The Genetic Association between CDKN1A and Heart Failure:Genome-Wide Exploration of m6A-SNPs and Mendelian Randomization

Objective N6-methyladenosine(m^(6)A)is a common epigenetic modification in eukaryotes.In this study,we explore the potential impact of m^(6)A-associated single nucleotide polymorphisms(m^(6)A-SNPs)on heart failure(HF).Methods Data from genome-wide association studies(GWAS)investigating HF in humans and from m^(6)A-SNPs datasets were used to identify HF-associated m^(6)A-SNPs.Their functions were explored using expression quantitative trait locus(eQTL),gene expression,and gene enrichment analyses.Mediation protein quantitative trait locus(pQTL)-Mendelian randomization(MR)was used to investigate the potential mechanism between critical protein levels and risk factors for HF.Results We screened 44 HF-associated m^(6)A-SNPs,including 10 m^(6)A-SNPs that showed eQTL signals and differential expressions in HF.The SNP rs1801270 in CDKN1A showed the strongest association with HF(P=7.75×10^(−6)).Additionally,MR verified the genetic association between the CDKN1A protein and HF,as well as the mediating effect of blood pressure(BP)in this pathway.Higher circulating level of CDKN1A was associated with a lower risk of HF(odds ratio[OR]=0.82,95%confidence interval[CI]:0.69 to 0.99).The proportions of hypertension,systolic BP,and diastolic BP were 48.10%,28.94%,and 18.02%,respectively.Associations of PDIA6(P=1.30×10^(−2))and SMAD3(P=4.80×10^(−2))with HF were also detected.Conclusion Multiple HF-related m^(6)A-SNPs were identified in this study.Genetic associations of CDKN1A and other proteins with HF and its risk factors were demonstrated,providing new ideas for further exploration of the molecular mechanisms of HF.

Psychiatric comorbidities in epilepsy:population co-occurrence,genetic correlations and causal effects

Background Psychiatric comorbidities are common in patients with epilepsy.Reasons for the co-occurrence of psychiatric conditions and epilepsy remain poorly understood.Aim We aimed to triangulate the relationship between epilepsy and psychiatric conditions to determine the extent and possible origins of these conditions.Methods Using nationwide Swedish health registries,we quantified the lifetime prevalence of psychiatric disorders in patients with epilepsy.We then used summarydata from genome-wide association studies to investigate whether the identified observational associations could be attributed to a shared underlying genetic aetiology using cross-trait linkage disequilibrium score regression.Finally,we assessed the potential bidirectional relationships using two-sample Mendelian randomisation.Results In a cohort of 7628495 individuals,we found that almost half of the 94435 individuals diagnosed with epilepsy were also diagnosed with a psychiatric condition in their lifetime(adjusted lifetime prevalence,44.09%;95%confidence interval(Cl)43.78%to 44.39%).We found evidence for a genetic correlation between epilepsy and some neurodevelopmental and psychiatric conditions.For example,we observed a genetic correlation between epilepsy and attention-deficit/hyperactivity disorder(r,=0.18,95%Cl 0.09 to 0.27,p<0.001)—a correlation that was more pronounced in focal epilepsy(r=0.23,95%CI 0.09 to 0.36,p<0.001).Findings from Mendelian randomisation using common genetic variants did not support bidirectional effects between epilepsy and neurodevelopmental or psychiatric conditions.Conclusions Psychiatric comorbidities are common in patients with epilepsy.Genetic correlations may partially explain some comorbidities;however,there is little evidence of a bidirectional relationship between the genetic liability of epilepsy and psychiatric conditions.These findings highlight the need to understand the role of environmental factors or rare genetic variations in the origins of psychiatric comorbidities in epilepsy.

Prostate cancer risk-associated genetic markers and their potential clinical utility

Prostate cancer （PCa） is one of the most common cancers among men in Western developed countries and its incidence has increased considerably in many other parts of the world, including China. The etiology of PCa is largely unknown but is thought to be multifactorial, where inherited genetics plays an important role. In this article, we first briefly review results from studies of familial aggregation and genetic susceptibility to PCa. We then recap key findings of rare and high-penetrance PCa susceptibility genes from linkage studies in PCa families. We devote a significant portion of this article to summarizing discoveries of common and Iow-penetrance PCa risk-associated single-nucleotide polymorphisms （SNPs） from genetic association studies in PCa cases and controls, especially those from genome-wide association studies （GWASs）. A strong focus of this article is to review the literature on the potential clinical utility of these implicated genetic markers. Most of these published studies described PCa risk estimation using a genetic score derived from multiple risk-associated SNPs and its utility in determining the need for prostate biopsy. Finally, we comment on the newly proposed concept of genetic score; the notion is to treat it as a marker for genetic predisposition, similar to family history, rather than a diagnostic marker to discriminate PCa patients from non-cancer patients. Available evidence to date suggests that genetic score is an objective and better measurement of inherited risk of PCa than family history. Another unique feature of this article is the inclusion of genetic association studies of PCa in Chinese and Japanese populations.

