Genome-wide studies of knee osteoarthritis (review)

Introduction. Knee Osteoarthritis (OA) is a multifactorial disease resulting from the interaction of many environmental, epigenetic and genetic risk factors, and the latter account for 40% to 65%. Genetic bases of the knee OA based on genome-wide association search (GWAS) are being actively studied by many scientific teams around the world. At the same time, the results obtained are often contradictory and ambiguous, as for the conducted replicative studies of knee OA. This dictates the need for additional replicative studies in various populations, including populations of Russia, which are characterized by significant ethno-territorial variability, in order to identify specific GWAS-significant polymorphic markers of candidate genes associated with OA in these individual populations. The aim of the study was to analyze genome-wide studies of knee OA and to establish GWAS-significant polymorphic loci associated with OA. Materials and methods. The search for publications was carried out in the electronic databases PubMed, PubMedCentral, eLIBRARY, in the GWAS catalog for the period from 2008 to the present by the keywords: knee osteoarthritis, GWAS studies, candidate genes. Results. First, to date, 14 genome-wide studies of knee OA have been performed, as a result of which about 80 GWAS-significant polymorphic loci associated with the risk of knee OA have been identified. Secondly, all GWAS of the knee OA were carried out abroad on samples from various foreign populations, and the samples from the Russian Federation were not included in these studies. Third, only two GWAS-significant polymorphic loci for OA (rs143384 of the GDF5 gene and rs3771501 of the TGFA gene) were replicated at the genome-wide significance level (p5x10-08) in two different studies. Fourth, the data obtained indicate the presence of two regions of chromosomes (6p21.32 and 7q22.3), in which the largest number of GWAS-significant polymorphic loci for OA is located - 3SNPs in each (6p21.32 - rs10947262, rs7775228, rs9277552; 7q22.3 - rs4730250, rs10953541, rs3815148). Fifth, with an increase in the volume of the studied samples of patients and control in genome-wide studies of knee OA, the number of identified GWAS-significant polymorphisms also increases. Conclusion. The main genome-wide studies of knee OA were reviewed and GWAS-significant polymorphisms associated with OA were identified. The obtained materials on GWAS-significant loci can be used both in the selection of polymorphisms in replicative studies of OA in various populations of Russia, and for expanding the understanding of the molecular genetic mechanisms of the disease development.

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Genome-Wide Analysis of Sex Disparities in the Genetic Architecture of Lung and Colorectal Cancers

Genes ◽

10.3390/genes12050686 ◽

2021 ◽

Vol 12 (5) ◽

pp. 686

Author(s):

Alireza Nazarian ◽

Alexander M. Kulminski

Keyword(s):

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Significance Level ◽

Association Analyses ◽

Complex Disorders ◽

Specific Effects ◽

Genome Wide ◽

Genetic Mechanisms ◽

Sex Disparities ◽

Almost All

Almost all complex disorders have manifested epidemiological and clinical sex disparities which might partially arise from sex-specific genetic mechanisms. Addressing such differences can be important from a precision medicine perspective which aims to make medical interventions more personalized and effective. We investigated sex-specific genetic associations with colorectal (CRCa) and lung (LCa) cancers using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent datasets. The genome-wide association analyses revealed that 33 SNPs were associated with CRCa/LCa at P < 5.0 × 10−6 neither males or females. Of these, 26 SNPs had sex-specific effects as their effect sizes were statistically different between the two sexes at a Bonferroni-adjusted significance level of 0.0015. None had proxy SNPs within their ±1 Mb regions and the closest genes to 32 SNPs were not previously associated with the corresponding cancers. The pathway enrichment analyses demonstrated the associations of 35 pathways with CRCa or LCa which were mostly implicated in immune system responses, cell cycle, and chromosome stability. The significant pathways were mostly enriched in either males or females. Our findings provided novel insights into the potential sex-specific genetic heterogeneity of CRCa and LCa at SNP and pathway levels.

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Age by Single Nucleotide Polymorphism Interactions on Bronchodilator Response in Asthmatics

Journal of Personalized Medicine ◽

10.3390/jpm11010059 ◽

2021 ◽

Vol 11 (1) ◽

pp. 59

Author(s):

Kirsten Voorhies ◽

Joanne E. Sordillo ◽

Michael McGeachie ◽

Elizabeth Ampleford ◽

Alberta L. Wang ◽

...

