposure to SFA-rich high-fat dietary (HFD) can responsively induce epigenome reprogramming of some oncogenes and pathological activation of fatty acid metabolism pathway, which may contribute to CRC development through changes in gut microbiomes, metabolites, and tumor-infiltrating immune cells. These findings suggest that individuals with high genetic risk of CRC may benefit from reducing SFA intake. The incorporation of SFA intake and PRS into traditional clinical risk factors will help improve high-risk sub-populations in individualized CRC prevention.

Comparison of Colonoscopy, Fecal Immunochemical Test, and Risk-Adapted Approach in a Colorectal Cancer Screening Trial (TARGET-C).

BACKGROUND & AIMS: The screening yield and related cost of a risk-adapted screening approach compared with established screening strategies in population-based colorectal cancer (CRC) screening are not clear. METHODS: We randomly allocated 19,373 participants into 1 of the 3 screening arms in a 1:2:2 ratio: (1) one-time colonoscopy (n = 3883); (2) annual fecal immunochemical test (FIT) (n = 7793); (3) annual risk-adapted screening (n = 7697), in which, based on the risk-stratification score, high-risk participants were referred for colonoscopy and low-risk ones were referred for FIT. Three consecutive screening rounds were conducted for both the FIT and the risk-adapted screening arms. Follow-up to trace the health outcome for all the participants was conducted over the 3-year study period. The detection rate of advanced colorectal neoplasia (CRC and advanced precancerous lesions) was the main outcome. The trial was registered in the Chinese Clinical Trial Registry (number: ChiCTR1800015506). RESULTS: In the colonoscopy, FIT, and risk-adapted screening arms over 3 screening rounds, the participation rates were 42.4%, 99.3%, and 89.2%, respectively; the detection rates for advanced neoplasm (intention-to-treat analysis) were 2.76%, 2.17%, and 2.35%, respectively, with an odds ratio (OR)colonoscopy vs FIT of 1.27 (95% confidence interval [CI]: 0.99-1.63; P = .056), an ORcolonoscopy vsrisk-adapted screening of 1.17 (95% CI, 0.91-1.49; P = .218), and an ORrisk-adapted screeningvs FIT of 1.09 (95% CI, 0.88-1.35; P = .438); the numbers of colonoscopies needed to detect 1 advanced neoplasm were 15.4, 7.8, and 10.2, respectively; the costs for detecting 1 advanced neoplasm from a government perspective using package payment format were 6928 Chinese Yuan (CNY) ($1004), 5821 CNY ($844), and 6694 CNY ($970), respectively. CONCLUSIONS: The risk-adapted approach is a feasible and cost-favorable strategy for population-based CRC screening and therefore could complement the well-established one-time colonoscopy and annual repeated FIT screening strategies. (Chinese Clinical Trial Registry; ChiCTR1800015506).

A variant in CYP26B1 associated with esophageal squamous cell carcinoma risk by affecting retinoic acid metabolism.

All-trans retinoic acid (ATRA) is the natural and synthetic analogue of vitamin A, playing an essential tumor suppressive role in multiple cancers including the esophageal squamous cell carcinoma (ESCC). Cytochrome P450 family 26 subfamily B member 1 (CYP26B1) exerts a critical regulator of ATRA levels through specific inactivation of ATRA to hydroxylated forms. Our previous exome-wide analyses revealed a rare missense variant in CYP26B1 significantly associated with ESCC risk in the Chinese population. However, it is still unclear whether there are common variants in CYP26B1 affect the susceptibility of ESCC and the tumor promotion role of CYP26B1 in vivo. In this research, we conducted a two-stage case-control study comprised of 5057 ESCC cases and 5397 controls, followed by a series of biochemical experiments to explore the function of CYP26B1 and its common variants in the tumorigenesis of ESCC. Intriguingly, we identified a missense variant rs2241057[A>G] in the fourth exon of CYP26B1 significantly associated with the ESCC risk (combined odds ratio = 1.28; 95% confidence interval = 1.15-1.42; p = 2.96 × 10-6 ). Through further functional analysis, we demonstrated that ESCC cells with the overexpression of rs2241057[G] had a significant lower level of retinoic acid, compared with the overexpression of rs2241057[A] or the control vector. In addition, the CYP26B1 overexpression and knock-out ESCC cells affected cell proliferation rate both in vitro and in vivo. These results highlighted the carcinogenicity of CYP26B1 related to the ATRA metabolism in ESCC risk.

