The single nucleotide polymorphism rs1814521 in long non-coding RNA ADGRG3 associates with the susceptibility to silicosis: a multi-stage study

BACKGROUND@#This study aimed to evaluate the correlation between long non-coding RNA (lncRNA)-related single nucleotide polymorphisms (SNPs) and susceptibility to silicosis.@*METHODS@#First, RNA-sequencing (RNA-seq) data were comprehensively analyzed in the peripheral blood lymphocytes of eight participants (four silicosis cases and four healthy controls) exposed to silica dust to identify differentially expressed lncRNAs (DE-lncRNAs). The functional SNPs in the identified DE-lncRNAs were then identified using several databases. Finally, the association between functional SNPs and susceptibility to silicosis was evaluated by a two-stage case-control study. The SNPs of 155 silicosis cases and 141 healthy silica-exposed controls were screened by genome-wide association study (GWAS), and the candidate SNPs of 194 silicosis cases and 235 healthy silica-exposed controls were validated by genotyping using the improved Mutiligase Detection Reaction (iMLDR) system.@*RESULTS@#A total of 76 DE-lncRNAs were identified by RNA-seq data analysis (cut-offs: fold change > 2 or fold change < 0.5, P < 0.05), while 127 functional SNPs among those 76 DE-lncRNAs were identified through multiple public databases. Furthermore, five SNPs were found to be significantly correlated with the risk of silicosis by GWAS screening (P < 0.05), while the results of GWAS and iMLDR validation indicated that the variant A allele of rs1814521 was associated with a reduced risk of silicosis (OR = 0.76, 95% CI = 0.62-0.94, P = 0.011).@*CONCLUSION@#The presence of the SNP rs1814521 in the lncRNA ADGRG3 is associated with susceptibility to silicosis. Moreover, ADGRG3 was found to be lowly expressed in silicosis cases. The underlying biological mechanisms by which lncRNA ADGRG3 and rs1814521 regulate the development of silicosis need further study.

Current status and progress of precision nutritional weight management guided by single nucleotide polymorphism / 中华预防医学杂志

The incidence of obesity in our country is increasing year by year. Diet and lifestyle interventions are the most commonly used weight loss measures, but their intervention effects are affected by individual genetics, environment and other factors. Genome-wide association analysis has found many SNPs related to weight loss, and explored the interaction between these loci and diet, intestinal flora and other environmental factors. This article summarizes the study of single nucleotide polymorphisms, the analysis of gene-environment interactions related to diet interventions for weight loss, and the multi-loci analysis and prediction models such as genetic risk scores and machine learning modeling in weight loss, which provides reference for the further application and development of the precise nutrition in medical weight loss.

Phagocytosis of microglia in neurodegenerative diseases / 生理学报

With the acceleration of the aging society, neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), have become a rapidly growing global health crisis. Recent studies have indicated that microglia-neuron interactions are critical for maintaining homeostasis of the central nervous system. Genome-Wide Association Studies and brain imaging studies have suggested that microglia are activated in early stage of neurodegenerative diseases. Microglia are specialized phagocytes in the brain. The discovery of a new phagocytic pathway, trogocytosis, suggests that there is a close interaction between microglia and surviving neurons. In this review, we summarize the important roles of microglia in neurodegenerative diseases, and further analyze the functions and molecular mechanisms of microglia phagocytosis and trogocytosis.

Interaction between ischemic stroke risk loci identified by genome-wide association studies and sleep habits / 北京大学学报(医学版)