Keyword(s):

Candidate Genes ◽

P Value ◽

Genome Wide Association Studies ◽

Genetic Associations ◽

Single Nucleotide ◽

Significance Level ◽

Bronchodilator Response ◽

Genome Wide ◽

A Genome ◽

Β2 Agonists

An unaddressed and important issue is the role age plays in modulating response to short acting β2-agonists in individuals with asthma. The objective of this study was to identify whether age modifies genetic associations of single nucleotide polymorphisms (SNPs) with bronchodilator response (BDR) to β2-agonists. Using three cohorts with a total of 892 subjects, we ran a genome wide interaction study (GWIS) for each cohort to examine SNP by age interactions with BDR. A fixed effect meta-analysis was used to combine the results. In order to determine if previously identified BDR SNPs had an age interaction, we also examined 16 polymorphisms in candidate genes from two published genome wide association studies (GWAS) of BDR. There were no significant SNP by age interactions on BDR using the genome wide significance level of 5 × 10−8. Using a suggestive significance level of 5 × 10−6, three interactions, including one for a SNP within PRAG1 (rs4840337), were significant and replicated at the significance level of 0.05. Considering candidate genes from two previous GWAS of BDR, three SNPs (rs10476900 (near ADRB2) [p-value = 0.009], rs10827492 (CREM) [p-value = 0.02], and rs72646209 (NCOA3) [p-value = 0.02]) had a marginally significant interaction with age on BDR (p < 0.05). Our results suggest age may be an important modifier of genetic associations for BDR in asthma.

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Comparative transcriptome analysis of mule uncovered several heterosis-related genes for improving muscular endurance and cognition

10.1101/823047 ◽

2019 ◽

Author(s):

Shan Gao

Keyword(s):

Alternative Splicing ◽

Molecular Genetic ◽

Hybrid Vigor ◽

Neuronal System ◽

Future Studies ◽

Genome Wide ◽

A Genome ◽

Genetic Mechanisms ◽

Productive Traits ◽

Genome Wide Gene Expression

AbstractHeterosis has been widely exploited in animal and plant breeding to enhance the productive traits of hybrid progeny of two breeds or two species. Although, there were multiple models for explaining the hybrid vigor, such as dominance and over-dominance hypothesis, its underlying molecular genetic mechanisms remain equivocal. The aim of this study is through comparing the different expression genes (DEGs) and different alternative splicing (DAS) genes to explore the mechanism of heterosis. Here, we performed a genome-wide gene expression and alternative splicing analysis of two heterotic crosses between donkey and horse in three tissues. The results showed that the DAS genes influenced the heterosis-related phenotypes in a unique than DEGs and about 10% DEGs are DAS genes. In addition, over 69.7% DEGs and 87.2% DAS genes showed over-dominance or dominance, respectively. Furthermore, the “Muscle Contraction” and “Neuronal System” pathways were significantly enriched both for the DEGs and DAS genes in muscle. TNNC2 and RYR1 genes may contribute to mule’s great endurance while GRIA2 and GRIN1 genes may be related with mule’s cognition. Together, these DEGs and DAS genes provide the candidates for future studies of the genetic and molecular mechanism of heterosis in mule.

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Alteration of Screw-home Movement in Patients With Knee Osteoarthritis: A Cross-sectional Study

10.21203/rs.3.rs-35701/v1 ◽

2020 ◽

Author(s):

Jeongwoo Jeon ◽

Dongyeop Lee ◽

Jaeho Yu ◽

Jinseop Kim ◽

Sang Hoon Lhee ◽

...

Keyword(s):

Knee Osteoarthritis ◽

Knee Extension ◽

Cross Sectional Study ◽

Measurement Unit ◽

Tibial Rotation ◽

Sectional Study ◽

Control Groups ◽

Cross Sectional ◽

Knee Oa ◽

And Control

Abstract Background: Tibial rotation accompanying sagittal movement contains the phenomenon of screw-home movement of the knee, which plays an important role in knee stability during extension. This study aimed to investigate the alteration of screw-home movement in patients with knee osteoarthritis (OA).Methods: Participants (n =67) in this cross-sectional study were outpatients in the department of orthopedics of a general hospital and included patients with knee OA (n=31) and asymptomatic control subjects (n=36).Knee kinematic data were measured using an inertial measurement unit. The total tibial rotation was obtainedduring knee sagittal movement. The acquired angle of tibial rotation was divided into four periodseach extension and flexion. The total tibial rotation and the variation of each period were compared between the OA and control groups.Results: Significant differences arose between the OA and control groups in the total tibial rotation during knee extension and flexion(P< 0.001).The variation of tibial rotation was also significantly different between groups for all periods (P< 0.001; knee extensionat 70° to 45°,P = 0.014).Conclusions: We found a reduction in the total tibial rotation and loss of the screw-home movement in the unloaded OA knee. To normalize the screw-home movement, it is necessary to promote proper articular movement of the knee joint and suppress the hyperexcitability of the medial muscles.