Repurposed Tocilizumab in Patients with Severe COVID-19.

The coronavirus disease 2019 (COVID-19) has caused a global pandemic, resulting in considerable morbidity and mortality. Tocilizumab, an inhibitor of IL-6, has been widely repurposed as a treatment of severely ill patients without robust evidence supporting its use. In this study, we aimed to systematically describe the effectiveness of treatment and prevention of the cytokine storms in COVID-19 patients with tocilizumab. In this multicentered retrospective and observational cohort study, 65 patients with COVID-19 receiving tocilizumab and 130 not receiving tocilizumab were propensity score matched at a ratio of 2:1 based on age, sex, and comorbidities from January 20, 2020 to March 18, 2020 in Wuhan, China. After adjusting for confounding, the detected risk for in-hospital death was lower in the tocilizumab group versus nontocilizumab group (hazard ratio = 0.47; 95% confidence interval = 0.25-0.90; p = 0.023). Moreover, use of tocilizumab was associated with a lower risk of acute respiratory distress syndrome (odds ratio = 0.23; 95% confidence interval = 0.11-0.45; p < 0.0001). Furthermore, patients had heightened inflammation and more dysregulated immune cells before treatment, which might aggravate disease progression. After tocilizumab administration, abnormally elevated IL-6, C-reactive protein, fibrinogen, and activated partial thromboplastin time decreased. Tocilizumab may be of value in prolonging survival in patients with severe COVID-19, which provided a novel strategy for COVID-19-induced cytokine release syndrome. Our findings could inform bedside decisions until data from randomized, controlled clinical trials become available.

Genetic variants associated with expression of TCF19 contribute to the risk of head and neck cancer in Chinese population.

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common cancers worldwide and includes cancers arising from the oral cavity, pharynx and larynx. Genome-wide association studies have found several genetic variants related to the risk of SCCHN; however, they could only explain a small fraction of the heritability. Thus, more susceptibility loci associated with SCCHN need to be identified. METHODS: An association study was conducted by genotyping 555 patients with SCCHN and 1367 controls in a Chinese population. Single-variant association analysis was conducted on 63 373 SNPs, and the promising variants were then confirmed by a two-stage validation with 1875 SCCHN cases and 4637 controls. Bioinformatics analysis and functional assays were applied to uncover the potential pathogenic mechanism of the promising variants and genes associated with SCCHN. RESULTS: We first identified three novel genetic variants significantly associated with the risk of SCCHN (p=7.45×10-7 for rs2517611 at 6p22.1, p=1.76×10-9 for rs2524182 at 6p21.33 and p=2.17×10-10 for rs3131018 at 6p21.33). Further analysis and biochemical assays showed that rs3094187, which was in a region in high linkage disequilibrium with rs3131018, could modify TCF19 expression by regulating the binding affinity of the transcription factor SREBF1 to the promoter of TCF19. In addition, experiments revealed that the inhibition of TCF19 may affect several important pathways involved in tumourigenesis and attenuate the cell proliferation and migration of SCCHN. CONCLUSION: These findings offer important evidence that functional genetic variants could contribute to development of SCCHN and that TCF19 may function as a putative susceptibility gene for SCCHN.

Risk SNP in a transcript of RP11-638I2.4 increases lncRNA-YY1 interaction and pancreatic cancer susceptibility.

Tens of thousands of long non-coding RNAs (lncRNAs) have been identified through RNA-seq analysis, but the biological and pathological significance remains unclear. By integrating the genome-wide lncRNA data with a cross-ancestry meta-analysis of PDAC GWASs, we depicted a comprehensive atlas of pancreatic ductal adenocarcinoma (PDAC)-associated lncRNAs, containing 1,204 lncRNA (445 novel lncRNAs and 759 GENCODE annotated lncRNAs) and 4,368 variants. Furthermore, we found that PDAC-associated lncRNAs could function by altering chromatin activity, transcription factors, and RNA-binding proteins binding affinity. Importantly, genetic variants linked to PDAC are preferentially found at PDAC-associated lncRNA regions, supporting the biological and clinical relevance of PDAC-associated lncRNAs. Finally, we prioritized a novel transcript (MICT00000110172.1) of RP11-638I2.4 as a potential tumor promoter. MICT00000110172.1 is able to reinforce the interaction with YY1, which could reverse the effect of YY1 on pancreatic cancer cell cycle arrest to promote the pancreatic cancer growth. G > A change at rs2757535 in the second exon of MICT00000110172.1 induces a spatial structural change and creates a target region for YY1 binding, which enforces the effect of MICT00000110172.1 in an allele-specific manner, and thus confers susceptibility to tumorigenesis. In summary, our results extend the repertoire of PDAC-associated lncRNAs that could act as a starting point for future functional explorations, and the identification of lncRNA-based target therapy.