Human Nail Clippings as a Source of DNA for Genetic Studies

Blood samples have traditionally been used as the main source of DNA for genetic analysis. How-ever, this source can be difficult in terms of collection, transportation, and long-term storage. In this study, we investigated whether human nail clippings could be used as a source of DNA for SNP genotyping, null-allele detection, and whole-genome amplification. From extracted nail DNA, we achieved amplicons up to a length of ~400 bp and >96% concordance for SNP genotyping and 100% concordance for null-allele detection compared to DNA derived from matched blood sam-ples. For whole-genome amplification, OmniPlex performed better than Multiple Displacement Amplification with a success rate of 89.3% and 76.8% for SNP genotyping and null-allele detection, respectively. Concordance was ~98% for both methods. When combined with OmniPlex whole-genome amplification, human nail clippings could potentially be used as an alternative to whole blood as a less invasive and more convenient source of DNA for genotyping studies.

Identification of new genetic risk factors for prostate cancer

There is evidence that a substantial part of genetic predisposition to prostate cancer （PCa） may be due to lower penetrance genes which are found by genome-wide association studies. We have recently conducted such a study and seven new regions of the genome linked to PCa risk have been identified. Three of these loci contain candidate susceptibility genes： MSMB, LMTK2 and KLK2/3. The MSMB and KLK2/3 genes may be useful for PCa screening, and the LMTK2 gene might provide a potential therapeutic target. Together with results from other groups, there are now 23 germline genetic variants which have been reported. These results have the potential to be developed into a genetic test. However, we consider that marketing of tests to the public is premature, as PCa risk can not be evaluated fully at this stage and the appropriate screening protocols need to be developed. Follow-up validation studies, as well as studies to explore the psychological implications of genetic profile testing, will be vital prior to roll out into healthcare.

Circadian rhythm dysfunction and psychopathology in the offspring of parents with bipolar disorder:a highrisk study in the Chinese population

Background Understanding the evolution of circadian rhythm dysfunction and psychopathology in the high-risk population has important implications for the prevention of bipolar disorder.Nevertheless,some of the previous studies on the emergence of psychopathologies and circadian dysfunction among high-risk populations were inconsistent and limited.Aims To examine the prevalence rates of sleep and circadian dysfunctions,mental disorders and their symptoms in the offspring of parents with(O-BD)and without bipolar disorder(O-control).Methods The study included 191 O-BD and 202 O-control subjects aged 6-21 years from the Greater Bay Area,China.The diagnoses and symptoms of sleep/circadian rhythm and mental disorders were assessed by the Diagnostic Interview for Sleep Patterns and Disorders,and the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version,respectively.Generalised estimating equations and shared frailty proportional hazards models of survival analysis were applied to compare the outcomes in the offspring.Results Adjusting for age,sex and region of recruitment,there was a significantly higher risk of delayed sleep phase symptoms(9.55%vs 2.58%,adjusted OR:4.04)in O-BD than in O-control.O-BD had a nearly fivefold higher risk of mood disorders(11.70%vs 3.47%,adjusted OR:4.68)and social anxiety(6.28%vs 1.49%,adjusted OR:4.70),a fourfold higher risk of depressive disorders(11.17%vs 3.47%,adjusted OR:3.99)and a threefold higher risk of mood symptoms(20.74%vs 10.40%,adjusted OR:2.59)than O-control.Subgroup analysis revealed that O-BD children(aged under 12 years)had a nearly 2-fold higher risk of any mental and behavioural symptoms than O-control,while there was a nearly 4-fold higher risk of delayed sleep phase symptoms,a 7.5-fold higher risk of social anxiety and a 3-fold higher risk of mood symptoms in O-BD adolescents(aged 12 years and over).Conclusions There was an increase in delayed sleep phase symptoms in O-BD adolescents compared with their control counterparts,confirming the central role of circadian rhythm dysfunction in bipolar disorder.The findings of the specific age-related and stage-related developmental patterns of psychopathologies and circadian dysfunction in children and adolescent offspring of parents with bipolar disorder paved the way to develop specific and early clinical intervention and prevention strategies.