OBJECTIVE@#To explore the relationship between sleep habits (sleep duration, sleep efficiency, sleep onset timing) and ischemic stroke, and whether there is an interaction between sleep habits and ischemic stroke susceptibility gene loci.@*METHODS@#A questionnaire survey, physical examination, blood biochemical testing and genotyping were conducted among rural residents in Beijing, and the gene loci of ischemic stroke suggested by previous genome-wide association studies (GWAS) were screened. Multivariable generalized linear model was used to analyze the correlation between sleep habits, sleep-gene interaction and ischemic stroke.@*RESULTS@#A total of 4 648 subjects with an average age of (58.5±8.7) years were enrolled, including 1 316 patients with ischemic stroke. Compared with non-stroke patients, stroke patients with sleep duration ≥9 hours, sleep efficiency < 80%, and sleep onset timing earlier than 22:00 accounted for a higher proportion (P < 0.05). There was no significant association between sleep duration and risk of ischemic stroke (OR=1.04, 95%CI: 0.99-1.10, P=0.085). Sleep efficiency was inversely associated with the risk of ischemic stroke (OR=0.18, 95%CI: 0.06-0.53, P=0.002). The risk of ischemic stroke in the subjects with sleep efficiency < 80% was 1.47-fold (95%CI: 1.03-2.10, P=0.033) of that in the subjects with sleep efficiency ≥80%. Falling asleep earlier than 22:00 was associated with 1.26 times greater risk of stroke than falling asleep between 22:00 and 22:59 (95%CI: 1.04-1.52, P=0.017). Multifactorial adjustment model showed that rs579459 on ABO gene had an interaction with sleep time (P for interaction =0.040). When there were two T alleles for rs579459 on the ABO gene, those who fell asleep before 22:00 had 1.56 times (95%CI: 1.20-2.04, P=0.001) the risk of stroke compared with those who fell asleep between 22:00 and 22:59, and there was no significant difference when the number of pathogenic alleles was 0 or 1. In the model adjusted only for gender, age and family structure, sleep duration and the number of T allele rs2634074 on PITX2 gene had an interaction with ischemic stroke (P for interaction=0.033).@*CONCLUSION@#Decreased sleep efficiency is associated with increased risk of ischemic stroke, and falling asleep earlier than 22:00 is associated with higher risk of ischemic stroke. Sleep onset timing interacted with rs579459 in ABO gene and the risk of ischemic stroke. Sleep duration and PITX2 rs2634074 may have a potential interaction with ischemic stroke risk.

Association study between haplotypes of WNT signaling pathway genes and nonsyndromic oral clefts among Chinese Han populations / 北京大学学报(医学版)

OBJECTIVE@#To explore whether WNT signaling pathway genes were associated with non-syndromic oral clefts (NSOC) based on haplotypes analyses among 1 008 Chinese NSOC case-parent trios.@*METHODS@#The genome-wide association study (GWAS) data of 806 Chinese non-syndromic cleft lip with or without cleft palate (NSCL/P) trios and 202 Chinese non-syndromic cleft palate (NSCP) case-parent trios were drawn from the International Consortium to Identify Genes and Interactions Controlling Oral Clefts (ICOCs) study GWAS data set, whose Chinese study population were recruited from four provinces in China, namely Taiwan, Shandong, Hubei, and Sichuan provinces. The process of DNA genotyping was conducted by the Center for Inherited Disease Research in the Johns Hopkins University, using Illumina Human610-Quad v.1_B Bead Chip. The method of sliding windows was used to determine the haplotypes for analyses, including 2 SNPs haplotypes and 3 SNPs haplotypes. Haplotypes with a frequency lower than 1% were excluded for further analyses. To further assess the association between haplotypes and NSOC risks, and the transmission disequilibrium test (TDT) was performed. The Bonferroni method was adopted to correct multiple tests in the study, with which the threshold of statistical significance level was set as P < 0.05 divided by the number of tests, e.g P < 3.47×10-4 in the current stu-dy. All the statistical analyses were performed by using plink (v1.07).@*RESULTS@#After quality control, a total of 144 single nucleotide polymorphisms (SNPs) mapped in seven genes in WNT signaling pathway were included for the analyses among the 806 Chinese NSCL/P trios and 202 Chinese NSCP trios. A total of 1 042 haplotypes with frequency higher than 1% were included for NSCL/P analyses and another 1 057 haplotypes with frequency higher than 1% were included for NSCP analyses. Results from the TDT analyses showed that a total of 69 haplotypes were nominally associated with the NSCL/P risk among Chinese (P < 0.05). Another 34 haplotypes showed nominal significant association with the NSCP risk among Chinese (P < 0.05). However, none of these haplotypes reached pre-defined statistical significance level after Bonferroni correction (P>3.47×10-4).@*CONCLUSION@#This study failed to observe any statistically significant associations between haplotypes of seven WNT signaling pathway genes and the risk of NSOC among Chinese. Further studies are warranted to replicate the findings here.

Exploring the association between de novo mutations and non-syndromic cleft lip with or without palate based on whole exome sequencing of case-parent trios / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design.@*METHODS@#Whole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database.@*RESULTS@#A total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes.@*CONCLUSION@#Our study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.