HSPA12A was identified as a key driver in colorectal cancer GWAS loci 10q26.12 and modulated by an enhancer-promoter interaction.

Although genome-wide association studies (GWASs) have identified over 100 colorectal cancer (CRC) risk loci, an understanding of causal genes or risk variants and their biological functions in these loci remain unclear. Recently, genomic loci 10q26.12 with lead SNP rs1665650 was identified as an essential CRC risk loci of Asian populations. However, the functional mechanism of this region has not been fully clarified. Here, we applied an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk loci 10q26.12. Notably, HSPA12A had the most significant effect among the identified genes and functioned as a crucial oncogene facilitating cell proliferation. Moreover, we conducted an integrative fine-mapping analysis to identify putative casual variants and further explored their association with CRC risk in a large-scale Chinese population consisting of 4054 cases and 4054 controls and also independently validated in 5208 cases and 20,832 controls from the UK biobank cohort. We identified a risk SNP rs7093835 in the intron of HSPA12A that was significantly associated with an increased risk of CRC (OR 1.23, 95% CI 1.08-1.41, P = 1.92 × 10-3). Mechanistically, the risk variant could facilitate an enhancer-promoter interaction mediated by the transcriptional factor (TF) GRHL1 and ultimately upregulate HSPA12A expression, which provides functional evidence to support our population findings. Collectively, our study reveals the important role of HSPA12A in CRC development and illustrates a novel enhancer-promoter interaction module between HSPA12A and its regulatory elements rs7093835, providing new insights into the etiology of CRC.

CancerImmunityQTL: a database to systematically evaluate the impact of genetic variants on immune infiltration in human cancer.

Tumor-infiltrating immune cells as integral component of the tumor microenvironment are associated with tumor progress, prognosis and responses to immunotherapy. Genetic variants have been demonstrated to impact tumor-infiltrating, underscoring the heritable character of immune landscape. Therefore, identification of immunity quantitative trait loci (immunQTLs), which evaluate the effect of genetic variants on immune cells infiltration, might present a critical step toward fully understanding the contribution of genetic variants in tumor development. Although emerging studies have demonstrated the determinants of germline variants on immune infiltration, no database has yet been developed to systematically analyze immunQTLs across multiple cancer types. Using genotype data from TCGA database and immune cell fractions estimated by CIBERSORT, we developed a computational pipeline to identify immunQTLs in 33 cancer types. A total of 913 immunQTLs across different cancer types were identified. Among them, 5 immunQTLs are associated with patient overall survival. Furthermore, by integrating immunQTLs with GWAS data, we identified 527 immunQTLs overlapping with known GWAS linkage disequilibrium regions. Finally, we constructed a user-friendly database, CancerImmunityQTL (http://www.cancerimmunityqtl-hust.com/) for users to browse, search and download data of interest. This database provides an informative resource to understand the germline determinants of immune infiltration in human cancer and benefit from personalized cancer immunotherapy.

Systematic Functional Interrogation of Genes in GWAS Loci Identified ATF1 as a Key Driver in Colorectal Cancer Modulated by a Promoter-Enhancer Interaction.

Genome-wide association studies (GWASs) have identified approximately 100 colorectal cancer (CRC) risk loci. However, the causal genes in these loci have not been systematically interrogated. We conducted a high-throughput RNA-interference functional screen to identify the genes essential for proliferation in the CRC risk loci of Asian populations. We found that ATF1, located in the 12q13.12 region, functions as an oncogene that facilitates cell proliferation; ATF1 has the most significant effect of the identified genes and promotes CRC xenograft growth by affecting cell apoptosis. Next, by integrating a fine-mapping analysis, a two-stage affected-control study consisting of 6,213 affected individuals and 10,388 controls, and multipronged experiments, we elucidated that two risk variants, dbSNP: rs61926301 and dbSNP: rs7959129, that located in the ATF1 promoter and first intron, respectively, facilitate a promoter-enhancer interaction, mediated by the synergy of SP1 and GATA3, to upregulate ATF1 expression, thus synergistically predisposing to CRC risk (OR = 1.77, 95% CI = 1.42-2.21, p = 3.16 × 10-7; Pmultiplicative-interaction = 1.20 × 10-22; Padditive-interaction = 6.50 × 10-3). Finally, we performed RNA-seq and ChIP-seq assays in CRC cells treated with ATF1 overexpression in order to dissect the target programs of ATF1. Results showed that ATF1 activates a subset of genes, including BRAF, NRAS, MYC, BIRC2, DAAM1, MAML2, STAT1, ID1, and NKD2, related to apoptosis, Wnt, TGF-ß, and MAPK pathways, and these effects could cooperatively increase the risk of CRC. These findings reveal the clinical potential of ATF1 in CRC development and illuminate a promoter-enhancer interaction module between the ATF1 regulatory elements dbSNP: rs61926301 and dbSNP: rs7959129, and they bring us closer to understanding the molecular drivers of cancer.