Contribution of pancreatic enzyme replacement therapy to survival and quality of life in patients with pancreatic exocrine insufficiency

The objective of this study was to analyze the current evidence for the use of pancreatic enzyme replacement therapy (PERT) in affecting survival and quality of life in patients with pancreatic exocrine insufficiency (PEI). Systematic searches of the literature were performed using the PubMed database. Articles were selected for inclusion if they reported findings from trials assessing the effects of PERT on quality of life, survival, malabsorption, growth parameters (such as height, body weight and body mass index), or gastrointestinal symptoms (such as abdominal pain, stool consistency and flatulence). PERT improved PEI-related malabsorption and weight maintenance in patients with cystic fibrosis, chronic pancreatitis, pancreatic cancer, and post-surgical states. In patients with chronic pancreatitis, PERT improved PEI-related symptoms and quality of life measures. Several small retrospective studies have also suggested that PERT may have a positive impact on survival, but long-term studies assessing this effect were not identified. PERT is effective for treating malnutrition and supporting weight maintenance, and it is associated with improved quality of life and possibly with enhanced survival in patients with PEI. However, there is evidence that not all patients with PEI receive adequate PERT. Future work should aim to assess the long-term effects of PERT on the survival of patients with PEI.

Role of discs large homolog 5

In 2004, an association of genetic variation in the discs large homolog 5 （DLG5＇） gene with inflammatory bowel disease （IBD） was described in two large European study samples. The initial report of DLG5 as a novel IBD susceptibility gene sparked a multitude of studies investigating its effect on CD and IBD, respectively, leading to controversial findings and ongoing discussions concerning the validity of the initial association finding and its role in the aetiology of Crohn disease. This review aims to summarize the current state of knowledge and to place the reported findings in the context of current concepts of complex diseases. This includes aspects of statistical power, phenotype differences and genetic heterogeneity between different populations as well as gene-gene and gene-environment interactions.

Serum bile acid profiling reflects enterohepatic detoxification state and intestinal barrier function in inflammatory bowel disease

AIM： To determine free and conjugated serum bile acid （BA） levels in inflammatory bowel disease （IBD） subgroups with defined clinical manifestations. METHODS： Comprehensive serum BA profiling was performed in 358 IBD patients and 310 healthy con- trols by liquid chromatography coupled to electrospray ionization tandem mass spectrometry. RESULTS： Serum levels of hyodeoxycholic acid, the CYP3A4-mediated detoxification product of the second- ary BA lithocholic acid （LCA）, was increased significantly in Crohn＇s disease （CD） and ulcerative colitis （UC）, while most other serum BA species were decreased signifi- cantly. Total BA, total BA conjugate, and total BA glyco- conjugate levels were decreased only in CD, whereas total unconjugated BA levels were decreased only in UC. In UC patients with hepatobiliary manifestations, the conjugated primary BAs glycocholic acid, taurocholic acid, and glycochenodeoxycholic acid were as signifi- cantly increased as the secondary BAs LCA, ursodeoxy- cholic acid, and tauroursodeoxycholic acid compared to UC patients without hepatobiliary manifestations. Finally, we found that in ileocecal resected CD patients, the unconjugated primary BAs, cholic acid and chenode- oxycholic acid, were increased significantly compared to controls and patients without surgical interventions. CONCLUSION： Serum BA profiling in IBD patients that indicates impaired intestinal barrier function and increased detoxification is suitable for advanced diag- nostic characterization and differentiation of IBD sub- groups with defined clinical manifestations.

Potential Biomolecules Capable of Assessing Risk of Osteoporotic Fracture: A Scoping Review

Osteoporosis as a systemic chronic skeletal disease is characterized by low bone mineral density and increased risk to osteoporotic fractures.Osteoporosis is prevalent in the middle-aged and elderly population,especially in the postmenopausal women.With population aging,osteoporosis has become a world-wide serious public health problem.Early recognition of the high-risk population followed by timely and efficient intervention and/or treatment is important for preventing osteoporotic fractures.In light of the high heritability and complex pathogenesis of osteoporosis,comprehensive consideration of vital biological/biochemical factors is necessary for accurate risk evaluation of fractures.For this purpose,we review recent research progress on molecules which can be applied to assess risk for osteoporotic fractures.Future integrative analyses and systematic evaluation of these molecules may facilitate developing novel methodologies and/or test strategies,i.e.,biochips,for early recognition of osteoporosis,hence contributing to preventing osteoporotic fractures.