The risk of nonsyndromic cleft lip with or without cleft palate and Vax1 rs7078160 polymorphisms in southern Han Chinese / Risco de fenda labial não sindrômica com ou sem fenda palatina e polimorfismo Vax1 rs7078160 em indivíduos da etnia Han do sul da China

Abstract Introduction: Non-syndromic cleft lip with or without cleft palate is a common worldwide birth defect due to a combination of environmental and genetic factors. Genome-wide association studies reported the rs7078160 of Vax1 is closely related to non-syndromic cleft lip with or without cleft palate in European populations. The following studies showed the same results in Mongolian, Japanese, Filipino, Vietnamese populations etc. However, conflicting research had been reported in Chinese population, Objective: The aim of this study was to investigate the association between the rs7078160 polymorphism and non-syndromic cleft lip with or without cleft palate in Southern Chinese patients. Methods: In this study, we investigated the polymorphism distribution of rs7078160 in 100 complete patient trios (39 patients with non-syndromic cleft lip and palate; 36 patients with non-syndromic cleft lip only; 25 had non-syndromic cleft palate only; and their parents) from Southern ethnic Han Chinese. 60 healthy trios were selected as control. Polymerase chain reaction and Sanger sequencing were used to genotype rs7078160 in Vax1; both case-control and family-based associations were analyzed. Results: The case-control analyses revealed the rs7078160 polymorphism was significant, associated with non-syndromic cleft lip with or without cleft palate (p = 0.04) and non-syndromic cleft lip and palate (p = 0.01), but not associated with non-syndromic cleft lip only and nonsyndromic cleft palate only patients. The genotype composition of rs7078160 comprises mutated homozygous AA, heterozygous AG and wild homozygous GG. Cases with AG + AA genotypes compared with GG homozygotes showed an increased risk of non-syndromic cleft lip with or without cleft palate (p = 0.04, OR = 2.05, 95% CI: 1.01-4.16) and non-syndromic cleft lip and palate (p = 0.01, OR = 3.94, 95% CI: 1.34-11.54). In addition, we did not detect any transmissiondisequilibrium in rs7078160 (p = 0.68). Conclusion: This study suggests that rs7078160 polymorphism is a risk factor of non-syndromic cleft lip with or without cleft palate, and Vax1 is strongly associated with non-syndromic cleft lip with or without cleft palate in Southern Chinese Han populations.

Resumo Introdução: A fenda labial não sindrômica, com ou sem fenda palatina, é um defeito congênito comum em todo o mundo, devido a uma combinação de fatores ambientais e genéticos. O genome-wide association studies relatou que o polimorfismo rs7078160 do Vax1 está intimamente relacionado à fenda labial não sindrômica, com ou sem fenda palatina em populações europeias. Estudos subsequentes mostraram os mesmos resultados nas populações mongol, japonesa, filipina e vietnamita etc. No entanto, pesquisas conflitantes foram relatadas na população chinesa. Objetivo: Investigar a associação entre o polimorfismo rs7078160 e fenda labial não sindrômica, com ou sem fenda palatina, em pacientes do sul da China. Método: Tentamos investigar a distribuição do polimorfismo rs7078160 em 100 trios completos de pacientes (39 pacientes com fenda labial e palatina não sindrômica; 36 pacientes com fenda labial somente, não sindrômica; 25 com fenda palatina somente, não sindrômica e seus pais), da etnia Han do sul da China, e em 60 trios saudáveis selecionados como controle. Reação de polimerase em cadeia e o sequenciamento de Sanger foram uszados para genotipar o polimorfismo rs7078160 do Vax1 e tanto os casos-controle quanto as associações baseadas na família foram analisadas. Resultados: As análises de caso-controle revelaram que o polimorfismo rs7078160 estava significativamente associado a fenda labial não sindrômica, com ou sem fenda palatina (p = 0,04) e fenda labial e palatina não sindrômica (p = 0,01), mas não estava associado a pacientes com fenda labial somente não sindrômica e fenda palatina somente não sindrômica. A composição do genótipo de rs7078160 compreende AA homozigoto mutado, AG heterozigoto e GG homozigoto selvagem. Casos com genótipos AG + AA comparados com GG homozigotos mostraram um risco aumentado de fenda labial não sindrômica, com ou sem fenda palatina (p = 0,04, OR = 2,05, IC de 95%: 1,01 ± 4,16) e fenda labial e palatina não sindrômica (p = 0,01, OR = 3,94, IC 95%: 1,34-11,54). Além disso, não detectamos desequilíbrio de transmissão em rs7078160 (p = 0,68). Conclusão: Este estudo sugere que o polimorfismo rs7078160 foi um fator de risco para fenda labial não sindrômica, com ou sem fenda palatina, e o gene Vax1 está fortemente associado com fenda labial não sindrômica, com ou sem fenda palatina em populações da etnia Han do sul da China.

