The Genetic Epidemiology of Lung Cancer-What have we learned?

With the completion of the Human Genome Project new opportunities have been arisen to more fully characterize the genomic factor contributing to human susceptibility to chemical and pharmacological toxicity. Over 6 million single nucleotide polymorphisms（SNPs） have been identified and cataloged in public databases. Research efforts are now underway to identify which SNPs are associated with variation in disease risk, chemical sensitivity, drug toxicity, as well as drug responsiveness.

Evaluating genetic insights into ulcerative colitis and anxiety:Limitations and future directions

We reviewed the study by He et al,which investigates the genetic correlation between ulcerative colitis(UC)and anxiety using bidirectional Mendelian rando-mization.This study reveals a genetic link between UC and anxiety,diverging from prior research associating higher anxiety with Crohn’s disease.While the study's use of large-scale genome-wide association studies data is commendable,it faces limitations such as single nucleotide polymorphism selection biases,lack of multiple testing corrections,and a reliance on European populations.Future research should address these limitations,incorporate diverse populations,and explore psychotherapeutic interventions to improve UC management and patient outcomes.

The Impact of Lipid-metabolizing Genetic Polymorphisms on Body Mass Index and Their Interactions with Soybean Food Intake: A Study in a Chinese Population

Objective To evaluate the association of known polymorphisms in the lipid metabolic pathway with body mass index （BMI）, and estimate their interactions with soybean food intake. Methods A community-based cross-sectional survey was conducted in a Chinese Han population. BMI, soybean food intake, and single nucleotide polymorphisms of rs599839, rs3846662, rs3846663, rs12916, rs174547, rs174570, rs4938303, and rs1558861 were measured in 944 subjects. A multivariate logistic regression was used to analyze the association of the studied polymorphisms with BMIs. The expectation-maximization algorithm was employed to evaluate the extent of linkage disequilibrium between pairwise polymorphisms. The gene-environment interaction was assessed in the general multifactor dimensionality reduction model. Results The polymorphisms of rs3846662 and rs3846663 were associated with 10% highest BMIs when comparing to the 10% lowest values both in individuals and haplotype-based association tests. Although no statistically significant gene-environment interactions were found, people with the haplotype composed of C allele in rs3846662 and T allele in rs3846663 and low frequency of soybean intake had significantly hisher risk to overweight and obesity as compared with those with the haplotype consisting of T allele in rs3846662 and C allele in rs3846663 and highly frequent soybean food intake, with an odds ratio of 1.64 （95% confidence interval： 1.15-2.34, P〈0.01） after adjusting for the common confounders. Conclusion Our study has sugsested that rs3846662 and rs3846663 may be the potential candidate polymorphisms for obesity, and their effect on the pathogenesis could be mediated by the frequency of soybean food intake.

The genetic load for hereditary hearing impairment in Chinese population and its clinical implication

Objective To understand the genetic load in the Chinese population for improvement in diagnosis, prevention and rehabilitation of deafness. Methods DNA samples, immortalized cell lines as well as detailed clinical and audiometric data were collected through a national genetic resources collecting network. Two conventional genetic approaches were used in the studies. Linkage analysis in X chromosome and autosomes with microsatellite markers were performed in large families for gene mapping and positional cloning of novel genes. Candidate gene approach was used for screening the mtDNA 12SrRNA, GJB2 and SLC26A4 mutations in population -based samples. Results A total of 2,572 Chinese hearing loss families or sporadic cases were characterized in the reported studies, including seven X-linked, one Y-linked, 28 large and multiplex autosomal dominant hearing loss families, 607 simplex autosomal recessive hereditary hearing loss families, 100 mitochondrial inheritance families, 147 GJB2 induced hearing loss cases, 230 cases with enlarged vestibular aqueduct (EVA) syndrome, 169 sporadic cases with auditory neuropathy, and 1,283 sporadic sensorineural hearing loss cases. Through linkage analysis or sequence analysis, two X-linked families were found transmitting two novel mutations in the POU3F4 gene, while another X -linked family was mapped onto a novel locus, nominated as AUNX1 (auditory neuropathy, X-linked locus 1). The only Y-linked family was mapped onto the DFNY1 locus(Y-linked locus 1, DFNY1). Eight of the 28 autosomal dominant families were linked to various autosomal loci. In population genetics studies, 2,567 familial cases and sporadic patients were subjected to mutation screening for three common hearing loss genes: mtDNA 12S rRNA 1555G, GJB2 and SLC26A4. The auditory neuropathy cases in our samples were screened for OTOF gene mutations. Conclusions These data show that the Chinese population has a genetic load on hereditary hearing loss. Establishing personalized surveillance and prevention models for hearing loss based on genetic research will provide the opportunity to decrease the prevalence of deafness in the Chinese population.