Risk factors for the mortality of hemodialysis patients with COVID-19: A multicenter study from the overall hemodialysis population in Wuhan.

INTRODUCTION: Maintenance hemodialysis (MHD) patients are highly threatened in the novel coronavirus disease 2019 (COVID-19) pandemic, but evidence of risk factors for mortality in this population is still lacking. METHODS: We followed outcomes of the overall MHD population of Wuhan, including 7154 MHD patients from 65 hemodialysis centers, from January 1 to May 4, 2020. Among them, 130 were diagnosed with COVID-19. The demographic and clinical data of them were collected and compared between survivors and nonsurvivors. RESULTS: Compared to the corresponding period of last year, the all-cause mortality rate of the Wuhan MHD population significantly rose in February, and dropped down in March 2020. Of the 130 COVID-19 cases, 51 (39.2%) were deceased. Advanced age, decreased oxygen saturation, low diastolic blood pressure (DBP) on admission, and complications including acute cardiac injury (HR 5.03 [95% CI 2.21-11.14], p < 0.001), cerebrovascular event (HR 2.80 [95% CI 1.14-6.86], p = 0.025) and acute respiratory distress syndrome (HR 3.50 [95% CI 1.63-7.51], p = 0.001) were identified as independent risk factors for the death of COVID-19. The median virus shedding period of survivors was 25 days, longer than the general population. CONCLUSIONS: Maintenance hemodialysis patients are a highly vulnerable population at increased risk of mortality and prolonged virus shedding period in the ongoing COVID-19 pandemic. Advanced age, decreased oxygen saturation, low DBP on admission, and complications like acute cardiac injury are parameters independently associated with poor prognosis.

Hepatocellular carcinoma risk variant modulates lncRNA HLA-DQB1-AS1 expression via a long-range enhancer-promoter interaction.

Substantial evidence highlighted the critical role of long non-coding RNAs (lncRNA) in driving hepatocarcinogenesis. We hypothesized that functional variants in genome-wide association studies (GWASs) associated loci might alter the expression levels of lncRNAs and contribute to the development of hepatocellular carcinoma (HCC). Here, we prioritized potentially cis-expression quantitative trait loci-based single nucleotide polymorphism (SNP)-lncRNA association together with the physical interaction by the analyses from Hi-C data in GWAS loci of chronic hepatitis B and HCC. Subsequently, by leveraging two-stage case-control study (1738 hepatitis B [HBV]) related HCC cases and 1988 HBV persistent carriers) and biological assays, we identified that rs2647046 was significantly associated with HCC risk (odds ratio = 1.26, 95% CI = 1.11 to 1.43, P = 4.14 × 10-4). Luciferase reporter assays and electrophoretic mobility shift assays showed that rs2647046 A allele significantly increased transcriptional activity via influencing transcript factor binding affinity. Allele-specific chromosome conformation capture assays revealed that enhancer with rs2647046 interacted with the HLA-DQB1-AS1 promoter to allele-specifically influence its expression by CTCF-mediated long-range loop. Cell proliferation assays indicated that HLA-DQB1-AS1 is a potential oncogene in HCC. Our study showed HLA-DQB1-AS1 regulated by a causal SNP in a long-range interaction manner conferred the susceptibility to HCC, suggesting an important mechanism of modulating lncRNA expression for risk-associated SNPs in the etiology of HCC.

Potential Influence of Menstrual Status and Sex Hormones on Female Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Cross-sectional Multicenter Study in Wuhan, China.