Spontaneous elimination of hepatitis C virus infection: A retrospective study on demographic, clinical, and serological correlates

To find correlates to spontaneous clearance of hepatitis C virus （HCV） infection, this study compared individuals with self-limited and chronic infection with regard to clinical, demographic, and serological pa- rameters. METHODS： Sixty-seven anti-HCV positive and repeatedly HCV RNA negative individuals were considered to have resolved HCV infection spontaneously. To determine the viral genotype these patients had been infected with HCV serotyping was performed. For comparison reasons, 62 consecutive patients with chronic hepatitis C were enrolled. Cases and controls were compared stratified for age and sex. RESULTS： Retrospective analysis showed （1） a lower humoral reactivity to HCV in patients with self-limited compared to chronic HCV-infection and （2） that younger age, history of iv drug use, and acute/post-acute hepatitis A or B co-infections, but not viral genotypes, are independent correlates for spontaneous HCV clearance. CONCLUSION： The stronger humoral reactivity to HCV in patients with persistent infections and in those with a history of iv drug use is supposed to be due to continuous or repeated contact（s） to the antigen. Metachronous hepatitis A or hepatitis B infections might favor HCV clearance.

Genome-wide association studies of hypertension:Achievements,difficulties and strategies

Estimated from family studies,the heritability of hypertension ranges from 31%to 68%.Linkage studies and candidate gene association studies were once widely used to investigate the genetic mechanisms of hypertension.However,results from these studies could only explain 1%-2%heritability.With the technological advances and subsequently the accomplishment of the Human Genome Project,genome-wide association studies(GWA studies)have been applied to find genome-wide significant signals for many common diseases.Current GWA studies of hypertension have identified dozens of hypertension or blood pressure associated variants.However,different GWA study identified different variants and the results could hardly be replicated in other studies.Therefore,a debate took place on whether GWA studies will unlock the genetic basis of hypertension and whether we shall continue throwing millions of dollars on GWA studies.This review gives a short introduction to the history of genetic study on hypertension and summarizes the current findings for GWA studies of hypertension or blood pressure.Finally,we will discuss that debate and try to find alternative strategies and technologies that may hold a greater chance to make progress in understanding the genetic risk factors of hypertension and blood pressure regulation.

非高密度脂蛋白胆固醇、载脂蛋白A-I及B100、标准脂质测量、脂质比值以及CRP作为女性心血管病危险因素的临床用途

背景：关于不同脂质测定、非高密度脂蛋白胆固醇（non-HDL-C）、脂质比值、载脂蛋白和C-反应蛋白（CRP）的临床应用，现行心血管危险检测指南仍有争议。 目的：直接比较总胆固醇（totalcholesterol，TC）、低密度脂蛋白胆固醇（LDL-C）、HDL-C、non-HDL-C、载脂蛋白A-I（apoA-I）及B100（apoB100）、高敏C-反应蛋白（高敏CRP）以及TC与HDL-C、LDL-C与HDL-C、apoB100与apoA-I、apoB100与HDL-C比值，在妇女作为将来心血管事件预测指标的临床用途。 设计、地点及参试者：于15 632例起始健康美国妇女进行的前瞻性队列研究。1992年11月至1995年7月人组时年龄≥45岁（4分位范围48～59岁）。所有参试者均经10年随访，观察将来心血管事件的发生情况。 主要观测指标：按照各项生化指标不同基线值而确定的首次主要心血管事件（n=4 764）的风险比（hazard ratios，HRs）及95％可信区间（confidence intervals，CIs）。 结果：在校正年龄、吸烟状况、血压、糖尿病及体重指数后，测量结果在最高5分位者将来发生心血管事件的风险比LDL-C为1．62（95％CI，1．17～2．25），apoA-I为1．75（95％CI，1．30～2．38），TC为2．08（95％CI，1．45～2．97），HDL-C为2．32（95％CI，1．64～3．33），apoB100为2．50（95％CI，1．68～3．72），non-HDL-C为2．51（95％CI，1．69～3．72），高敏CRP为2．98（95％CI，1．90～4．67）（P＜0．001，趋势贯穿所有5分位）。脂质比值风险比，apoBl00与apoA-I为3．01（95％CI，2．01～4．50），LDL-C与HDL-C为3．18（95％CI，2．12～4．75），apoB100与HDL-C为3．56（95％CI，2．31～5．47），TC与HDL-C为3．81（95％CI，2．47～5．86）（P＜0．001，趋势贯穿所有5分位）。高敏CRP与脂质参数的相关系数范围为-0．33到0．15，以CRP＜1、1～3和＞3 ms／L为临床分割点，可对每项脂质测量及脂质比值水平增加提供预后危险信息。 结论：non-HDL-C以及TC与HDL-C比值对将来心血管事件的预测效果与载脂蛋白相同或者更好。校正年龄、血压、吸烟、糖尿病和肥胖后，高敏CRP提供的预后信息超越各项脂质测量。

