Genetic variant in a BaP-activated super-enhancer increases prostate cancer risk by promoting AhR-mediated FAM227A expression

Genetic variants in super-enhancers(SEs)are increasingly implicated as a disease risk-driving mechanism.Previous studies have reported an associations between benzo[a]pyrene(BaP)exposure and some malignant tumor risk.Currently,it is unclear whether BaP is involved in the effect of genetic variants in SEs on prostate cancer risk,nor the associated intrinsic molecular mechanisms.In the current study,by using logistic regression analysis,we found that rs5750581T>C in 22q-SE was significantly associated with prostate cancer risk(odds ratio=1.26,P=7.61×10^(-5)).We also have found that the rs6001092T>G,in a high linkage disequilibrium with rs5750581T>C(r^(2)=0.98),is located in a regulatory aryl hydrocarbon receptor(AhR)motif and may interact with the FAM227A promoter in further bioinformatics analysis.We then performed a series of functional and BaP acute exposure experiments to assess biological function of the genetic variant and the target gene.Biologically,the rs6001092-G allele strengthened the transcription factor binding affinity to AhR,thereby upregulating FAM227A,especially upon exposure to BaP,which induced the malignant phenotypes of prostate cancer.The current study highlights that AhR acts as an environmental sensor of BaP and is involved in the SE-mediated prostate cancer risk,which may provide new insights into the etiology of prostate cancer associated with the inherited SE variants under environmental carcinogen stressors.

A computational framework for improving genetic variants identification from 5,061 sheep sequencing data

Background Pan-genomics is a recently emerging strategy that can be utilized to provide a more comprehensive characterization of genetic variation.Joint calling is routinely used to combine identified variants across multiple related samples.However,the improvement of variants identification using the mutual support information from mul-tiple samples remains quite limited for population-scale genotyping.Results In this study,we developed a computational framework for joint calling genetic variants from 5,061 sheep by incorporating the sequencing error and optimizing mutual support information from multiple samples’data.The variants were accurately identified from multiple samples by using four steps:(1)Probabilities of variants from two widely used algorithms,GATK and Freebayes,were calculated by Poisson model incorporating base sequencing error potential;(2)The variants with high mapping quality or consistently identified from at least two samples by GATK and Freebayes were used to construct the raw high-confidence identification(rHID)variants database;(3)The high confidence variants identified in single sample were ordered by probability value and controlled by false discovery rate(FDR)using rHID database;(4)To avoid the elimination of potentially true variants from rHID database,the vari-ants that failed FDR were reexamined to rescued potential true variants and ensured high accurate identification variants.The results indicated that the percent of concordant SNPs and Indels from Freebayes and GATK after our new method were significantly improved 12%-32%compared with raw variants and advantageously found low frequency variants of individual sheep involved several traits including nipples number(GPC5),scrapie pathology(PAPSS2),sea-sonal reproduction and litter size(GRM1),coat color(RAB27A),and lentivirus susceptibility(TMEM154).Conclusion The new method used the computational strategy to reduce the number of false positives,and simulta-neously improve the identification of genetic variants.This strategy did not incur any extra cost by using any addi-tional samples or sequencing data information and advantageously identified rare variants which can be important for practical applications of animal breeding.

Alternative polyadenylation-related genetic variants contribute to bladder cancer risk

Aberrant alternative polyadenylation(APA)events play an important role in cancers,but little is known about whether APA-related genetic variants contribute to the susceptibility to bladder cancer.Previous genome-wide association study performed APA quantitative trait loci(apaQTL)analyses in bladder cancer,and identified 17955 single nucleotide polymorphisms(SNPs).We found that gene symbols of APA affected by apaQTL-associated SNPs were closely correlated with cancer signaling pathways,high mutational burden,and immune infiltration.Association analysis showed that apaQTL-associated SNPs rs34402449 C>A,rs2683524 C>T,and rs11540872 C>G were significantly associated with susceptibility to bladder cancer(rs34402449:OR=1.355,95%confidence interval[CI]:1.159-1.583,P=1.33×10^(−4);rs2683524:OR=1.378,95%CI:1.164-1.632,P=2.03×10^(−4);rs11540872:OR=1.472,95%CI:1.193-1.815,P=3.06×10^(−4)).Cumulative effect analysis showed that the number of risk genotypes and smoking status were significantly associated with an increased risk of bladder cancer(P_(trend)=2.87×10^(−12)).We found that PRR13,being demonstrated the most significant effect on cell proliferation in bladder cancer cell lines,was more highly expressed in bladder cancer tissues than in adjacent normal tissues.Moreover,the rs2683524 T allele was correlated with shorter 3′untranslated regions of PRR13 and increased PRR13 expression levels.Collectively,our findings have provided informative apaQTL resources and insights into the regulatory mechanisms linking apaQTL-associated variants to bladder cancer risk.