Susceptibilidad genética y enfermedad autoinmune reumática: Revisión narrativa / Genetic susceptibility and autoimmune rheumatic disease: Narrative review

La autoinmunidad es la consecuencia de la pérdida de control y regulación de la respuesta inmune. Se re-porta que ocurre entre 5 y 9% de patologías a nivel mundial. A las enfermedades con esta anomalía se les denomina autoinmunes y se clasifican de acuerdo con el órgano o sistema afectado. Las reumáticas involucran al tejido conectivo y las articulaciones. Los factores asociados a su aparición incluyen: edad, género, medioam-biente y genéticos. La susceptibilidad genética indica la presencia de uno o varios genes asociados al desarrollo de determinada enfermedad, cuya expresión podría ser el producto de la migración, selección, recombinación y adaptación de genes entre las poblaciones, lo que explica la variación fenotípica y la expresión clínica resultan-te. Los estudios de asociación del genoma completo (GWAS por sus siglas en inglés) han permitido identificar múltiples genes involucrados con enfermedades reumáticas, destacan el lupus eritematoso sistémico y artritis reumatoide, asociadas con más de 60 alelos, y otras como la espondilitis anquilosante, en donde la asociación ha sido primordialmente con un gen y sus polimorfismos. Esta revisión tiene como objetivo informar el estado de la susceptibilidad determinada genéticamente para estas enfermedades y el impacto que tiene sobre la expresión clínica. Se realizó una búsqueda en PubMed y la base de datos de la biblioteca Cochrane, se incluyeron artículos relacionados con las palabras clave propuestas desde el 2000. La revisión identifica genes y la asociación con estas enfermedades, expone la diversidad existente y justifica continuar la búsqueda de genes en todas las poblaciones.

Autoimmunity is the consequence of the loss of control and regulation of the immune response. It is reported that between 5 and 9% of pathologies occur worldwide. Diseases with this abnormality are called autoimmune and are classified according to the organ or system affected. Rheumatic diseases involve connective tissue and joints. Factors associated with its appearance include age, gender, environment, and genetics. Genetic suscepti-bility indicates the presence of one or more genes associated with the development of a certain disease, whose expression could be the product of migration, selection, recombination and adaptation of genes between popu-lations, which explains the phenotypic variation and the resulting clinical expression. Genome wide association studies (GWAS) have allowed the identification of multiple genes involved with rheumatic diseases, including systemic lupus erythematosus and rheumatoid arthritis, associated with more than 60 alleles, and others such as ankylosing spondylitis, where the association has been primarily with a gene and its polymorphisms. This review aims to report the status of genetically determined susceptibility to these diseases and the impact it has on clinical expression. A search was carried out in PubMed and the Cochrane library database, articles related to the proposed keywords from the year 2000 were included. The review identifies genes and the association with these diseases, exposes the existing diversity and justifies continuing the search for genes in all populations.

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma / 医学前沿

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Factors relating to bone mineral density in young and middle-aged patients with ankylosing spondylitis / 中华医学杂志(英文版)