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Prioritization of potato genes involved in the formation of agronomically valuable traits using the SOLANUM TUBEROSUM knowledge base

Vavilov Journal of Genetics and Breeding ◽

10.18699/vj19.501 ◽

2019 ◽

Vol 23 (3) ◽

pp. 312-319

Author(s):

P. S. Demenkov ◽

O. V. Saik ◽

T. V. Ivanisenko ◽

N. A. Kolchanov ◽

A. V. Kochetov ◽

...

Keyword(s):

Solanum Tuberosum ◽

Knowledge Base ◽

Candidate Genes ◽

Genetic Relationships ◽

Molecular Genetic ◽

Biological Data ◽

Targeted Mutagenesis ◽

Pubmed Database ◽

Genetic Mechanisms ◽

Selection Of

The development of highly efficient technologies in genomics, transcriptomics, proteomics and metabolomics, as well as new technologies in agriculture has led to an “information explosion” in plant biology and crop production, including potato production. Only a small part of the information reaches formalized databases (for example, Uniprot, NCBI Gene, BioGRID, IntAct, etc.). One of the main sources of reliable biological data is the scientific literature. The well-known PubMed database contains more than 18 thousand abstracts of articles on potato. The effective use of knowledge presented in such a number of non-formalized documents in natural language requires the use of modern intellectual methods of analysis. However, in the literature, there is no evidence of a widespread use of intelligent methods for automatically extracting knowledge from scientific publications on cultures such as potatoes. Earlier we developed the SOLANUM TUBEROSUM knowledge base (http://www-bionet.sysbio.cytogen. ru/and/plant/). Integrated into the knowledge base information about the molecular genetic mechanisms underlying the selection of significant traits helps to accelerate the identification of candidate genes for the breeding characteristics of potatoes and the development of diagnostic markers for breeding. The article searches for new potential participants of the molecular genetic mechanisms of resistance to adverse factors in plants. Prioritizing candidate genes has shown that the PHYA, GF14, CNIH1, RCI1A, ABI5, CPK1, RGS1, NHL3, GRF8, and CYP21-4 genes are the most promising for further testing of their relationships with resistance to adverse factors. As a result of the analysis, it was shown that the molecular genetic relationships responsible for the formation of significant agricultural traits are complex and include many direct and indirect interactions. The construction of associative gene networks and their analysis using the SOLANUM TUBEROSUM knowledge base is the basis for searching for target genes for targeted mutagenesis and marker-oriented selection of potato varieties with valuable agricultural characteristics.

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Clinically Relevant Molecular Biomarkers for Use in Human Knee Osteoarthritis: A Systematic Review

Cartilage ◽

10.1177/1947603520941239 ◽

2020 ◽

pp. 194760352094123

Author(s):

James G. Convill ◽

Gwenllian F. Tawy ◽

Anthony J. Freemont ◽

Leela C. Biant

Keyword(s):

Systematic Review ◽

Knee Osteoarthritis ◽

English Language ◽

Type Ii Collagen ◽

Molecular Biomarkers ◽

Keywords Knee ◽

Clinical Indicators ◽

Disease Modifying Drugs ◽

Knee Oa ◽

Cellular Markers

Objective Biomarkers in osteoarthritis (OA) could serve as objective clinical indicators for various disease parameters, and act as surrogate endpoints in clinical trials for disease-modifying drugs. The aim of this systematic review was to produce a comprehensive list of candidate molecular biomarkers for knee OA after the 2013 ESCEO review and discern whether any have been studied in sufficient detail for use in clinical settings. Design MEDLINE and Embase databases were searched between August 2013 and May 2018 using the keywords “knee osteoarthritis,” “osteoarthritis,” and “biomarker.” Studies were screened by title, abstract, and full text. Human studies on knee OA that were published in the English language were included. Excluded were studies on genetic/imaging/cellular markers, studies on participants with secondary OA, and publications that were review/abstract-only. Study quality and bias were assessed. Statistically significant data regarding the relationship between a biomarker and a disease parameter were extracted. Results A total of 80 studies were included in the final review and 89 statistically significant individual molecular biomarkers were identified. C-telopeptide of type II collagen (CTXII) was shown to predict progression of knee OA in urine and serum in multiple studies. Synovial fluid vascular endothelial growth factor concentration was reported by 2 studies to be predictive of knee OA progression. Conclusion Despite the clear need for biomarkers of OA, the lack of coordination in current research has led to incompatible results. As such, there is yet to be a suitable biomarker to be used in a clinical setting.