Genetic variants in RAN, DICER and HIWI of microRNA biogenesis genes and risk of cervical carcinoma in a Chinese population

Objective：Recent evidence indicates that dysregulation of microRNA （miRNA） biogenesis is implicated in cancer development and progression.Based on the important role of miRNA biogenesis genes in carcinogenesis,we hypothesized that genetic variations of the miRNA biogenesis genes may modulate susceptibility to cervical cancer.Methods：We identified three single nucleotide polymorphisms （SNPs） located in the 3＇-untranslated regions （3＇-UTR） of of miRNA biogenesis key genes （rs1057035 in DICER,rs3803012 in RAN and rs10773771 in HIWI） and genotyped these SNPs in a case-control study of 1,486 cervical cancer cases and 1,549 cancer-free controls in Chinese women.Results：Logistic regression analyses showed that no significant associations were observed between the three SNPs and cervical cancer risk [rs3803012 in RAN AG/GG vs.AA adjusted OR =1.104,95 ％ confidence interval （CI）：0.859-1.419; rs1057035 in DICER CT/CC vs.TT adjusted OR =0.962,95％ CI：0.805-1.149;rs10773771 in HIWICT/CC vs.TT adjusted OR =0.963,95％ CI：0.826-1.122].Conclusions：The findings did not suggest that genetic variants in the 3＇-UTR of RAN,DICER and HIWI of miRNA biogenesis genes were associated with the risk of cervical cancer in this Chinese population.

Genetic variant of cyclooxygenase-2 in gastric cancer:More inflammation and susceptibility

Gastric cancer accounts for the majority cancer-related deaths worldwide.Although various methods have considerably improved the screening,diagnosis,and treatment of gastric cancer,its incidence is still high in Asia,and the 5-year survival rate of advanced gastric cancer patients is only 10%-20%.Therefore,more effective drugs and better screening strategies are needed for reducing the incidence and mortality of gastric cancer.Cyclooxygenase-2(COX-2)is considered to be the key inducible enzyme in prostaglandins(PGs)synthesis,which is involved in multiple pathways in the inflammatory response.For example,inflammatory cytokines stimulate innate immune responses via Toll-like receptors and nuclear factor-kappa B to induce COX-2/PGE2 pathway.In these processes,the production of an inflammatory microenvironment promotes the occurrence of gastric cancer.Epidemiological studies have also indicated that non-steroidal antiinflammatory drugs can reduce the risk of malignant tumors of the digestive system by blocking the effect of COX-2.However,clinical use of COX-2 inhibitors to prevent or treat gastric cancer may be limited because of potential side effects,especially in the cardiovascular system.Given these side effects and low treatment efficacy,new therapeutic approaches and early screening strategies are urgently needed.Some studies have shown that genetic variation in COX-2 also play an important role in carcinogenesis.However,the genetic variation analysis in these studies is incomplete and isolated,pointing out only a few single nucleotide polymorphisms(SNPs)and the risk of gastric cancer,and no comprehensive study covering the whole gene region has been carried out.In addition,copy number variation(CNV)is not mentioned.In this review,we summarize the SNPs in the whole COX-2 gene sequence,including exons,introns,and both the 5’and 3’untranslated regions.Results suggest that COX-2 does not increase its expression through the CNV and the SNPs in COX-2 may serve as the potential marker to establish risk stratification in the general population.This review synthesizes emerging insights of COX-2 as a biomarker in multiple studies,summarizes the association between whole COX-2 sequence variation and susceptibility to gastric cancer,and discusses the future prospect of therapeutic intervention,which will be helpful for early screening and further research to find new approaches to gastric cancer treatment.

Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk

The present study was designed to examine the contributions of the fatty acid elongase （ELOVL） gene polymorphisms to the levels of polyunsaturated fatty acids （PUFAs） in breast milk. Two hundred and nine healthy Han Chinese mothers were included in the study. Carriers of minor alleles of SNPs （rs2397142 and rs9357760） in ELOVL5 were associated with higher levels of linoleic acid （LA）, dihomo-γ-linolenic acid （DGLA）, arachidonic acid （AA）, docosatetraenoic acid （DTA）, docosahexenoic acid （DHA）, while in rs209512 of ELOVL5 the carriers of minor alleles had lower levels of DTA compared to major homozygote alleles （P ranged from 0.004-0.046）, and genetically explained variability ranged from 3.2% for eicosapentaenoic acid （EPA） to 6.0% for LA. Our findings demonstrated that common variation in ELOVL5 gene encoding rate-limiting enzymes in the metabolism of PUFAs contribute to the PUFAs in breast milk.