BACKGROUND@#Ankylosing spondylitis (AS) is a common chronic progressive rheumatic disease. The aim of this study was to explore factors influencing abnormal bone mineral density (BMD) in young and middle-aged patients with AS.@*METHODS@#From July 2014 to August 2018, hospitalized patients with AS and health examinees in the health examination center of our clinics, ranging in age from 20 to 50 years, were monitored. The BMD of the lumbar spine and femoral neck of AS patients and those of a healthy control group were measured using dual-energy X-ray absorption. The BMDs of AS patients were compared with respect to age, course of disease, iritis, smoking habits, sex, height, weight, body mass index (BMI), medication use, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), platelet volume, platelet count, uric acid (UA), alkaline phosphatase (AKP), and calcium ion levels. Single-nucleotide polymorphisms (SNPs) related to BMD were screened using genome-wide association analysis.@*RESULTS@#There was no statistical difference in the proportion of abnormal bone masses between the different body parts. The BMD of all bones in AS patients was lower than that in healthy controls (P < 0.05). Additionally, BMD was correlated with serum calcium and CRP in AS patients (P < 0.05), but not with age, platelet volume, platelet count, ESR, UA, AKP, height, weight, and BMI. The incidence of abnormal bone mass in AS patients was correlated with sex (P < 0.05), but not with medication use, iritis, or smoking. BMD of the lumbar spine in AS patients did not correlate linearly with the course of the disease, but BMD of the femoral neck correlated linearly with the course of the disease (P < 0.05). BMD was correlated with multiple SNPs in patients with AS. Lumbar BMD was correlated with rs7025373 and rs7848078. Femoral head BMD was correlated with 3:102157365, 3:102157417, rs1252202, rs1681355, rs3891857, rs7842614, and rs9870734, suggesting that genetic factors play a role in BMD in patients with AS.@*CONCLUSIONS@#The proportion of abnormal bone mass in AS patients was higher than that in healthy individuals of the same age. The factors related to BMD in patients with AS are gender, CRP, and blood calcium. The BMD of the femoral neck of AS patients decreases with the course of the disease, but BMD of the lumbar spine is not related to the course of the disease. BMD in AS patients is associated with multiple SNPs.

Genome-wide long non-coding RNA association study on Han Chinese women identifies lncHSAT164 as a novel susceptibility gene for breast cancer / 中华医学杂志(英文版)

BACKGROUND@#Single-nucleotide polymorphisms (SNPs)-associated genes and long non-coding RNAs (lncRNAs) can contribute to human disease. To comprehensively investigate the contribution of lncRNAs to breast cancer, we performed the first genome-wide lncRNA association study on Han Chinese women.@*METHODS@#We designed an lncRNA array containing >800,000 SNPs, which was incorporated into a 96-array plate by Affymetrix (CapitalBio Technology, China). Subsequently, we performed a two-stage genome-wide lncRNA association study on Han Chinese women covering 11,942 individuals (5634 breast cancer patients and 6308 healthy controls). Additionally, in vitro gain or loss of function strategies were performed to clarify the function of a novel SNP-associated gene.@*RESULTS@#We identified a novel breast cancer-associated susceptibility SNP, rs11066150 (Pmeta = 2.34 × 10-8), and a previously reported SNP, rs9397435 (Pmeta = 4.32 × 10-38), in Han Chinese women. rs11066150 is located in NONHSAT164009.1 (lncHSAT164), which is highly expressed in breast cancer tissues and cell lines. lncHSAT164 overexpression promoted colony formation, whereas lncHSAT164 knockdown promoted cell apoptosis and reduced colony formation by regulating the cell cycle.@*CONCLUSIONS@#Based on our lncRNA array, we identified a novel breast cancer-associated lncRNA and found that lncHSAT164 may contribute to breast cancer by regulating the cell cycle. These findings suggest a potential therapeutic target in breast cancer.

Three Novel Blood Group Systems Registered by ISBT in 2019 --Review / 中国实验血液学杂志

There were three new blood group systems including the KANNO blood group system, the Sid blood group system and the CTL2 blood group system (provisional status), have been registered by the International Society of Blood Transfusion (ISBT) registered Science August 2019. The main reason for this update is that the significant SNPs of the KANNO blood group system (rs1800014) and the Sid blood group system (rs7224888) have been found through genome-wide association studies and whole exome sequencing. The new genetic evidences are consistent with the current immunological findings. In addition, although CTL2 antigen has been found on erythrocyte ghost (erythrocyte membrane) since 2017, CTL2 blood group system is still in provisional status due to lack of serological and genetic evidence. In this review, the experimental research advances of these three ISBT blood group systems and discuss the clinical value of the relevant researches was summarized briefly.