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Genome-Wide DNA Methylation Profile Reveals Potential Therapeutic Targets at the Late Stage of Knee Osteoarthritis

10.21203/rs.3.rs-27526/v1 ◽

2020 ◽

Author(s):

Hongyan Shen ◽

Jie Long ◽

Mingmei Zhang ◽

Xing Chen ◽

Tao Wang ◽

...

Keyword(s):

Dna Methylation ◽

Knee Osteoarthritis ◽

Late Stage ◽

Methylation Profile ◽

Functional Enrichment ◽

Intact Group ◽

Knee Oa ◽

Genome Wide ◽

A Genome ◽

Dna Methylation Profile

Abstract Background: The aim of this study was to use the latest BeadChip technology to obtain a genome-wide DNA methylation profile for cartilage from patients with primary knee osteoarthritis (OA), providing the first comprehensive description of DNA methylation changes in advanced knee OA. Methods: Cartilage tissues were taken from patients after total knee arthroplasty and were divided into eroded group and intact group according to the cartilage status. The genome-wide DNA methylation profile was obtained using the Infinium MethylationEPIC BeadChip kit, which enables the analysis of >850,000 CpG sites. Comparisons of the two groups were performed to identify differentially methylated (DM) probes (DMPs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were applied to the functional annotation clustering of the DM genes. Results: There was significant differential methylation between the two groups, and a total of 16,776 DMPs covering approximately 6,700 genes were identified, 92% of which were hypomethylated. Functional enrichment results revealed that the DM genes were significantly enriched for the extracellular matrix (ECM) proteins, cell adhesion molecules (CAM) and proteins in some inflammatory response pathways, especially the PI3K/Akt signalling pathway. Six genes including RNF43, SEMA4D, F11R, PKN1, FLT-1 and PTPN11 may be the potential biomarkers for OA.Conclusion: Our data demonstrate the epigenetic dysregulation of many genes and pathways in the late stage of knee OA that appear to be involved in potential aetiological mechanisms of OA. DM genes closely associated with OA may become targets for treatment and may open new avenues for further research in the field.

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Therapeutic modalities and postural balance of patients with knee osteoarthritis: systematic review

Fisioterapia em Movimento ◽

10.1590/0103-5150.028.003.ar01 ◽

2015 ◽

Vol 28 (3) ◽

pp. 605-616

Author(s):

Andressa Silva ◽

Marco Túlio de Mello ◽

Sebastião Augusto Gávea Junior ◽

Sandra Souza de Queiroz ◽

Sergio Tufik ◽

...

Keyword(s):

Systematic Review ◽

Knee Osteoarthritis ◽

Postural Balance ◽

Methodological Quality ◽

Keywords Knee ◽

Therapeutic Modalities ◽

Knee Oa ◽

Randomized Controlled Clinical Trials ◽

Randomized Controlled

AbstractObjective The objective of this review was to evaluate the evidence of the influence of therapeutic modalities on postural balance in patients with knee osteoarthritis (OA).Methods A search for published papers on therapeutic modalities was conducted using the Pubmed, Medline, Lilacs and SciELO databases. The keywords “knee” and “balance” in combination with “osteoarthritis” were used as the search strategy. Randomized controlled clinical trials published in the last 10 years in either English or Portuguese were selected. The PEDro scale was applied to assess the quality of the selected clinical trials.Results A total of 46 studies of patients with knee OA were found, of which seven were analyzed in full and 39 were excluded because they did not meet the inclusion criteria. Of the seven studies reviewed, six were considered to have a high methodological quality on the PEDro scale. Several therapeutic modalities were found (physical exercise, hydrotherapy, electrotherapy and manual therapy), and postural balance improved in only three studies.Conclusion The studies included in this systematic review had a high methodological quality, so it can be concluded that the therapeutic modalities used in those studies improved postural balance in patients with knee OA.