Genes for the high life： New genetic variants point to positive selection for high altitude hypoxia in Tibetans

People living on the high plateaus of the world have long fascinated biological anthropologists and geneticists because they live in ＂thin air＂ and epitomize an extreme of human biological adaptation.

GLTSCR1, ATM, PPPIR13L and CD3EAP Genetic Variants and Lung Cancer Risk in a Chinese Population

Genetic variants in glioma tumor suppressor candidate region gene 1 （GLTSCR1） and ATM serine/threonine kinase （ATM） have been associated with various cancer risks. Epidemiological studies also revealed the association of variants of GLTSCR1 and ATM genes with different brain tumors. However, little is known about the relationship between both gene polymorphisms and lung cancer risk. We conducted a Chinese hospital-based casecontrol study involving 384 lung cancer cases and 387 cancer-free controls. No significant differences in the single polymorphism （GLTSCR1 rs1035938 and ATM rs11212592） association were found in five genetic models （co-dominant, dominant, recessive, overdominant and log-additive models） （adjusted by smoking duration）. Join effect of three SNPs （PPPIR13L rs1970764, CD3EAP rs967591, GLTSCR1 rs1035938） on chromosome 19q 13.3 showed that the designated haplotype2 （rs 1970764 G-rs967591 A-rs 1035938 C） [OR （95% CI）=1.60 （1.11-2.32）, P=0.012] and haplotype8 （rs 1970764 G-rs967591 G-rs 1035938 T） [OR （95% CI）=2.45 （1.17-5.12）, P=0.018] were associated with increased risk of lung cancer （adjusted by smoking duration）. The analysis ofmultifactor dimensionality reduction revealed that two 3-way models were the best fit models in analyses of 2 loci （P〈0.001） or 4 loci （P=0.015-0.016）. The entropy-based analysis indicated the strongest synergistic effect between PPPIR13L rs1970764 and ATM rs11212592 in analysis of four genes. In conclusion, our study suggests that haplotypes consisting of PPPIR13L rs1970764- CD3EAP rs967591-GLTSCR1 rs1035938 on Chr19q13.3, interaction of smoking and GLTSCR1 rs1035938-ATM rs11212592, and synergistic action of PPPIR13L rs1970764 and ATM rs 11212592 may associate with lung cancer risk in the Chinese population.

Exploring the Novel Genetic Variant of PITX1 Gene and Its Effect on Milk Performance in Dairy Goats

Paired-like homeodomain transcription factor 1 （PITX1） plays an important role in pituitary development by indirectly regulating the expression of the GH and PRL genes, and therefore PITX1 gene is regarded as a potential candidate gene for building the relationship between the gene polymorphism and milk traits. The aim of this study was to explore the novel genetic variant in PITX1 gene and its effect on milk performance in dairy goats. Herein, a novel genetic variation （NW_00314033： g.201GA or IVS1＋41GA） located at nt41 position of the first intron of the goat PITX1 gene was reported at the P1 locus, which can be genotyped by the Msp I PCR-RFLP. In the Msp I PCR-RFLP analyis, the GG variant was a major genotype, and the A variant was a minor allele in Guanzhong dairy goats which was at Hardy-Weinberg disequilibrium （chi-square χ2=140, P0.01）. The establishment of associations between different genotypes and milk performance was performed in the analyzed population. A total of three significant associations of the polymorphism with average milk fat content （%） （P=0.045）, morning milk fat content （%） （P=0.049）, and afternoon milk fat content （%） （P=0.050）, were found, respectively. A significant relationship between the polymorphism and average total solid content （P=0.029） was also detected. This novel single nucleotide polymorphism （SNP） extended the spectrum of genetic variation of the goat PITX1 gene, and its significant association with milk performance would benefit from the application of DNA markers related to improving milk performance through marker-assisted selection （MAS） in dairy goats.