Assessment of causal effects of physical activity on neurodegenerative diseases:A Mendelian randomization study

Background:Physical activity has been hypothesized to play a protective role in neurodegenerative diseases.However,effect estimates previously derived from observational studies were prone to confounding or reverse causation.Methods:We performed a two-sample Mendelian randomization(MR)analysis to explore the causal association of accelerometer-measured physical activity with 3 common neurodegenerative diseases:Alzheimer’s disease(AD),Parkinson’s disease(PD),and amyotrophic lateral sclerosis(ALS).We selected genetic instrumental variants reaching genome-wide significance(p<5×10^(-8))from 2 largest meta-analyses of about 91,100 UK Biobank participants.Summary statistics for AD,PD,and ALS were retrieved from the up-to-date studies in European ancestry led by the international consortia.The random-effect,inverse-variance weighted MR was employed as the primary method,while MR pleiotropy residual sum and outlier(MR-PRESSO),weighted median,and MR-Egger were implemented as sensitivity tests.All statistical analyses were performed using the R programming language(Version 3.6.1;R Foundation for Statistical Computing,Vienna,Austria).Results:Primary MR analysis and replication analysis utilized 5 and 8 instrumental variables,which explained 0.2%and 0.4%variance in physical activity,respectively.In each set,one variant at 17q21 was significantly associated with PD,and MR sensitivity analyses indicated them it as an outlier and source of heterogeneity and pleiotropy.Primary results with the removal of outlier variants suggested odds ratios(ORs)of neurodegenerative diseases per unit increase in objectively measured physical activity were 1.52 for AD(95%confidence interval(95%CI):0.88-2.63,p=0.13)and 3.35 for PD(95%CI:1.32-8.48,p=0.01),while inconsistent results were shown in the replication set for AD(OR=1.06,95%CI:1.01-1.12,p=0.02)and PD(OR=0.99,95%CI:0.88-0.12,p=0.97).Similarly,the beneficial effect of physical activity on ALS(OR=0.51,95%CI:0.29-0.91,p=0.02)was not confirmed in the replication analysis(OR=0.96,95%CI:0.91-1.02,p=0.22).Conclusion:Genetically predicted physical activity was not robustly associated with risk of neurodegenerative disorders.Triangulating evidence across other studies is necessary in order to elucidate whether enhancing physical activity is an effective approach in preventing the onset of AD,PD,or ALS.

Genetic epidemiological survey of esophageal cancer in one-tenth of the population of Yangquan city

To understand the role of genetic factors in the occurrence of esophageal cancer (EC) Methods A genetic epidemiological survey of 132?039 subjects, one tenth of the whole population of Yangquan city, Shanxi Province in Northern China, was conducted in 1994 A total of 228 families with at least one newly occurring EC patient in each family were matched with equal number of control families for a 1∶1 case control study Results The heritability of esophageal cancer among first degree relatives was 52 6%, that among second degree relatives was 31 2%, and the weighted average heritability was 49 2% The segregation ratio was 0 176±0 033, significantly less than 0 25, suggesting a multifactorial inheritance or decreased penetrance of a major locus EC patients in families did not fit the binominal distribution, suggesting evidently familial aggregation The relative risks among the first degree relatives were 10 49 for males, 7 69 for females, and 9 17 for combined data The attributive risks among first degree relatives were 62 13/100?000 for males, 99 94/100?000 for females and 75 15/100?000 for combined data All of these figures were higher than 40 17/100?000, the average of general population of the city Conclusion Genetic factors play an important role in the pathogenesis of esophageal cancer in this area

A common variation within the STEAP4 gene exons is associated with obesity in Uygur general population