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Sarcopenic Knee Osteoarthritis: A Risk Factor for Recurrent Falls

10.21203/rs.3.rs-435543/v1 ◽

2021 ◽

Author(s):

Hirotaka Iijima ◽

Tomoki Aoyama

Keyword(s):

Older Adults ◽

Knee Osteoarthritis ◽

Knee Oa ◽

Recurrent Falls ◽

Increased Risk ◽

Risk Of Falls ◽

Interactive Relationship ◽

Falls In Older Adults ◽

Risk Factors For Falls ◽

And Control

Abstract Background: Sarcopenia and knee osteoarthritis (OA) are major risk factors for falls in older adults. The coexistence of these two conditions may exacerbate the risk of falls through the sarcopenia-OA interaction. This study aimed to test the hypothesis that older adults with coexisting sarcopenia and knee OA, defined as “sarcopenic OA,” displayed an increased risk of falls.Methods: Patients in an orthopedics clinic (n = 298, age: 60–90 years, 78.9% women) were divided into 4 groups according to the presence of sarcopenia and radiographic knee OA: isolated sarcopenia, isolated knee OA, sarcopenic knee OA, and control (i.e., non-sarcopenia with non-OA) groups. We used questionnaires to assess fall experience in the prior 12 months. We performed binary and ordinal logistic regression analyses to evaluate the relationship between the 4 groups and falls experience.Results: Of 298 participants, 27 (9.1%) had sarcopenic knee OA. Patients with sarcopenic knee OA had 4.70 times (95% confidence interval: 1.08, 20.5) higher odds of recurrent falls (≥ 2 falls) than those with control after adjustment for age, sex, and body mass index.Conclusions: Patients with sarcopenic knee OA displayed higher frailty. This study provides novel interactive relationship between sarcopenia and knee OA in the context of recurrent falls experience.Trial registration: Not applicable.

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Identification of a Goat Intersexuality-Associated Novel Variant Through Genome-Wide Resequencing and Hi-C

Frontiers in Genetics ◽

10.3389/fgene.2020.616743 ◽

2021 ◽

Vol 11 ◽

Author(s):

Guang-Xin E ◽

Dong-Ke Zhou ◽

Zhu-Qing Zheng ◽

Bai-Gao Yang ◽

Xiang-Long Li ◽

...

Keyword(s):

Candidate Genes ◽

Molecular Genetic ◽

Genetic Mechanism ◽

Chromosome 1 ◽

Future Research ◽

Whole Genome ◽

Chromosome Conformation ◽

Next Generation Sequencing Technology ◽

Genome Wide ◽

Novel Variant

Background: Polled intersex syndrome (PIS) leads to reproductive disorders in goats and exerts a heavy influence on goat breeding. Since 2001, the core variant of an 11.7 kb deletion at ~129 Mb on chromosome 1 (CHI1) has been widely used as a genetic diagnostic criterion. In 2020, a ~0.48 Mb insertion within the PIS deletion was identified by sequencing in XX intersex goats. However, the suitability of this variation for the diagnosis of intersex goats worldwide and its further molecular genetic mechanism need to be clarified.Results: The whole-genome selective sweep of intersex goats from China was performed with whole-genome next-generation sequencing technology for large sample populations and a case–control study on interbreeds. A series of candidate genes related to the goat intersexuality phenotype were found. We further confirmed that a ~0.48 Mb duplicated fragment (including ERG and KCNJ15) downstream of the ~20 Mb PIS region was reversely inserted into the PIS locus in intersex Chinese goats and was consistent with that in European Saanen and Valais black-necked goats. High-throughput chromosome conformation capture (Hi-C) technology was then used to compare the 3D structures of the PIS variant neighborhood in CHI1 between intersex and non-intersex goats. A newly found structure was validated as an intrachromosomal rearrangement. This inserted duplication changed the original spatial structure of goat CHI1 and caused the appearance of several specific loop structures in the adjacent ~20 kb downstream region of FOXL2.Conclusions: Results suggested that the novel complex PIS variant genome was sufficient as a broad-spectrum clinical diagnostic marker of XX intersexuality in goats from Europe and China. A series of private dense loop structures caused by segment insertion into the PIS deletion might affect the expression of FOXL2 or other neighboring novel candidate genes. However, these structures require further in-depth molecular biological experimental verification. In general, this study provided new insights for future research on the molecular genetic mechanism underlying female-to-male sex reversal in goats.

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