Genome-wide enrichment of m6A-associated single nucleotide polymorphisms in the lipid loci

Background and Objective N6-methyladenosine(m6A)plays critical roles in many fundamental biological processes and a variety of diseases.The aim of this study was to investigate the effect of the m6ASNPs on lipid levels.Methods We examined the association of m6A-SNPs with lipid levels in a GWAS of 188,578 individuals.Furthermore,we performed eQTL and differential expression analyses to add additional information for the identified m6A-SNPs.

Emotional Distress and Metabolic Control in Diabetic Patients Attending Primary Health Care in the Eastern Province, Saudi Arabia

Background:Recognition and treatment of emotional distress,which affects 20 to 40%of outpatients with type 1 or type 2 diabetes,are important because of its association with worse diabetes self-care,poor glycemic control,increased rates of mortality and diabetes-related complications,and a rise in healthcare expenditure.However,although the symptoms of emotional distress improve in diabetic patients after psychological and pharmacological interventions,evidence of benefits in glycemic control is still uncertain.Objective:The aim of this study was to assess the metabolic control in diabetic patients with emotional distress attending primary mental care clinics(PMCC)in the Eastern Province of Saudi Arabia.Method:This study was a single group pretest-posttest design conducted on adult diabetic patients with emotional distress attending PMCC.Out of 194 attendees,62 patients who fulfilled the selection criteria were studied.Data were collected from the patients’records using a worksheet designed for the study.Metabolic parameters including BMI,BP,FBS,HbA1c and lipid profile were recorded before and after the management of emotional distress.Socio-demographic characteristics,complications related to diabetes and co-morbidities were also recorded.Paired t-test was used appropriately to compare continuous variables.A p-value of less than 0.05 was considered significant in all statistical analysis.Results:The majority of the patients had type 2 DM(98.2%)and the presence of co-morbidities was high(83.9%).A comparison of the metabolic parameters before and after management of emotional distress,showed a significant reduction in HbA1c(p=0.020)and elevation in HDL(p=0.010).No differences in BMI,BP,FBS,TC,TG or LDL were found.Conclusions:Treating emotional distress in diabetic patients is associated with an improvement in HbA1c and HDL.

X-Linked Dominant Congenital Ptosis Cosegregating with an Interstitial Insertion of a Chromosome 1p21.3 Fragment into a Quasipalindromic Sequence in Xq27.1

Blepharoptosis (ptosis) is defined as the abnormal drooping of the upper eyelid and is a feature of many conditions. It can be in isolated or syndromic form, bilateral or unilateral and congenital or acquired. Previously we have carried out linkage analysis on a family with dominantly inherited congenital bilateral isolated ptosis and found the condition to be linked to a region of approximately 20 megabases of chromosome Xq24-Xq27.1 with a cumulative LOD score of 5.89. We now describe further analysis using array comparative genomic hybridisation (array CGH), fluorescence in situ hybridisation (FISH), long range PCR and sequencing. This has enabled us to identify and characterise at the level of DNA sequence an insertional duplication and rearrangement involving chromosomes 1p21.3 and a small quasipalindromic sequence in Xq27.1, disruption of which has been associated with other phenotypes but which is cosegregating with X-linked congenital bilateral isolated ptosis in this family. This work highlights the significance of the small quasipalindromic sequence in genomic rearrangements involving Xq27.1 and the importance of comprehensive molecular and molecular cytogenetic investigations to fully characterise genomic structural complexity.

近期晒床的使用:黑色素瘤的一个危险因素

Background: Individuals at increased risk of melanoma should use sun-protective measures to decrease their risk of developing melanoma. Observation: We report a case of a 39-year-old patient with a CDKN2A mutation who developed 3 primary melanomas within a few years of initiating tanning bed use. Conclusion: Intense UV exposure as an adult likely contributed to the development of addition al primary melanomas in this individual.

Is prostate cancer a Lynch syndrome cancer？

The question of whether men with an inherited genetic condition called Lynch syndrome have an increased risk of developing prostate cancer has been controversial. It is important to answer this question, for understanding the role of DNA mismatch repair in carcinogenesis of prostate as well as for clinical implications for screening.

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

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 15581 lung adenocarcinoma(AD)cases,8350 squamous cell carcinoma(SqCC)cases,and 27355 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 genebased 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 wellstudied 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.