BACKGROUND: Recent studies have indicated that females with coronavirus disease 2019 (COVID-19) have a lower morbidity, severe case rate, and mortality and better outcome than those of male individuals. However, the reasons remained to be addressed. METHODS: To find the factors that potentially protect females from COVID-19, we recruited all confirmed patients hospitalized at 3 branches of Tongji Hospital (N = 1902), and analyzed the correlation between menstrual status (n = 509, including 68 from Mobile Cabin Hospital), female hormones (n = 78), and cytokines related to immunity and inflammation (n = 263), and the severity/clinical outcomes in female patients <60 years of age. RESULTS: Nonmenopausal female patients had milder severity and better outcome compared with age-matched men (P < .01 for both). Menopausal patients had longer hospitalization times than nonmenopausal patients (hazard ratio [HR], 1.91 [95% confidence interval {CI}, 1.06-3.46]; P = .033). Both anti-Müllerian hormone (AMH) and estradiol (E2) showed a negative correlation with severity of infection (adjusted HR, 0.146 [95% CI, .026-.824], P = .029 and 0.304 [95% CI, .092-1.001], P = .05, respectively). E2 levels were negatively correlated with interleukin (IL) 2R, IL-6, IL-8, and tumor necrosis factor alpha in the luteal phase (P = .033, P = .048, P = .054, and P = .023) and C3 in the follicular phase (P = .030). CONCLUSIONS: Menopause is an independent risk factor for female COVID-19 patients. AMH and E2 are potential protective factors, negatively correlated with COVID-19 severity, among which E2 is attributed to its regulation of cytokines related to immunity and inflammation.

Identification of genetic variants in m6A modification genes associated with pancreatic cancer risk in the Chinese population.

N6-Methyladenosine (m6A) is the most prevalent modification of RNA in eukaryotes, and is associated with many cellular processes and even the development of cancers. We hypothesized that single-nucleotide polymorphisms (SNPs) in m6A modification genes, including its "writers", "erasers" and "readers", might affect the m6A functions and associate with the susceptibility to pancreatic ductal adenocarcinoma (PDAC). We first conducted a two-stage case-control study in Chinese population to interrogate all SNPs in 22 m6A modification genes. In the discovery stage, a total of 2735 SNPs were genotyped in 980 patients and 1991 controls. Then, the promising SNP was replicated in another independent population consisting of 858 cases and 2084 controls. As a result, we found the rs7495 in 3'UTR of hnRNPC was significantly associated with increased risk of PDAC in both stages (combined odds ratio = 1.22, 95% confidence interval = 1.12-1.32, P = 2.39 × 10-6). To further reveal the biological function of rs7495 and hnRNPC, we performed a series of biochemical experiments. Luciferase reporter assays indicated that rs7495G allele promoted hnRNPC expression through disrupting a putative binding site for has-miR-183-3p. Cell viability assay demonstrated that knockdown of hnRNPC suppressed the proliferation of PDAC cells. RNA-seq analysis suggested that as an m6A "reader", hnRNPC played an important role in RNA biological processes. In conclusion, our findings elucidated that rs7495G could confer higher risk of PDAC via promoting the expression of hnRNPC through a miRNA-mediated manner. These results provided a novel insight into the critical role of m6A modification in tumorigenesis.

Pancan-meQTL: a database to systematically evaluate the effects of genetic variants on methylation in human cancer.

DNA methylation is an important epigenetic mechanism for regulating gene expression. Aberrant DNA methylation has been observed in various human diseases, including cancer. Single-nucleotide polymorphisms can contribute to tumor initiation, progression and prognosis by influencing DNA methylation, and DNA methylation quantitative trait loci (meQTL) have been identified in physiological and pathological contexts. However, no database has been developed to systematically analyze meQTLs across multiple cancer types. Here, we present Pancan-meQTL, a database to comprehensively provide meQTLs across 23 cancer types from The Cancer Genome Atlas by integrating genome-wide genotype and DNA methylation data. In total, we identified 8 028 964 cis-meQTLs and 965 050 trans-meQTLs. Among these, 23 432 meQTLs are associated with patient overall survival times. Furthermore, we identified 2 214 458 meQTLs that overlap with known loci identified through genome-wide association studies. Pancan-meQTL provides a user-friendly web interface (http://bioinfo.life.hust.edu.cn/Pancan-meQTL/) that is convenient for browsing, searching and downloading data of interest. This database is a valuable resource for investigating the roles of genetics and epigenetics in cancer.