Relationship of GSTM1 and GSTT1 genetic variant and markers of oxidative stress and inflammation in smokers with coronary artery disease

Objective： To investigate the role of glutathione S-transferase （GST） genetic variants and markers of oxidative stress and inflammation in smokingrelated coronary artery disease （CAD） patients. Methods： Five hundred and thirty-five Chinese CAD patients were successfully genotyped. Plasma total antioxidant status （TAOS）, glutathione, C-reactive protein （CRP）, fibrinogen（FIB） and white blood cell count （WBC） were determined to evaluate the oxidative stress and inflammatory response. Results： GSTM1-0/ GSTT1-0 subjects had a higher CRP, FIB, WBC and GSH and a lower TAOS compared to patients with wild-type GSTM1/GSTT1 genes, but there was significant difference only with regards to TAOS. Smokers with the null genotype of GSTT1 had the highest CRP and the lowest TAOS and GSH when compared to the GSTTI-1 genotype with smoking status, or the GSTT1-0 genotype with non-smoking status, or the GSTTI-I genotype with non-smoking status. However, we found no significant difference between these groups. Also, no significant interaction was observed between genotypes and smoking status in determining CRP levels. Conclusion： Our results suggest that GST polymorphisms do not modify the effect of smoking on markers of oxidative stress and inflammation in Chinese CAD patients.

Genetic variants associated with endometriosis patients:a systematic review

Endometriosis is defined as the presence of endometrium-like tissue outside the uterus,80%of which occur in the ovaries.It is characterized by an estrogen-dependent produces periodic and repeated bleeding,and may be accompanied by clinical symptoms such as dysmenorrhea,fatigue,dysuria,deep dyspareunia,and infertility.Due to the complex etiology and the yet-unknown pathogenesis of endometriosis,and the treatment effect is not ideal,causing significant physical and mental harm to reproductive-age women;thus,it has become a hot research topic.Endometriosis is still a mysterious disease of unknown origin and pathogenesis.Genetic factors are known to affect the manifestation and progression of endometriosis.A selection of genetic studies revealed genetic mutations and polymorphisms of endometriosis and their effects on the risk of developing this disease.This paper aimed to discuss the genetic variants associated with the risk of endometriosis and provided information to enrich the gene spectrum of endometriosis.

BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes

Brain-specific serine/threonine-protein kinase 2(BRSK2)plays critical roles in insulin secretion andβ-cell biology.However,whether BRSK2 is associated with human type 2 diabetes mellitus(T2DM)has not been determined.Here,we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.BRSK2 protein levels are significantly elevated inβcells from T2DM patients and high-fat diet(HFD)-fed mice due to enhanced protein stability.Mice with inducibleβ-cell-specific Brsk2 knockout(βKO)exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions.Moreover,βKO mice are protected from HFD-induced hyperinsulinemia,obesity,insulin resistance,and glucose intolerance.Conversely,gain-of-function BRSK2 in matureβcells reversibly triggers hyperglycemia due toβ-cell hypersecretion-coupled insulin resistance.Mechanistically,BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner.The enhanced basal insulin secretion drives insulin resistance andβ-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 inβcells.These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay betweenβcells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.

Genetic screening of liver cancer:State of the art

Liver cancer,primarily hepatocellular carcinoma,remains a global health challenge with rising incidence and limited therapeutic options.Genetic factors play a pivotal role in the development and progression of liver cancer.This state-of-the-art paper provides a comprehensive review of the current landscape of genetic screening strategies for liver cancer.We discuss the genetic underpinnings of liver cancer,emphasizing the critical role of risk-associated genetic variants,somatic mutations,and epigenetic alterations.We also explore the intricate interplay between environmental factors and genetics,highlighting how genetic screening can aid in risk stratification and early detection via using liquid biopsy,and advancements in high-throughput sequencing technologies.By synthesizing the latest research findings,we aim to provide a comprehensive overview of the state-of-the-art genetic screening methods for liver cancer,shedding light on their potential to revolutionize early detection,risk assessment,and targeted therapies in the fight against this devastating disease.

Comparison of Aspirin and Naoxintong Capsule(脑心通胶囊)with Adjusted-Dose Warfarin in Elderly Patients with High-Risk of Non-Valvular Atrial Fibrillation and Genetic Variants of Vitamin K Epoxide Reductase

