Age-specific heterogeneity of genetic susceptibility to cardiovascular disease might have opposite outcomes depending on the presence of prediabetes

Examining age-specific heterogeneity of susceptibility to cardiovascular disease is also essential in individuals without prediabetes to determine its relative size and direction compared to those with prediabetes.Of particular interest,age-specific heterogeneity in genetic susceptibility may exhibit opposite directions depending on the presence or absence of prediabetes.

Bladder cancer epidemiology and genetic susceptibility

Bladder cancer is the most common malignancy of the urinary system. The incidence of bladder cancer of men is higher than that of women （approximately 4：1）. Here, we summarize the bladder cancer-related risk factors, in- cluding environmental and genetic factors. In recent years, although the mortality rate induced by bladder cancer has been stable or decreased gradually, the public health effect may be pronounced. The well-established risk fac- tors for bladder cancer are cigarette smoking and occupational exposure. Genetic factors also play important roles in the susceptibility to bladder cancer. A recent study demonstrated that hereditary non-polyposis colorectal cancer is associated with increased risk of bladder cancer. Since 2008, genome-wide association study （GWAS） has been used to identify the susceptibility loci for bladder cancer. Further gene-gene or gene-environment interaction stud- ies need to be conducted to provide more information for the etiology of bladder cancer.

A non-synonymous coding SNP Lys45Glu of mmp3 associated with ESCC genetic susceptibility in population of Henan, China

Objective： The aim of the study was to investigate the association of esophageal squamous cell carcinoma （ESCC） genetic susceptibility with the single nucleotide polymorphism （SNP） rs679620 （-Lys45Glu-） in exon 2 of the romp3 gene, and the population in high incidence region of Henan （China） was selected for exploring the mechanism by case-control study, Methods： The romp3 SNP was genotyped by PCR-RFLP analysis in total 605 cases of Henan population, in which there were 227 ESCC cases and 197 controls of An-yang in Henan plus 181 controls of emigrants in Hubei from Xi-chuan of Henan, China. Results： The statistic data showed that GIG and G/A genotype frequencies of SNP rs679620 were significantly different between the controls of emigrants of Xi-chuan in Hubei and controls of An-yang in Henan （P 〈 0.01） also the ESCC cases of An-yang in Henan （P 〈 0.01）, respectively. Conclusion： This study suggests that the SNP rs679620 （-Lys45Glu-） in exon 2 of the mmp3 gene might be associated with ESCC genetic susceptibility.

Regional differences in genetic susceptibility to nonalcoholic liver disease in two distinct Indian ethnicities

AIM To validate the association of variants in PNPLA3(rs2281135) and TM6SF2(rs58542926) genes with ultrasound detected non-alcoholic fatty liver disease(NAFLD).METHODS A total of 503 individuals with and without fatty infiltration were recruited. Fatty infiltration was confirmed based on ultrasound findings. Anthropometric data and blood samples were collected from the study group. DNA was isolated from peripheral blood, quality and quantity was assessed by gel electrophoresis and spectrophotometer respectively. Genotyping of the variants in PNPLA3 and TM6SF2 genes was carried out by employing taqman probes(C_15875080_10 for PNPLA3 and C_8946351_10 for TM6SF2 SNP) on real time PCR(Stepone-Lifetechnologies). Genotype data was tested for deviations from Hardy-Weinbergequilibrium. χ~2 test was used to analyze the statistical significance of the difference in genotype distribution of the studied variants in patients and controls and the strength of association was expressed as odds ratio(95%CI). A two-tailed P value of ≤ 0.05 was considered statistically significant. RESULTS The study group comprised of 503 individuals of which 256 had fatty infiltration and 247 without fatty infiltration and thus formed the patient and control groups respectively. As the patient group could be divided in to two distinct ethnicities(ancestral South Indians-ASI and North-East Indians-NEI), further recruitment of control cohort and association analyses was carried out based on ethnicities. Of the 256 with fatty infiltration 93 were ASI and 163 were NEI and of the 247 controls 138 were ASI and 109 were NEI. As expected, there were significant differences in the anthropometric and other clinical data between the control and the patient groups. However significant differences within the ethnicities were also noted. While rs2281135 in PNPLA3 gene was significantly associated(P = 0.03) with higher risk(odds 1.9, 95%CI: 1.5-3.14, P = 0.03) of NAFLD in NEI ethnicity, rs58542926 in TM6SF2 gene was significantly associated with NAFLD with a 2.7 fold higher risk(odds 2.7, 95%CI: 1.37-5.3, P = 0.0004) of the disease. There were significantly higher proportions of individuals with variants in both the genes in the patient group in both ASI(patients-14/93 and controls-7/138; P = 0.009) and NEI ethnicities(patients-17/163 and controls-7/109; P = 0.01). CONCLUSION Although the study identified distinct genetic susceptibility in the two ethnicities, transheterozygosity of the variants suggests higher risk of NAFLD in individuals with both the variants.