Research Status and Hot Trends in Atherosclerosis Genomics between 2010 and 2019 / 中国医学科学院学报

Objective To analyze the research status,hotspots,and frontiers of atherosclerosis genomics from 2010 to 2019.Methods CiteSpace software was used to conduct data statistics and visual analysis on countries,institutions,authors,journals,co-cited papers,and keywords of the related papers published in the Web of Science from 2010 to 2019.Results A total of 1021 papers in English were included,and the annual number of publications generally showed an upward trend.The knowledge base in the research of atherosclerosis mostly focused on the genetic risk sites and biomarkers for coronary artery diseases such as coronary heart disease,myocardial infarction,and dyslipidemia.The related journals mainly involved the fields of molecular biology,biology,genetics,immunology,medicine,pharmacy,and clinical medicine.The latest research in atherosclerosis concentrated on genome-wide association study,DNA methylation,microRNA,messenger RNA and so on.The research frontiers involved long noncoding RNA,DNA methylation,and immune metabolism.Conclusion The studies in atherosclerotic genomics have gradually increased.

Genetic study of cardiovascular disease subtypes defined by International Classification of Diseases / 北京大学学报(医学版)

OBJECTIVE@#To study the molecular connection among cardiovascular diseases (CVD) subtypes defined by the International Classification of Diseases (ICD) version 10 (ICD-10).@*METHODS@#Both phenotypic data and genotypic data used in this study were obtained from the UK Biobank. A total of 380 083 participants aged between 40 and 69 years were included. Those without any cardiovascular disease (either no ICD-10 code at all or no ICD-10 code containing letter I) were assigned to the control group. The five CVD subtypes were: ischaemic heart diseases (IHD), pulmonary heart disease and diseases of pulmonary circulation (PHD), cerebrovascular diseases (CRB), diseases of arteries, arterioles and capillaries (AAC), diseases of veins, lymphatic vessels and lymph nodes, and diseases not elsewhere classified (VLL). We first performed a genome-wide association study (GWAS) for each of the five subtypes. We summarized novel loci using genome-wide significance threshold P=5×10-8. Next, we used linkage disequilibrium score regression (LDSC) method to assess genetic correlation among the five subtypes. Lastly, we applied mendelian randomization (MR) approach to assess the causal relationship among the subtypes. The particular software that we used was generalised summary-data-based mendelian randomisation (GSMR).@*RESULTS@#Through GWAS, we identified hundreds of genome-wide significant SNPs: 672 for IHD, 241 for PHD, 31 for CRB, 48 for AAC, and 193 for VLL. By comparing with published literature, we found 28 novel loci, for PHD (n=14), CRB (n =7) and AAC (n =7). Eight of these 28 loci were rare, where the lead SNP had minor allele frequency (MAF) less than 1%. LDSC analyses indicated IHD had significant genetic correlation with VLL (P=2.52×10-7), PHD (P=3.77×10-3) and AAC (P=4.90×10-3), respectively. Bidrectional GSMR analyses showed that IHD had a positive causal relationship with VLL (P=7.40×10-5) and AAC (P=1.50×10-3), while reverse causality was not supported.@*CONCLUSION@#This study adopted an innovative approach to study the molecular connection among CVD subtypes that are defined by ICD. We identified potentially positive genetic correlation and causal effects among some of these subtypes. Research along this line will provide scientific insights and serve as a guidance for future ICD standards.

Genetic Architecture of Circulating Very-Long-Chain (C24:0 and C22:0) Ceramide Concentrations

OBJECTIVE: Total ceramide concentrations are linked with increased insulin resistance and cardiac dysfunction. However, recent studies have demonstrated that plasma concentrations of specific very-long-chain fatty ceramides (C24:0 and C22:0) are associated with a reduced incidence of coronary heart disease and all-cause mortality. We hypothesized that specific genetic loci are associated with plasma C22:0 and C24:0 concentrations.METHODS: Heritability and genome-wide association studies of plasma C24:0 and C22:0 ceramide concentrations were performed among 2,217 participants in the Framingham Heart Study Offspring Cohort, adjusting for cardiovascular risk factor covariates and cardiovascular drug treatment.RESULTS: The multivariable-adjusted heritability for C22:0 and C24:0 ceramides was 0.42 (standard error [SE], 0.07; p=1.8E-9) and 0.25 (SE, 0.08; p=0.00025), respectively. Nineteen single nucleotide polymorphisms (SNPs), all on chromosome 20, significantly associated with C22:0 concentrations; the closest gene to these variants was SPTLC3. The lead SNP (rs4814175) significantly associated with 3% lower plasma C22:0 concentrations (p=2.83E-11). Nine SNPs, all on chromosome 20 and close to SPTLC3, were significantly associated with C24:0 ceramide concentrations. All 9 were also significantly related to plasma C22:0 levels. The lead SNP (rs168622) was significantly associated with 10% lower plasma C24:0 ceramide concentrations (p=9.94E-09).CONCLUSION: SNPs near the SPTLC3 gene, which encodes serine palmitoyltransferase long chain base subunit 3 (SPTLC3; part of the enzyme that catalyzes the rate-limiting step of de novo sphingolipid synthesis) were associated with plasma C22:0 and C24:0 ceramide concentrations. These results are biologically plausible and suggest that SPTLC3 may be a potential therapeutic target for C24:0 and C22:0 ceramide modulation.