Objective： To compared the therapeutic effect of a Chinese patent medicine Naoxintong Capsule（脑心通胶囊, NXT） and aspirin with adjusted-dose warfarin in Chinese elderly patients（over 65 years） with nonvalvular atrial fibrillation（NVAF） and genetic variants of vitamin K epoxide reductase（VKORC1）, who are at high-risk of thromboembolism. Methods： A total of 151 patients, with NVAF and AA genotype of VKORC1-1639（a sensitive genotype to warfarin） and a CHA2 DS2-VASc clinical risk score of 2 or above, were chosen for this study. Patients were randomized into two groups and orally treated with a combination of aspirin（100 mg/day） and NXT（1.6 g thrice a day） or adjusted-dose warfarin [international normalized ratio 2.0–3.0）. The primary end points including ischemic stroke and death as well as the secondary end points including hemorrhage events were followed up for at least 1 year. Results： Baseline clinical data and the rates of primary end points were similar between groups. However, the rate of serious bleeding（secondary event） in the combination therapy group was lower than that in the adjusted-dose warfarin group（0% vs. 7.9%, odds ratio： 0.921, 95% confidence interval： 0.862–0.984, P=0.028）. Conclusions： Aspirin combined with NXT and warfarin displayed comparable rates of primary end point including ischemic stroke and all-cause death during the 1-year follow-up. However, as compared with warfarin, the combination therapy reduced the rate of serious bleeding. Therefore, aspirin combined with NXT might provide an alternative pharmacotherapy in preventing ischemic stroke for elderly patients with NAVF who cannot tolerate warfarin.（No. ChiC TR-TRC-13003596）

Association of a genetic variant in AKT1 gene with features of the metabolic syndrome

Metabolic syndrome(MetS)is a clustering of metabolic abnormalities that is associated with increased risk of developing cardiovascular disease and type 2 diabetes.There is growing body of data showing the associations of genetic variants of the genes involved in the PI3K/AKT/mTOR pathway with diabetes and obesity.We aimed to investigate the association between MetS and its components with the genetic polymorphism in AKT1,rs1130233(T>C).Total of 618 participants,recruited from Mashhad stroke and heart atherosclerosis disorder cohort(MASHAD study).Patients with MetS were defined by using international diabetes federation(IDF)criteria(n Z 326)and those without MetS(n Z 261)were recruited.Anthropometric and biochemical parameters were measured in all subjects.Genetic analysis for the rs1130233 polymorphism was performed,using the ABI-StepOne instruments with SDS version-2.0 software.Individuals with MetS had a significantly higher levels of BMI,waistcircumference,total cholesterol,triglyceride,high sensitivity-c reactive protein(hs-CRP)and blood-pressure,and lower concentrations of high density lipoprotein(HDL-C),compared to non-MetS individuals(P<0.05).The association between the rs1130233 and MetS was not significant.Subjects with a CC or CT genotypes had a significantly higher serum hs-CRP-level(OR:1.5;95%CI(1.05e2.1),P Z 0.02).Additionally,subjects who carried the TC genotype had a higher BMI compared to the CC genotype(p value Z 0.045).Our findings demonstrated that AKT1,rs1130233(T>C)polymorphism was associated with major components of MetS such as hs-CRP,and BMI,indicating further investigation in a multi-center setting to explore its value as an emerging biomarker of risk stratification marker.

MTP genetic variants associated with non-alcoholic fatty liver in metabolic syndrome patients

This study was performed for investigation the relationship between variants of MTP gene polymorphism and the development of NAFLD in patients with and without MS.The study was included 174 NAFLD patients(106 with MS and 68 without MS),and 141 healthy control subjects.The 493 G/T polymorphism of MTP gene was evaluated by PCR-RFLP method.The frequency of MTP TT genotype and T allele were significantly higher in NAFLD patients when compared to healthy controls.Moreover,a significant association in MTP gene polymorphism was observed in NAFLD patients with MS compared to NAFLD patients without MS and controls.Our study suggested that MTP 493 G/T gene polymorphism may act as susceptibility biomarker for NAFLD and MS.

Association between Genetic Variants and Characteristic Symptoms of Type 2 Diabetes:A Matched Case-Control Study