A Genetic Susceptibility Study of Lung Cancer Risk Potentially Associated with Polycyclic Aromatic Hydrocarbon Inhalation Exposure

For lifetime non-smokers, lung cancer risk is mainly associated with inhalation exposure to air pollution. For the Chinese population, indoor air pollution due to solid fuel combustion has been the primary source of inhalation exposure for decades. Polycyclic aromatic hydrocarbons （PAHs） are the by-products of incomplete combustion.

Functional gastrointestinal disorders,mental health,genetic susceptibility,and incident chronic kidney disease

Background:Whether functional gastrointestinal disorders(FGIDs)are associated with the long-term risk of chronic kidney disease(CKD)remains unclear.We aimed to investigate the prospective association of FGIDs with CKD and examine whether mental health mediated the association.Methods:About 416,258 participants without a prior CKD diagnosis enrolled in the UK Biobank between 2006 and 2010 were included.Participants with FGIDs(including irritable bowel syndrome[IBS],dyspepsia,and other functional intestinal disorders[FIDs;mainly composed of constipation])were the exposure group,and non-FGID participants were the non-exposure group.The primary outcome was incident CKD,ascertained from hospital admission and death registry records.A Cox proportional hazard regression model was used to investigate the association between FGIDs and CKD,and the mediation analysis was performed to investigate the mediation proportions of mental health.Results:At baseline,33,156(8.0%)participants were diagnosed with FGIDs,including 21,060(5.1%),8262(2.0%),and 6437(1.6%)cases of IBS,dyspepsia,and other FIDs,respectively.During a mean follow-up period of 12.1 years,11,001(2.6%)participants developed CKD.FGIDs were significantly associated with a higher risk of incident CKD compared to the absence of FGIDs(hazard ratio[HR],1.36;95%confidence interval[CI],1.28-1.44).Similar results were observed for IBS(HR,1.27;95%CI,1.17-1.38),dyspepsia(HR,1.30;95%CI,1.17-1.44),and other FIDs(HR,1.60;95%CI,1.43-1.79).Mediation analyses suggested that the mental health score significantly mediated 9.05%of the association of FGIDs with incident CKD and 5.63-13.97%of the associations of FGID subtypes with CKD.Specifically,the positive associations of FGIDs and FGID subtypes with CKD were more pronounced in participants with a high genetic risk of CKD.Conclusion:Participants with FGIDs had a higher risk of incident CKD,which was partly explained by mental health scores and was more pronounced in those with high genetic susceptibility to CKD.

Screening for pancreatic cancer in individuals with genetic susceptibility

Pancreatic cancer is a highly lethal disease with a five-year survival rate of only about 10%(1).Early detection is crucial for improving patient outcomes,but pancreatic cancer is often diagnosed at an advanced stage when treatment options are limited(2).Individuals with a genetic susceptibility to pancreatic cancer,such as those with a strong family history or a genetic mutation associated with the disease,are at higher risk of developing pancreatic cancer than the general population.Screening these high-risk individuals could potentially lead to earlier detection and improved outcomes.