Anemia and insomnia: a cross-sectional study and meta-analysis / 中华医学杂志(英文版)

BACKGROUND@#Several recent genome-wide association studies suggested insomnia and anemia may share some common genetic components. We thus examined whether adults with anemia had higher odds of having insomnia relative to those without anemia in a cross-sectional study and a meta-analysis.@*METHODS@#Included in this cross-sectional study were 12,614 Chinese adults who participated in an ongoing cohort, the Kailuan Study. Anemia was defined as hemoglobin levels below 12.0 g/dL in women and 13.0 g/dL in men. Insomnia was assessed using the Chinese version of the Athens Insomnia Scale (AIS). A total AIS score ≥6 was considered insomnia. The association between anemia and insomnia was assessed using a logistic regression model, adjusting for potential confounders such as age, sex, chronic disease status, and plasma C-reactive protein concentrations. A meta-analysis was conducted using the fixed effects model to pool results from our study and three previously published cross-sectional studies on this topic in adult populations.@*RESULTS@#Individuals with anemia had greater odds of having insomnia (adjusted odds ratio [OR]: 1.32; 95% confidence interval [CI]: 1.03-1.70) compared with individuals without anemia. A significant association persisted after we excluded individuals with chronic inflammation, as suggested by C-reactive protein levels >1 mg/L (adjusted OR: 1.68; 95% CI: 1.22-2.32). The meta-analysis results, including 22,134 participants, also identified a positive association between anemia and insomnia (pooled OR: 1.39; 95% CI: 1.22-1.57).@*CONCLUSIONS@#The presence of anemia was significantly associated with a higher likelihood of having insomnia in adults. Due to the nature of the cross-sectional study design, results should be interpreted with caution.

Matrix Metallopeptidase 3 Polymorphisms: Emerging genetic Markers in Human Breast Cancer Metastasis / 한국유방암학회지

Matrix metallopeptidase 3 or MMP3, is a zinc-dependent proteolytic enzyme that is involved in various physiological processes via modification of the extracellular matrix. In particular, its over-expression has been associated with cancer metastasis and tumor growth in various cancers including breast cancer. MMP3 gene expression is regulated by several factors such as DNA polymorphisms which also serve as risk factors for breast cancer. As such, DNA polymorphisms of MMP3 have the potential to be utilized as genetic biomarkers for prediction and prognosis of metastatic breast cancer. Presently, genome-wide association studies of MMP3 gene polymorphisms which are associated with breast cancer risk and patient survival in a variety of populations are reviewed. In order to understand the potential role of MMP3 polymorphisms as genetic markers for breast cancer metastasis, the domain structure of MMP3, the regulation of its expression and its role in breast cancer metastasis are also briefly discussed in this review. The emergence of MMP3 gene polymorphisms as prognostic biomarker candidates for breast cancer metastasis may contribute towards improving targeted therapies and categorization of breast cancer cases in order to provide a better and more accurate prognosis.