Background Coordinated regulation of nutrient and inflammatory responses by six transmembrane epithelial antigen of prostate 4 （STEAP4） was essential for metabolic homeostasis. STEAP4 expression in human white adipose tissuewas associated with obesity. This study aimed to evaluate association between STEAP4 genetic polymorphisms and obesity in Uygur Chinese general population.Methods The functional regions of STEAP4 gene were sequenced in 96 Uygur with obesity （body mass index （BMI）〉30 kg/m2）. Representative variations were selected according to the function and linkage disequilibrium and genotyped in 1507 obesity （BMI ≥25 kg/m2） and 825 non-obesity control （BMI ＜25 kg/m2）, all of whom were selected from epidemiology study of obesity-related diseases during January to February 2007 among Uygur population in Hetian area of Xinjiang Uygur Autonomous Region.Results Fourteen novel and 6 known single nucleotide polymorphism （SNPs）, including 2 nonsynonymous SNPs （nsSNPs）, in the STEAP4 gene were identified. Of the 3 representative SNPs, the nsSNP rs1981529 （Gly75Asp, 224A/G）was significantly associated with obesity phenotype （additive P/Pc=0.001/0.006, dominant P/Pc=0.003/0.018, odds ratio （OR） and 95％ confidence interval （CI） adjusted for age, gender and drinking 0.755 （0.641-0.890） and 0.750（0.621-0.907）, respectively）. By the multiple linear regression analysis, the quantitative phenotypes of BMI （P/Pc=0.002/0.004） and waist circumference （P/Pc=0.004/0.008） were found to be significantly associated with the genotypes of rs1981529 （Gly75Asp, 224A/G） in Uygur general population, and effect size （beta value） of one allele G of rs1981529 （Gly75Asp, 224A/G） was-0.553 kg/m2 for BMI and -1.311 cm for waist circumference after controlling age,gender and drinking factors.Conclusions The present study shows an association of the common variation rs1981529 （Gly75Asp, 224A/G） in the STEAP4 gene with obesity in Uygur general population. Further studies should replicate the results using larger populations.

Population-based frequency of surfactant dysfunction mutations in a native Chinese cohort

Background: Rare mutations in surfactant-associatedgenes contribute to neonatal respiratory distress syndrome.The frequency of mutations in these genes in the Chinesepopulation is unknown.Methods: We obtained blood spots from the GuangxiNeonatal Screening Center in Nanning, China thatincluded Han (n=443) and Zhuang (n=313) ethnic groups.We resequenced all exons of the surfactant proteins-B(SFTPB), -C (SFTPC), and the ATP-binding cassettemember A3 (ABCA3) genes and compared the frequenciesof 5 common and all rare variants.Results: We found minor differences in thefrequencies of the common variants in the Han andZhuang cohorts. We did not find any rare mutations inSFTPB or SFTPC, but we found three ABCA3 mutationsin the Han [minor allele frequency (MAF)=0.003] and 7 inthe Zhuang (MAF=0.011) cohorts (P=0.10). The ABCA3mutations were unique to each cohort;five were novel.The collapsed carrier rate of rare ABCA3 mutations inthe Han and Zhuang populations combined was 1.3%,which is signifi cantly lower than that in the United States(P<0.001).Conclusions: The population-based frequency ofmutations in ABCA3 in south China newborns is signifi cantlylower than that in United States. The contribution of theserare ABCA3 mutations to disease burden in the south Chinapopulation is still unknown.

From 30 million to zero malaria cases in China: lessons learned for China-Africa collaboration in malaria elimination

Malaria was once one of the most serious public health problems in China,with more than 30 million malaria cases annually before 1949.However,the disease burden has sharply declined and the epidemic areas has shrunken after the implementation of an integrated malaria control and elimination strategy,especially since 2000.Till now,China has successfully scaled up its efforts to become malaria-free and is currently being evaluated for malaria-free certification by the WHO.In the battle against malaria,China's efforts have spanned generations,reducing from an incidence high of 122.9/10000(6.97 million cases)in 1954 to 0.06/10000(7855 cases)in 2010.In 2017,for the first time,China reached zero indigenous case of malaria,putting the country on track to record three consecutive years of zero transmission by 2020,accoding to the National Malaria Elimination Action Plan(2010-2020).China's efforts to eliminate malaria is impressive,and the country is dedicated to sharing its lessons learned in malaria elimination-including,but not limited to,the application of novel genetics-based approaches-with other nations through new initiatives.China will promote international relationships and establish collaborative platforms on a wide range of topics in roughly 65 countries,including 20 African nations.China's experience in applying innovative genetics-based approaches and tools to characterize malaria parasite populations,including surveillance of markers related to drug resistance,categorization of cases as indigenous or imported,and objective identification of the likely sources of infections to inform efforts towards malaria control and elimination in Africa could offer game-changing results when applied to settings with ongoing transmission.