Objective： To examine the association of genetic variants with characteristic symptoms of type 2 diabetes mellitus （T2DM）. Methods： A matched case-control study was performed to investigate the association between common variants in four genes （CDKAL1, GLIS3, GRK5, and TCFTL2） and symptoms of T2DM. Symptoms were examined with questionnaire for 710 subjects. Genomic DNA was extracted from peripheral blood mononuclear cell by salting-out procedure. Genotyping was carried out by direct sequencing of the unpurified polymerase chain reaction products. Result： Most of the T2DM patients pressented characteristic symptoms, such as feeling weak in limbs （P=0.0057）, hand tremor （P=0.0208）, bradymasesis （P=0.0234）, and polyuria （P=0.0051）. Some of the T2DM patients shared characteristic symptoms, such as desire for cold drinks （P=0.0304）, polyphagia （P=0.0051）, and furred tongue （P=0.028）. The impaired glucose regulation （IGR） cases took only one characteristic symptom of frequent micturition （P=0.0422）. GLIS3 rs7034200 and GRK5 rs10886471 were significantly associated with increased T2DM risk （GLIS3 rs7034200 under dominant model： P=0.0307; GRK5 rs 10886471 under recessive model： P=0.0092）. However, only the rs10886471 polymorphism in GRK5 showed a significant effect on both differentiated symptoms and T2DM risk. The C-allele was involved in both dampness-heat encumbering Pi （Spleen） syndrome （P=0.047） and qi-yin deficiency syndrome （P=0.002） via increased GRK5 expression. Conclnsions： Both T2DM and IGR exhibited its corresponding characteristic symptoms. The variants of GRK5 were involved with both qi-yin deficiency syndrome and dampness-heat encumbering Pi syndrome.

Pathogenesis of premature coronary artery disease:Focus on risk factors and genetic variants

The development of premature coronary artery disease(PCAD)is dependent on both genetic predisposition and traditional risk factors.Strategies for unraveling the genetic basis of PCAD have evolved with the advent of modern technologies.Genome-wide association studies(GWASs)have identified a considerable number of common genetic variants that are associated with PCAD.Most of these genetic variants are attributable to lipid and blood pressure-related single-nucleotide polymorphisms(SNPs).The genetic variants that predispose individuals to developing PCAD may depend on race and ethnicity.Some characteristic genetic variants have been identified in Chinese populations.Although translating this genetic knowledge into clinical applications is still challenging,these genetic variants can be used for CAD phenotype identification,genetic prediction and therapy.In this article we will provide a comprehensive review of genetic variants detected by GWASs that are predicted to contribute to the development of PCAD.We will highlight recent findings regarding CAD-related genetic variants in Chinese populations and discuss the potential clinical utility of genetic variants for preventing and managing PCAD.

The Association Between Epoxide Hydrolase Genetic Variant and Effectiveness of Nicotine Replacement Therapy in a Han Chinese Population

Dear Editor, Nicotine is a psychoactive alkaloid that is thought to play a key role in addiction to commercial tobacco products [1] and cotinine is its primary metabolite [2]. Pharmacological treatment, such as nicotine replacement therapy （NRT）, is a valid solution to this problem. Tobacco smoke contains many carcinogens such as nitrosamines .

Association between gut microbiota and hepatocellular carcinoma and biliary tract cancer:A mendelian randomization study

BACKGROUND An increasing number of studies have begun to discuss the relationship between gut microbiota and diseases,yet there is currently a lack of corresponding articles describing the association between gut microbiota and hepatocellular carcinoma(HCC)and biliary tract cancer(BTC).This study aims to explore the relationship between them using Mendelian randomization(MR)analysis method.AIM To assess the relationship between gut microbiota and HCC and BTC.METHODS We obtained Genome-wide association study(GWAS)data for the gut microbiome from the intestinal microbiota genomic library(MiBioGen,https://mibiogen.gcc.rug.nl/).Additionally,we accessed data pertaining to HCC and BTC from the IEU open GWAS platform(https://gwas.mrcieu.ac.uk/).Our analysis employed fundamental instrumental variable analysis methods,including inverse-variance weighted,MR and Egger.To ensure the dependability of the results,we subjected the results to tests for multiple biases and heterogeneity.RESULTS During our investigation,we discovered 11 gut microbiota linked to an increased risk to BTC and HCC.The former included the genus Eubacterium hallii group(P=0.017),Candidatus Soleaferrea(P=0.034),Flavonifractor(P=0.021),Lachnospiraceae FCS020(P=0.034),the order Victivallales(P=0.018),and the class Lentisphaeria(P=0.0.18).The latter included the genus Desulfovibrio(P=0.042),Oscillibacter(P=0.023),the family Coriobacteriaceae(P=0.048),the order Coriobacteriales(P=0.048),and the class Coriobacteriia(P=0.048).Furthermore,in BTC,we observed 2 protective gut microbiota namely the genus Dorea(P=0.041)and Lachnospiraceae ND3007 group(P=0.045).All results showed no evidence of multiplicity or heterogeneity.CONCLUSION This study explores a causal link between gut microbiota and HCC and BTC.These insights may enhance the mechanistic knowledge of microbiota-related HCC and BTC pathways,potentially informing therapeutic strategies.