Dataset Information

Trans-Ethnic Polygenic Analysis Supports Genetic Overlaps of Lumbar Disc Degeneration With Height, Body Mass Index, and Bone Mineral Density.

ABSTRACT: Lumbar disc degeneration (LDD) is age-related break-down in the fibrocartilaginous joints between lumbar vertebrae. It is a major cause of low back pain and is conventionally assessed by magnetic resonance imaging (MRI). Like most other complex traits, LDD is likely polygenic and influenced by both genetic and environmental factors. However, genome-wide association studies (GWASs) of LDD have uncovered few susceptibility loci due to the limited sample size. Previous epidemiology studies of LDD also reported multiple heritable risk factors, including height, body mass index (BMI), bone mineral density (BMD), lipid levels, etc. Genetics can help elucidate causality between traits and suggest loci with pleiotropic effects. One such approach is polygenic score (PGS) which summarizes the effect of multiple variants by the summation of alleles weighted by estimated effects from GWAS. To investigate genetic overlaps of LDD and related heritable risk factors, we calculated the PGS of height, BMI, BMD and lipid levels in a Chinese population-based cohort with spine MRI examination and a Japanese case-control cohort of lumbar disc herniation (LDH) requiring surgery. Because most large-scale GWASs were done in European populations, PGS of corresponding traits were created using weights from European GWASs. We calibrated their prediction performance in independent Chinese samples, then tested associations with MRI-derived LDD scores and LDH affection status. The PGS of height, BMI, BMD and lipid levels were strongly associated with respective phenotypes in Chinese, but phenotype variances explained were lower than in Europeans which would reduce the power to detect genetic overlaps. Despite of this, the PGS of BMI and lumbar spine BMD were significantly associated with LDD scores; and the PGS of height was associated with the increased the liability of LDH. Furthermore, linkage disequilibrium score regression suggested that, osteoarthritis, another degenerative disorder that shares common features with LDD, also showed genetic correlations with height, BMI and BMD. The findings suggest a common key contribution of biomechanical stress to the pathogenesis of LDD and will direct the future search for pleiotropic genes.

SUBMITTER: Zhou X

PROVIDER: S-EPMC6088183 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Trans-Ethnic Polygenic Analysis Supports Genetic Overlaps of Lumbar Disc Degeneration With Height, Body Mass Index, and Bone Mineral Density.

Zhou Xueya X Cheung Ching-Lung CL Karasugi Tatsuki T Karppinen Jaro J Samartzis Dino D Hsu Yi-Hsiang YH Mak Timothy Shin-Heng TS Song You-Qiang YQ Chiba Kazuhiro K Kawaguchi Yoshiharu Y Li Yan Y Chan Danny D Cheung Kenneth Man-Chee KM Ikegawa Shiro S Cheah Kathryn Song-Eng KS Sham Pak Chung PC

Frontiers in genetics 20180803

Lumbar disc degeneration (LDD) is age-related break-down in the fibrocartilaginous joints between lumbar vertebrae. It is a major cause of low back pain and is conventionally assessed by magnetic resonance imaging (MRI). Like most other complex traits, LDD is likely polygenic and influenced by both genetic and environmental factors. However, genome-wide association studies (GWASs) of LDD have uncovered few susceptibility loci due to the limited sample size. Previous epidemiology studies of LDD a ...[more]

PMID: 30127800

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Project description:BackgroundDisc height (DH) change is considered one of the most critical factors in assessing intervertebral disc degeneration (IVD). Pfirrmann et al. developed a scoring system for disc degeneration evaluation based on changes in DH in magnetic resonance imaging (MRI). While the relationship between DH measurements and Pfirrmann scores for disc degeneration has been explored, the validity of different DH measuring techniques or their connection with disc degeneration is yet uncertain. The present study investigates intra-rater and inter-rater agreement and reliability of different DH measurement methods on MRI and evaluates the relationship between different DH measurement methods and Pfirrmann scores of IVD degeneration, as well as between different Pfirrmann scores and clinical outcomes.MethodsAdult patients with MRI scans of the lumbar spine were recruited. Eight DH measuring techniques were tested for intra-rater and inter-rater agreement and reliability. Bland and Altman's Limits of Agreement (LOA) was used to evaluate intra-rater and inter-rater agreements. Intra-rater and inter-rater reliability were evaluated using intra-class correlations (ICC) with 95 % confidence intervals (95 % CI). The association between DH and Pfirrmann scores was examined using one-way ANOVA.ResultsExcellent intra-rater reliability was reported for 332 participants on DH (ranging from 0.912 (0.901, 0.923) to 0.973 (0.964, 0.981) and from 0.902 (0.892, 0.915) to 0.975 (0.962, 0.985) by two independent raters). All measuring methods had high intra-rater agreement, except for methods 4 and 5. All methods had good-to-excellent of inter-rater reliability on DH (ICCs ranging from 0.812 (0.795, 0.828) to 0.995 (0.994, 0.995)) except for the posterior disc material length of method 5 (ICC 0.740 (0.718, 0.761)). Methods 1 to 6 for evaluating DH in patients with spondylolisthesis had poor inter-rater reliability. The IVD levels with grades IV and V in Pfirrmann scores had significantly lower DH than the IVD levels with grades I to III in Pfirrmann scores. IVD levels with grades IV and V in Pfirrmann scores had significantly higher VAS and ODI than IVD levels with grades I in Pfirrmann scores.ConclusionA good-to-excellent intra-rater and inter-rater reliability was achieved on most DH measuring methods on MRI following a standardized and structured protocol. However, small anatomical structures and different tissue borders could influence measurements. Additionally, DH can differentiate between grade IV and V Pfirrmann scores, and severe IVD degeneration (IV and V Pfirrmann) is linked to clinical outcomes.

