Presence of Rare Variants is Associated with Poorer Survival in Chinese Patients with Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disorder with phenotypic and genetic heterogeneity.Recent studies have suggested an oligogenic basis of ALS,in which the co-occurrence of two or more genetic variants has additive or synergistic deleterious effects.To assess the contribution of possible oligogenic inheritance,we profiled a panel of 43 relevant genes in 57 sporadic ALS(sALS)patients and eight familial ALS(fALS)patients from five pedigrees in east China.We filtered rare variants using the combination of the Exome Aggregation Consortium,the 1000 Genomes and the HuaBiao Project.We analyzed patients with multiple rare variants in 43 known ALS causative genes and the genotype–phenotype cor-relation.Overall,we detected 30 rare variants in 16 different genes and found that 16 of the sALS patients and all the fALS patients examined harbored at least one variant in the investigated genes,among which two sALS and four fALS patients harbored two or more variants.Of note,the sALS patients with one or more variants in ALS genes had worse survival than the patients with no variants.Typically,in one fALS pedigree with three variants,the family member with three variants(Superoxide dismutase 1(SOD1)p.V48A,Optineurin(OPTN)p.A433V and TANK binding kinase 1(TBK1)p.R573H)exhibited much more severe disease phenotype than the member carrying one variant(TBK1 p.R573H).Our findings suggest that rare variants could exert a negative prognostic effect,thereby supporting the oligogenic inheritance of ALS.

α2,3-Sialylation with Fucosylation Associated with More Severe Anti-MDA5 Positive Dermatomyositis Induced by Rapidly Progressive Interstitial Lung Disease

Dermatomyositis(DM)is a heterogeneous autoimmune disease associated with numerous myositis specific antibodies(MSAs)in which DM with anti-melanoma differentiation-associated gene 5-positive(MDA5+DM)is a unique subtype of DM with higher risk of developing varying degrees of Interstitial lung disease(ILD).Glycosylation is a complex posttranslational modification of proteins associated with many autoimmune diseases.However,the association of total plasma N-glycome(TPNG)and DM,especially MDA5+DM,is still unknown.TPNG of 94 DM patients and 168 controls were analyzed by mass spectrometry with in-house reliable quantitative method called Bionic Glycome method.Logistic regression with age and sex adjusted was used to reveal the aberrant glycosylation of DM and the association of TPNG and MDA5+DM with or without rapidly progressive ILD(RPILD).The elastic net model was used to evaluate performance of glycans in distinguishing RPLID from non-RPILD,and survival analysis was analyzed with N-glycoslyation score by Kaplan-Meier survival analysis.It was found that the plasma protein N-glycome in DM showed higher fucosylation and bisection,lower sialylation(α2,3-notα2,6-linked)and galactosylation than controls.In MDA5+DM,more severe disease condition was associated with decreased sialylation(specificallyα2,3-sialylation with fucosylation)while accompanying elevated H6N5S3 and H5N4FSx,decreased galactosylation and increased fucosylation and the complexity of N-glycans.Moreover,glycosylation traits have better discrimination ability to distinguish RPILD from non-RPILD with AUC 0.922 than clinical features and is MDA5-independent.Survival advantage accrued to MDA5+DM with lower N-glycosylation score(p=3e-04).Our study reveals the aberrant glycosylation of DM for the first time and indicated that glycosylation is associated with disease severity caused by ILD in MDA5+DM,which might be considered as the potential biomarker for early diagnosis of RPILD and survival evaluation of MDA5+DM.

nvolvement of collagen-binding heat shock protein 47 in scleroderma-associated fibrosis

Uncontrolled fibrosis of skin and internal organs is the main characteristic of scleroderma, and collagen is a major extracellular matrix protein that deposits in the fibrotic organs. As the chaperone of collagen, heat shock protein 47 （HSP47） is closely related with the development of fbrosis. To explore the potential func- tion of HSP47 in the pathogenesis of scleroderma, the clinical, in vivo and in vitro studies were performed. In clinical, the increased mRNA level of HSP47 was observed in the skin fibroblasts and PBMC from scle- roderma patients, and the enhanced protein level of HSP47 was also detected in the skin biopsy and plasma of the above patients. Unexpectedly, the enhanced levels of HSP47 were positively correlated with the presence of anti-centromere antibody in scleroderma patients. Moreover, a high expression of HSP47 was found in the skin lesion of BLM-induced scleroderma mouse model. Further in vitro studies demonstrated that HSP47 knockdown could block the intracellular and extracellular collagen over-productions induced by exogenous TGF-13. Therefore, the results in this study provide direct evidence that HSP47 is involved in the pathogenesis of scleroderma. The high expression of HSP47 can be detected in the circulatory system of scleroderma patients, indicating that HSP47 maybecome a pathological marker to assess the progres- sion of scleroderma, and also explain the systemic fibrosis of scleroderma. Meanwhile, collagen over-ex- pression is blocked by HSP47 knockdown, suggesting the possibility that HSP47 can be a potential therapeutic target for scleroderma.