Genetics of non-alcoholic fatty liver disease: From susceptibility and nutrient interactions to management

Genetics plays an important role in determining the susceptibility of an individual to develop a disease. Complex, multi factorial diseases of modern day(diabetes, cardiovascular disease, hypertension and obesity) are a result of disparity between the type of food consumed and genes, suggesting that food which does not match the host genes is probably one of the major reasons for developing life style diseases. Non-alcoholic fatty liver is becoming a global epidemic leading to substantial morbidity. While various genotyping approaches such as whole exome sequencing using next generation sequencers and genome wide association studies have identified susceptibility loci for non-alcoholic fatty liver disease(NAFLD) including variants in patatin-like phospholipase domain containing 3 and transmembrane 6 superfamily member 2 genes apart from others; nutrient based studies emphasized on a combination of vitamin D, E and omega-3 fatty acids to manage fatty liver disease. However majority of the studies were conducted independent of each other and very few studies explored the interactions between the genetic susceptibility and nutrient interactions. Identifying such interactions will aid in optimizing the nutrition tailor made to an individual's genetic makeup, thereby aiding in delaying the onset of the disease and its progression. The present topic focuses on studies that identified the genetic susceptibility for NAFLD, nutritional recommendations, and their interactions for better management of NAFLD.

Polymorphism of the second exon of human leukocyte antigen-DQA1, -DQB1 gene and genetic susceptibility to idiopathic dilated cardiomyopathy in people of the Han nationality in northern China

Idiopathic dilated cardiomyopathy ( IDC) is characterized by dilation andimpaired contraction of the left ventricle or both, and it is a relevant cause of heart failure anda common indication for heart transplantation. The major pathogenetic hypothesis in IDC involvesautoimmune mediated damage to myocytes. The development of autoimmune inflammatory damage occursonly in patients with a predisposing genetic background. Changes in the immune system concerningcell-mediated and humoral immunity have been detected. The immune system is strictly related tohuman leukocyte antigen (HLA), which is located on the surface of antigen presenting cells. Itsprimary function is to restrict T-cell receptors in the process of recognizing auto- or exteriorantigen, and thus participates in or mediates immunological recognition, immunological response andimmune regulation at various levels. HLA is a genetic marker of susceptibility to autoimmunemyocardial damage. In the present study, the HLA-DQA1 and -DQB1 alleles in IDC patients weredetected with the techniques of polymerase chain reaction-sequence specific primers ( PCR-SSP) toexplore the immunogenetic mechanisms involved in the pathogenesis of IDC.

Towards system genetics analysis of head and neck squamous cell carcinoma using the mouse model,cellular platform,and clinical human data

Head and neck squamous cell cancer(HNSCC)is a leading global malignancy.Every year,More than 830000 people are diagnosed with HNSCC globally,with more than 430000 fatalities.HNSCC is a deadly diverse malignancy with many tumor locations and biological characteristics.It originates from the squamous epithelium of the oral cavity,oropharynx,nasopharynx,larynx,and hypopharynx.The most frequently impacted regions are the tongue and larynx.Previous investigations have demonstrated the critical role of host genetic susceptibility in the progression of HNSCC.Despite the advances in our knowledge,the improved survival rate of HNSCC patients over the last 40 years has been limited.Failure to identify the molecular origins of development of HNSCC and the genetic basis of the disease and its biological heterogeneity impedes the development of new therapeutic methods.These results indicate a need to identify more genetic factors underlying this complex disease,which can be better used in early detection and prevention strategies.The lack of reliable animal models to investigate the underlying molecular processes is one of the most significant barriers to understanding HNSCC tumors.In this report,we explore and discuss potential research prospects utilizing the Collaborative Cross mouse model and crossing it to mice carrying single or double knockout genes(e.g.Smad 4 and P53 genes)to identify genetic factors affecting the development of this complex disease using genome-wide association studies,epigenetics,micro RNA,long noncoding RNA,lnc RNA,histone modifications,methylation,phosphorylation,and proteomics.

The human leukocyte antigen and genetic susceptibility in human diseases

The human leukocyte antigen(HLA)complex is involved in immunity,belongs to a highly polymorphic family of genes,and is found in a disease-associated region of the human genome.The HLA region of the genome has been associated with more than hundreds of diseases,including autoimmune diseases,cancer,and infectious diseases.Because of its extensive linkage disequilibrium,HLA represents one of the most attractive and valuable regions that have been discovered in numerous feasibility studies.However,despite its critical role,attempts to apply comprehensive and traditional strategies towards the characterization of the HLA locus have been limited.The recent development of genotyping arrays and sequencing technologies has resulted in the development of technologies that are capable of addressing the extreme polymorphism nature of HLA.In this review,we summarized the current approaches being used to capture,sequence,and analyze HLA genes and loci.In addition,we discussed the new methodologies being used for these applications,including HLA genotyping,population genetics,and disease-association studies.