Evaluating the effect of WNT pathway genes considering interactions on the risk of non-syndromic oral clefts among Chinese populations / 北京大学学报(医学版)

OBJECTIVE@#In this study, we used genome-wide association study (GWAS) data to explore whether WNT pathway genes were associated with non-syndromic oral clefts (NSOC) considering gene-gene interaction and gene-environment interaction.@*METHODS@#We conducted the analysis using 806 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios and 202 non-syndromic cleft palate (NSCP) case-parent trios among Chinese populations selected from an international consortium established for a GWAS of non-syndromic oral clefts. Genotype data and maternal environmental exposures were collected through DNA samples and questionnaires. Conditional Logistic regression models were adopted to explore gene-gene interaction and gene-environment in teraction using trio package in R software. The threshold of significance level was set as 3.47×10-4 using Bonferroni correction.@*RESULTS@#A total of 144 single nucleotide polymorphisms (SNPs) in seven genes passed the quality control process in NSCL/P trios and NSCP trios, respectively. Totally six pairs of SNPs interactions showed statistically significant SNP-SNP interaction (P < 3.47×10-4) after Bonferroni correction, which were rs7618735 (WNT5A) and rs10848543 (WNT5B), rs631948 (WNT11) and rs556874 (WNT5A), and rs631948 (WNT11) and rs472631 (WNT5A) among NSCL/P trios; rs589149 (WNT11) and rs4765834 (WNT5B), rs1402704 (WNT11) and rs358792 (WNT5A), and rs1402704 (WNT11) and rs358793 (WNT5A) among NSCP trios, respectively. In addition, no significant result was found for gene-environment interaction analysis in both of the NSCL/P trios and NSCP trios.@*CONCLUSION@#Though this study failed to detect significant association based on gene-environment interactions of seven WNT pathway genes and the risk of NSOC, WNT pathway genes may influence the risk of NSOC through potential gene-gene interaction.

Exploring parent-of-origin effects for non-syndromic cleft lip with or without cleft palate on PTCH1, PTCH2, SHH, SMO genes in Chinese case-parent trios / 北京大学学报(医学版)

OBJECTIVE@#Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect, affecting 1.4 per 1 000 live births, and multiple genetic and environmental risk factors influencing its risk. All the known genetic risk factors accounted for a small proportion of the heritability. Several authors have suggested parent-of-origin effects (PoO) may play an important role in the etiology of this complex and heterogeneous malformation. To clarify the genetic association between PTCH1, PTCH2, SHH and SMO in hedgehog (HH) pathway and NSCL/P, as well as testing for potential PoO effects in Chinese case-parent trios.@*METHODS@#We tested for transmission disequilibrium tests (TDT) and PoO effects using 83 common single nucleotide polymorphic (SNP) markers of HH pathway genes from 806 NSCL/P case-parent trios. These trios were drawn from an international consortium established for a genome-wide association studies (GWAS) of non-syndromic oral clefts of multiple ethnicities. DNA samples were collected from each trio. Single marker and haplotype based analysis were performed both in TDT tests and PoO effects. SNPs were excluded if they (ⅰ) had a call rate of < 95%, (ⅱ) had a minor allele frequency (MAF) of < 0.05, (ⅲ) had Mendelian errors over all trios of >5%, (ⅳ) had a genotype distribution in the parents that deviated from the Hardy-Weinberg equilibrium (HWE) (<i>P</i> < 0.000 1). The process was done using Plink (version 1.07, <a href="http://pngu.mgh.harvard.edu/~purcell/plink/data.shtml" target="_blank">http://pngu.mgh.harvard.edu/~purcell/plink/data.shtml</a>). TDT test was performed in Plink v1.07. A log-linear model was used to explore PoO effects using Haplin v6.2.1 as implemented in R package v3.4.2. Significance level was assessed using the Bonferroni correction.@*RESULTS@#A total of 18 SNPs were dropped due to low MAF, thus leaving 65 SNPs available for the analysis. Thus the Bonferroni threshold was 7.7×10-4 (0.05/65). Nominal significant association with NSCL/P was found at a SNP (rs4448343 in PTCH1, P=0.023) and six haplotypes (rs10512249-rs4448343, rs1461208-rs7786445, rs10512249-rs4448343, rs16909865-rs10512249-rs4448343, rs1461208-rs7786445-rs12698335, and rs288756-rs288758-rs1151790, P < 0.05). A total of six haplotypes (rs288765-rs1233563, rs12537550-rs11765352, rs872723-rs288765-rs1233563, rs288765-rs1233563-rs288756, rs6459952-rs12537550-rs11765352, and rs12537550-rs11765352-rs6971211) showed PoO effect (P < 0.05). None of the results remained significant after the Bonferroni correction (P>7.7×10-4).@*CONCLUSION@#Neither significant association between SNPs within HH pathway and the risk of NSCL/P nor PoO effects was seen in this study.