Correlation of DNA methylation patterns to the phenotypic features of Tibetan elite alpinists in extreme hypoxia

High altitude is an extreme environment that imposes hypoxic pressure on physiological processes,and natives living at high altitudes are more adaptive in certain physiological processes.So far,epigenetic modifications under extreme changes in hypoxic pressures are relatively less understood.Here,we recruit 32 Tibetan elite alpinists(TEAs),who have successfully mounted Everest(8848 m)at least five times.Blood samples and physiological phenotypes of TEAs and 32 matched non-alpinist Tibetan volunteers(non-TEAs)are collected for analysis.Genome-wide DNA methylation analysis identifies 23,202 differentially methylated CpGs(P_(adj)<0.05,|β|>0.1)between the two groups.Some differentially methylated CpGs are in hypoxia-related genes such as PPP1R13L,MAP3K7CL,SEPTI-9,and CUL2.In addition,Gene ontology enrichment analysis reveals several inflammation-related pathways.Phenotypic analysis indicates that 12 phenotypes are significantly different between the two groups.In particular,TEAs exhibit higher blood oxygen saturation levels and lower neutrophil count,platelet count,and heart rate.For DNA methylation association analysis,we find that two CpGs(cg16687447,cg06947206)upstream of PTEN were associated with platelet count.In conclusion,extreme hypoxia exposure leads to epigenetic modifications and phenotypic alterations of TEA,providing us clues for exploring the molecular mechanism underlying changes under extreme hypoxia conditions.

The HuaBiao project:whole-exome sequencing of 5000 Han Chinese individuals

Next-generation sequencing technologies have significantly accelerated the identification of disease-causing mutations and facilitated the emergence of personalized medicine(Genomes Project Consortium et al.,2015;Goodwin et al.,2016;Sirugo et al.,2019).In comparison with whole-genome sequencing,whole-exome sequencing(WES),which covers the coding regions of the genome,offers a cost-efficacy balance.WES provides deeper sequencing depth(>100)and allows the more accurate detection of rare variants that are tailored for clinical applications(Lek et al.,2016).

Using Composite Phenotypes to Reveal Hidden Physiological Heterogeneity in High-Altitude Acclimatization in a Chinese Han Longitudinal Cohort

Altitude acclimatization is a human physiological process of adjusting to the decreased oxygen availability.Since several physiological processes are involved and their correlations are complicated,the analyses of single traits are insufficient in revealing the complex mechanism of high-altitude acclimatization.In this study,we examined these physiological responses as the composite phenotypes that are represented by a linear combination of physiological traits.We developed a strategy that combines both spectral clustering and partial least squares path modeling(PLSPM)to define composite phenotypes based on a cohort study of 883 Chinese Han males.In addition,we captured 14 composite phenotypes from 28 physiological traits of high-altitude acclimatization.Using these composite phenotypes,we applied k-means clustering to reveal hidden population physiological heterogeneity in high-altitude acclimatization.Furthermore,we employed multivariate linear regression to systematically model(Models 1 and 2)oxygen saturation(SpO_(2))changes in high-altitude acclimatization and evaluated model fitness performance.Composite phenotypes based on Model 2 fit better than single trait-based Model 1 in all measurement indices.This new strategy of using composite phenotypes may be potentially employed as a general strategy for complex traits research such as genetic loci discovery and analyses of phenomics.

Chinese Medicine Phenomics(Chinmedphenomics):Personalized,Precise and Promising

The systematicness of phenomics and Traditional Chinese Medicine(TCM)enable these two disciplines to interlink with each other.This article discussed the similarity in theory and application between TCM and phenomics and illustrates their respective advantages in diagnosis and treatment of diseases,forming a new discipline eventually.Chinese medicine phe-nomics(Chinmedphenomics)is built on classic TCM,combined with phenomics technology,and the development of which needs the mega cohort with TCM syndrome and the characteristics of precision medicine as well as multi-disciplinary coop-eration,which is personalized,precise and promising,providing unique scientific insights into understanding human health.

Mitochondria as the Essence of Yang Qi in the Human Body

The concept of Yang Qi in Traditional Chinese Medicine(TCM)has many similarities with mitochondria in modern medicine.Both are indispensable to human beings and closely related to life and death.This article discusses the similarities in various aspects between mitochondria and Yang Qi,including body temperature,aging,newborns,circadian rhythm,immunity,and meridian.It is well-known that Yang Qi is vital for human health.Interestingly,decreased mitochondrial function is thought to be key to the development of various diseases.Here,we further explain diseases induced by Yang Qi deficiency,such as cancer,chronic fatigue syndrome,sleep disorder,senile dementia,and metabolic diseases,from the perspective of mitochondrial function.We aim to establish similarities and connections between two important concepts,and hope our essay can stimulate further discussion and investigation on unifying important concepts in western medicine and alternative medicine,especially TCM,and provide unique holistic insights into understanding human health.

Skin Microbiome,Metabolome and Skin Phenome,from the Perspectives of Skin as an Ecosystem

Skin is a complex ecosystem colonized by millions of microorganisms,including bacteria,fungi,and viruses.Skin microbiota is believed to exert critical functions in maintaining host skin health.Profiling the structure of skin microbial community is the first step to overview the ecosystem.However,the community composition is highly individualized and extremely complex.To explore the fundamental factors driving the complexity of the ecosystem,namely the selection pressures,we review the present studies on skin microbiome from the perspectives of ecology.This review summarizes the following:(1)the composition of substances/nutrients in the cutaneous ecological environment that are derived from the host and the environment,highlighting their proposed function on skin microbiota;(2)the features of dominant skin commensals to occupy ecological niches,through self-adaptation and microbe–microbe interactions;(3)how skin microbes,by their structures or bioactive molecules,reshape host skin phenotypes,including skin immunity,maintenance of skin physiology such as pH and hydration,ultraviolet(UV)protection,odor production,and wound healing.This review aims to re-examine the host–microbe interactions from the ecological perspectives and hopefully to give new inspiration to this field.