AN EPIDEMIOLOGY AND MOLECULAR GENETIC STUDY ON BREAST CANCER SUSCEPTIBILITY

Objectives. To investigate the genetic susceptibility for breast cancer of Chinese, a hospital-based case-control study, pedigree survey and molecular genetic study were conducted. Methods. Logistic regression model and stratification methods were used in the risk factors analysis. Li-Mantel-Gart and Falconer methods were used to analyze the segregation ratio and heritability. Polymerase chain reaction(PCR) and polyacrylamide gel electrophoresis were used to detect AI, G-banding technique was used to detect the chromosome aberration of peripheral blood lymphocyte. Results. Family history of breast cancer is related to enhanced breast cancer risk significantly, OR is 3905(95%CI=1079～1413), and it widely interacts with other risk factors. Accumulative incidence of breast cancer in first degree relatives is 999%, which is larger than that in second, third degree and non-blood relatives. Segregation ratio is 0021, heritability among first degree relatives is 356±58%. Frequencies of LOH at BRCA1 and BRCA2 loci in sporadic breast cancer are 612% and 577% respectively. In the sibs, both of them show LOH at D13S173 locus, and high frequencies of chromosome aberrations were observed. Conclusions. Genetic susceptibility contributes to breast cancer occurrence of Chinese, and its racial variation may be one of the important reasons for the large difference of incidence between western and eastern countries.

Enumeration,Genetic Characterization and Antimicrobial Susceptibility of Lactobacillus and Streptococcus Isolates from Retail Yoghurt in Beijing,China

Lactic acid bacteria （LAB） are widely used in food industries. Correct identification and safety evaluation of these bacteria at the species even strain level should take considerations into account. In this study, the LAB were recovered from yoghurt and characterized phenotypically and genetically. Fifty-two isolates of LAB from 31 yoghurt samples were cultured and grouped into 6 species including Luctobucillus bulguricus （24 isolates）, Streptococcus thermophilus （15 isolates）, L. ucidophilus （7 isolates）, L. porucusei/cusei （3 isolates）, L. delbrueckii （2 isolates）, and L. fermentum （1 isolate）, based on their Gram-staining, colony morphology and biochemical properties.

A Comprehensive Study of the Association between LEPR Gene rs1137101 Variant and Risk of Digestive System Cancers

Objective The leptin receptor,encoded by the LEPR gene,is involved in tumorigenesis.A potential functional variant of LEPR,rs1137101(Gln223Arg),has been extensively investigated for its contribution to the risk of digestive system(DS)cancers,but results remain conflicting rather than conclusive.Here,we performed a case–control study and subsequent meta-analysis to examine the association between rs1137101 and DS cancer risk.Methods A total of 1,727 patients with cancer(gastric/liver/colorectal:460/480/787)and 800 healthy controls were recruited.Genotyping of rs1137101 was conducted using a polymerase chain reactionrestriction fragment length polymorphism(PCR-RFLP)assay and confirmed using Sanger sequencing.Twenty-four eligible studies were included in the meta-analysis.Results After Bonferroni correction,the case–control study revealed that rs1137101 was significantly associated with the risk of liver cancer in the Hubei Chinese population.The meta-analysis suggested that rs1137101 is significantly associated with the risk of overall DS,gastric,and liver cancer in the Chinese population.Conclusion The LEPR rs1137101 variant may be a genetic biomarker for susceptibility to DS cancers(especially liver and gastric cancer)in the Chinese population.

