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- Koromani, F., et al.
(författare)
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The "GEnomics of Musculo Skeletal Traits TranslatiOnal NEtwork": Origins, Rationale, Organization, and Prospects
- 2021
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Musculoskeletal research has been enriched in the past ten years with a great wealth of new discoveries arising from genome wide association studies (GWAS). In addition to the novel factors identified by GWAS, the advent of whole-genome and whole-exome sequencing efforts in family based studies has also identified new genes and pathways. However, the function and the mechanisms by which such genes influence clinical traits remain largely unknown. There is imperative need to bring multidisciplinary expertise together that will allow translating these genomic discoveries into useful clinical applications with the potential of improving patient care. Therefore "GEnomics of MusculoSkeletal traits TranslatiOnal NEtwork" (GEMSTONE) aims to set the ground for the: 1) functional characterization of discovered genes and pathways; 2) understanding of the correspondence between molecular and clinical assessments; and 3) implementation of novel methodological approaches. This research network is funded by The European Cooperation in Science and Technology (COST). GEMSTONE includes six working groups (WG), each with specific objectives: WG1-Study populations and expertise groups: creating, maintaining and updating an inventory of experts and resources (studies and datasets) participating in the network, helping to assemble focus groups defined by phenotype, functional and methodological expertise. WG2-Phenotyping: describe ways to decompose the phenotypes of the different functional studies into meaningful components that will aid the interpretation of identified biological pathways. WG3 Monogenic conditions - human KO models: makes an inventory of genes underlying musculoskeletal monogenic conditions that aids the assignment of genes to GWAS signals and prioritizing GWAS genes as candidates responsible for monogenic presentations, through biological plausibility. WG4 Functional investigations: creating a roadmap of genes and pathways to be prioritized for functional assessment in cell and organism models of the musculoskeletal system. WG5 Bioinformatics seeks the integration of the knowledge derived from the distinct efforts, with particular emphasis on systems biology and artificial intelligence applications. Finally, WG6 Translational outreach: makes a synopsis of the knowledge derived from the distinct efforts, allowing to prioritize factors within biological pathways, use refined disease trait definitions and/or improve study design of future investigations in a potential therapeutic context (e.g. clinical trials) for musculoskeletal diseases.
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- Pettersson, Ulrika, et al.
(författare)
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Polymorphisms of the CLCN7 gene are associated with BMD in women.
- 2005
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Ingår i: Journal of Bone and Mineral Research. - 0884-0431 .- 1523-4681. ; 20:11, s. 1960-7
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Tidskriftsartikel (refereegranskat)abstract
- UNLABELLED: Here we show that a common polymorphism causing a valine to methionine amino acid substitution at codon 418 (V418M) in the CLCN7 gene is associated with femoral neck BMD in women. Our study adds to accumulating evidence that shows that common allelic variants in monogenic bone disease genes often contribute to BMD regulation in normal subjects. INTRODUCTION: The CLCN7 gene is a strong candidate for regulation of BMD, because mutations in CLCN7 cause some forms of osteopetrosis, a disease characterized by impaired osteoclast function and increased BMD. In this study, we sought to determine whether common allelic variation within CLCN7 was associated with BMD in the normal population. MATERIALS AND METHODS: We conducted mutation screening of the exons and intron-exon boundaries in CLCN7 by DNA sequencing in 50 normal subjects. We conducted an association study between common polymorphisms in CLCN7 and haplotypes defined by these polymorphisms and BMD values at the lumbar spine and femoral neck in a population-based cohort study of 1077 Scottish women 45-55 years of age. RESULTS: We identified 24 polymorphisms, but most were rare and only 4 had allele frequencies of >5%. These were a conservative single nucleotide polymorphism (SNP) in exon 1 (rs3751884), a 50-bp tandem repeat polymorphism within intron 8, and two SNPs within exon 15 (rs12926089 and rs12926669), of which one (rs12926669) predicts an amino acid change from valine to methionine at codon 418 (V418M). The exon 15 SNPs were in strong linkage disequilibrium and were both associated with femoral neck BMD (p = 0.001-0.003). None of the other polymorphisms were associated with BMD, and long-range haplotypes showed a much weaker association with BMD than the exon 15 SNPs. The V418M polymorphism was an independent predictor of femoral neck BMD on multiple regression analysis accounting for 1% of the variance in BMD at this site. CONCLUSIONS: Our study indicates that the V418M polymorphism of CLCN7 contributes to the genetic regulation of femoral neck BMD in women and adds to accumulating evidence that indicates that subtle polymorphic variation in genes that cause monogenic bone diseases also contribute to regulation of BMD in normal subjects.