Relationship between XRCC1 polymorphisms and susceptibility to prostate cancer in men from Han, Southern China

Aim： To investigate the association among XRCC1 polymorphisms, smoking, drinking and the risk of prostate cancer （PCa） in men from Han, Southern China. Methods： In a case-control study of 207 patients with PCa and 235 cancerfree controls, frequency-matched by age, we genotyped three XRCC1 polymorphisms （codons 194, 280 and 399） using the polymerase chain reaction-restriction fragment length polymorphism （PCR-RELP） method. Results： Among the three polymorphisms, we found that the XRCC1 Arg399Gln variant allele was associated with increased PCa risk （adjusted odd ratio [OR]： 1.67, 95% confident interval [CI]： 1.11-2.51）, but the XRCC1 Arg 194Trp variant allele had a 38% reduction in risk of PCa （adjusted OR： 0.62, 95% CI： 0.41-0.93）. However, there was no significant risk of PCa associated with Arg280His polymorphism. When we evaluated the three polymorphisms together, we found that the individuals with 194Arg/Arg wild-type genotype, Arg280His and Arg399Gln variant genotypes had a significantly higher risk of PCa （adjusted OR： 4.31; 95% CI： 1.24-14.99） than those with three wild-type genotypes. In addition, we found that Arg399Gln variant genotypes had a significant risk of PCa among heavy smokers （adjusted OR： 2.04; 95% CI： 1.03-4.05）. Conclusion： These results suggest that polymorphisms of XRCC1 appear to influence the risk of PCa and may modify risks attributable to environmental exposure.

Relationship between interleukin 18 polymorphisms and susceptibility to chronic hepatitis B virus infection

AIM: To identify the relationship between the tagging single nucleotide polymorphism sites (tagSNPs) of the Interleukin-18 (IL-18) gene and genetic susceptibility to chronic hepatitis B virus infection in Chinese patients. METHODS: Five hundred and one cases of chronic hepatitis B virus (HBV) infection and 301 HBV natural clearance controls were studied. Two tagSNPs in the IL-18 gene (rs1946518A/C and rs574424C/G) were genotyped by the Multiplex Snapshot technique. The genotype and allele frequencies were calculated and analyzed. RESULTS: In the genotypes of rs1946518, the AA type was present at a higher frequency in the patients compared to those in the controls. Odds ratio (OR) of the AA genotype for the comparison with that of the AC and the CC genotype was 1.537 (95% confidence intervals (CI): 1.116-2.218, P = 0.009 < 0.025). In phenotypes, the allele C at rs1946518 was of a significantly lower frequency in the patients with chronic hepatitis B than that in the controls (P = 0.017 < 0.025). OR of the allele A for the comparison with that of the allele C was 1.279 (95% CI: 1.045-1.567). As for the rs574424 genotypes, no significant difference in this genotype distribution or in this allele frequency between the patients and the control subjects was observed. No significant difference in the haplotype frequencies between the patients with chronic hepatitis B and HBV natural clearance individuals was displayed. CONCLUSION: The data suggest that genotype AA and the allele A of the IL-18 at position rs1946518 are closely associated with the resistance to chronic hepatitis B and may be the dangerous gene. However, no statistical association was found between polymorphisms of rs574424 for IL-18 and hepatitis B.

No association between IRF3 polymorphism and susceptibility to hepatitis B virus infection in Chinese patients

AIM:To investigate the association between three tag single nucleotide polymorphisms (tagSNPs) in inter-feron regulatory factors (IRF3) and the genetic suscep-tibility to chronic hepatitis B virus (HBV) infection.METHODS:We performed a case-control study of 985 Chinese cases of chronic HBV infection and 294 self-limiting HBV-infected individuals as controls.Three tagSNPs in IRF3 (rs10415576,rs2304204,rs2304206) were genotyped with the Multiplex SNaPshot technique.The genotype and allele frequencies were calculatedand analyzed.RESULTS:The three SNPs showed no significant geno-type/allele associations with chronic HBV infection.Overall allele P values were:rs10415576,P=0.0908,odds ratio (OR) [95% confidence interval (CI)]=1.1798 (0.9740-1.4291);rs2304204,P=0.5959,OR (95% CI)=1.0597 (0.8552-1.3133);rs2304206,P=0.8372,OR (95% CI)=1.0250 (0.8097-1.2976).Overall genotype P values were:rs10415576,P=0.2106;rs2304204,P=0.8458;rs2304206,P=0.8315.There were no statisti-cally significant differences between patients with chron-ic HBV infection and controls.Haplotypes generated by these three SNPs were also not significantly different between the two groups.CONCLUSION:The three tagSNPs of IRF3 are not asso-ciated with HBV infection in the Han Chinese population.

Current progress and questions in germline genetics of prostate cancer

Dramatic progress has been made in the area of germline genetics of prostate cancer(PCa)in the past decade.Both common and rare genetic variants with effects on risk ranging from barely detectable to outright practice-changing have been identified.For men with high risk PCa,the application of genetic testing for inherited pathogenic mutations is becoming standard of care.A major question exists about which additional populations of men to test,as men at all risk levels can potentially benefit by knowing their unique genetic profile of germline susceptibility variants.This article will provide a brief overview of some current issues in understanding inherited susceptibility for PCa.

Association of genetic polymorphisms of GSTM1 and smoking status with lung cancer risk

Objective Long-term cigarette smoke exposure damages the airway epithelium.However,the correlation among GSTM1 gene polymorphism,smoking status,and lung cancer susceptibility remains unclear.This study aimed to identify the genetic polymorphism of GSTM1 and examine the association of GSTM1 polymorphism and smoking history with lung cancer susceptibility.Methods The genetic polymorphism of GSTM1 was genotyped by polymerase chain reaction(PCR) in 217 lung cancer patients and 198 controls.The demographic data and smoking history of the patients were collected.The age,sex,and residence of the two groups were also obtained.Results Significant differences in GSTM1 polymorphism were observed between the case and control groups(P=0.024).Smoking time and smoking index were significantly different between the case and control groups.With the increase in smoking time and smoking index,the differences became more obvious.There was a synergistic effect between GSTM1 and smoking(S=3.35).The risk of developing lung cancer increased 4.82 fold in smokers carrying deficient-type GSTM1.Compared with patients carrying wild-type GSTM1,the risk of developing lung cancer was higher in those carrying deficient-type GSTM1 with the increase in smoking time and smoking index.In different pathological types,no significant differences were observed in GSTM1 polymorphism.In different pathological types,the proportions of patients increased with the increase in smoking time and smoking index,especially the proportion of patients with squamous cell carcinoma.Compared with wild-type GSTM1,the proportion of patients with deficient-type GSTM1 increased with the increase in smoking time and smoking index(P=0.003 and 0.017).This trend was mainly observed in those with squamous cell carcinoma.Conclusion GSTM1 mutation is associated with lung cancer susceptibility.Smokers carrying deficienttype GSTM1 are more likely to develop lung cancer.Compared with patients carrying wild-type GSTM1,smokers with deficient-type GSTM1 are more likely develop lung cancer when smoking time is more than 30 years and smoking index is more than 400.In patients carrying deficient-type GSTM1,the risk of developing squamous cell carcinoma increases with an increase in smoking time and smoking dose.

Genetic variants in the Hedgehog signaling pathway genes are associated with gastric cancer risk in a Chinese Han population

The Hedgehog signaling pathway participates in the occurrence and progression of cancers including gastric cancer.We conducted this study to evaluate whether genetic variants in the Hedgehog signaling pathway genes would affect gastric cancer risk.Multi-marker Analysis of GenoMic Annotation(MAGMA)was used to investigate the aggregated genetic effects of single nucleotide polymorphisms(SNPs)assigned to candidate genes.The relationship between SNPs and gastric cancer risk was estimated by multivariate logistic regression analyses.Gene expression was calculated using databases obtained from The Cancer Genome Atlas(TCGA)and The Gene Expression Omnibus(GEO).Kaplan‐Meier plotter was used to evaluate the association between gene expression with gastric cancer survival.Tumor Immune Estimation Resource 2.0(TIMER 2.0)was applied to determine the correlation between selected gene expression and the immune cell infiltration degree.We identified that the G allele of rs2990912 in KIF27 was associated with higher gastric cancer risk,especially in the young and male subgroups.The expression of KIF27 in gastric cancer tissues was higher than that in normal tissues,leading to poor survival in gastric cancer patients.Besides,KIF27 expression was related to immune cell infiltration and positively correlated with PD-L1 expression.Our findings highlight the key role of genetic variation in the Hedgehog signaling pathway genes in gastric cancer susceptibility,which may provide important insights into the diagnosis,prognosis,and treatment of gastric cancer.