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- Suijkerbuijk, Mathijs A. M., et al.
(författare)
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Functional polymorphisms within the inflammatory pathway regulate expression of extracellular matrix components in a genetic risk dependent model for anterior cruciate ligament injuries.
- 2019
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Ingår i: Journal of Science and Medicine in Sport. - : Elsevier. - 1440-2440 .- 1878-1861. ; 22:11, s. 1219-1225
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To investigate the functional effect of genetic polymorphisms of the inflammatory pathway on structural extracellular matrix components (ECM) and the susceptibility to an anterior cruciate ligament (ACL) injury.DESIGN: Laboratory study, case-control study.METHODS: Eight healthy participants were genotyped for interleukin (IL)1B rs16944 C>T and IL6 rs1800795 G>C and classified into genetic risk profile groups. Differences in type I collagen (COL1A1), type V collagen (COL5A1), biglycan (BGN) and decorin (DCN) gene expression were measured in fibroblasts either unstimulated or following IL-1β, IL-6 or tumor necrosis factor (TNF)-α treatment. Moreover, a genetic association study was conducted in: (i) a Swedish cohort comprised of 116 asymptomatic controls (CON) and 79 ACL ruptures and (ii) a South African cohort of 100 CONs and 98 ACLs. Participants were genotyped for COL5A1 rs12722 C>T, IL1B rs16944 C>T, IL6 rs1800795 G>C and IL6R rs2228145 G>C.RESULTS: IL1B high-risk fibroblasts had decreased BGN (p=0.020) and COL5A1 (p=0.012) levels after IL-1β stimulation and expressed less COL5A1 (p=0.042) following TNF-α treatment. Similarly, unstimulated IL6 high-risk fibroblasts had lower COL5A1 (p=0.012) levels than IL6 low-risk fibroblasts. In the genetic association study, the COL5A1-IL1B-IL6 T-C-G (p=0.034, Haplo-score 2.1) and the COL5A1-IL1B-IL6R T-C-A (p=0.044, Haplo-score: 2.0) combinations were associated with an increased susceptibility to ACL injury in the Swedish cohort when only male participants were evaluated.CONCLUSIONS: This study shows that polymorphisms within genes of the inflammatory pathway modulate the expression of structural and fibril-associated ECM components in a genetic risk depended manner, contributing to an increased susceptibility to ACL injuries.
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- Ventura, M, et al.
(författare)
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Recurrent sites for new centromere seeding
- 2004
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1088-9051. ; 14:9, s. 1696-1703
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Tidskriftsartikel (refereegranskat)abstract
- Using comparative FISH and genomics, we have studied and compared the evolution of chromosome 3 in primates and two human neocentromere cases on the long arm of this chromosome. Our results show that one of the human neocentromere cases maps to the same 3q26 chromosomal region where a new centromere emerged in a common ancestor of the Old World monkeys ∼25-40 million years ago. Similarly, the locus in which a new centromere was seeded in the great apes' ancestor was orthologous to the site in which a new centromere emerged in the New World monkeys' ancestor. These data suggest the recurrent use of longstanding latent centromeres and that there is an inherent potential of these regions to form centromeres. The second human neocentromere case (3q24) revealed unprecedented features. The neocentromere emergence was not accompanied by any chromosomal rearrangement that usually triggers these events. Instead, it involved the functional inactivation of the normal centromere, and was present in an otherwise phenotypically normal individual who transmitted this unusual chromosome to the next generation. We propose that the formation of neocentromeres in humans and the emergence of new centromeres during the course of evolution share a common mechanism.
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