Project description:The association between growth differentiation factor 5 (GDF5), single nucleotide polymorphism (SNP) rs143383 and lumbar disc degeneration (LDD) was investigated. A total of 210 patients with LDD (observation group) and 320 patients without lumbar diseases (control group) diagnosed in Shanghai General Hospital of Nanjing Medical University from August 2013 to March 2017 were randomly selected. Then, deoxyribonucleic acid (DNA) was extracted from the blood of each patient, and Taq-man fluorescent quantitative polymerase chain reaction (qPCR) technique was used to detect rs143383 in GFD5 gene. The frequency of different genotypes in observation group and control group was counted, and the associations between different SNP genotypes and the incidence of LDD were analyzed. Good genotyping results were found in both LDD patient group and control group. There were no significant differences in distribution frequency of TT and TC genotypes at site rs143383 between LDD patient group and control group (P>0.05), but the distribution frequency of CC genotype at site rs143383 in LDD patient group had a statistically significant difference from that in control group (P<0.05). In dominant models, odds ratio (OR) of (TC+CC/TT) was 1.195 (P=0.532). In recessive models, OR of (CC/TT+TC) was 4.333 (P=0.028). In co-dominant models, ORs of (TC/TT) and (CC/TT) were 0.967 and 4.43, respectively (P=0.99). The differences in 3 genotypes showed no statistical significance among different pathological grades (Grade I to V) (?2=1.034, P=0.998), and there was no statistically significant difference in T and C (?2=0.012, P=0.999). Pathological grades in dominant models, recessive models and over dominant models were analyzed, and no statistically significant difference was found (P>0.05). In conclusion, CC mutant type at rs143383 in GDF5 gene has a strong association with the incidence of LDD, and a high prevalence risk, but it has no evident correlation with pathological grades.

Project description:Accumulating evidence has indicated that noncoding RNAs are involved in intervertebral disc degeneration (IDD); however, the competing endogenous RNA (ceRNA)‑mediated regulatory mechanisms in IDD remain rarely reported. The present study aimed to comprehensively investigate the alterations in expression levels of circular RNA (circRNA), long noncoding RNA (lncRNA), microRNA (miRNA/miR) and mRNA in the nucleus pulposus (NP) of patients with IDD. In addition, crucial lncRNA/circRNA‑miRNA‑mRNA ceRNA interaction axes were screened using the GSE67567 microarray dataset obtained from the Gene Expression Omnibus database. After data preprocessing, differentially expressed circRNAs (DECs), lncRNAs (DELs), miRNAs (DEMs) or genes (DEGs) between IDD and normal controls were identified using the Linear Models for Microarray data method. A protein‑protein interaction (PPI) network was constructed for DEGs based on protein databases, followed by module analysis. The ceRNA network was constructed based on the interaction between miRNAs and mRNAs, and lncRNAs/circRNAs and miRNAs. The underlying functions of mRNAs were predicted using the Database for Annotation, Visualization and Integrated Discovery database. The present study identified 636 DECs, 115 DELs, 84 DEMs and 1,040 DEGs between patients with IDD and control individuals. PPI network analysis demonstrated that Fos proto‑oncogene, AP‑1 transcription factor subunit (FOS), mitogen‑activated protein kinase 1 (MAPK1), hypoxia inducible factor 1 subunit α (HIF1A) and transforming growth factor β1 (TGFB1) were hub genes and enriched in modules. Metastasis‑associated lung adenocarcinoma transcript 1 (MALAT1)/hsa_circRNA_102348‑hsa‑miR‑185‑5p‑TGFB1/FOS, MALAT1‑hsa‑miR‑155‑5p‑HIF1A, hsa_circRNA_102399‑hsa‑miR‑302a‑3p‑HIF1A, MALAT1‑hsa‑miR‑519d‑3p‑MAPK1 and hsa_circRNA_100086‑hsa‑miR‑509‑3p‑MAPK1 ceRNA axes were obtained by constructing the ceRNA networks. In conclusion, these identified ceRNA interaction axes may be crucial targets for the treatment of IDD.

Dataset Information

Trans-Ethnic Polygenic Analysis Supports Genetic Overlaps of Lumbar Disc Degeneration With Height, Body Mass Index, and Bone Mineral Density.

Publications

Trans-Ethnic Polygenic Analysis Supports Genetic Overlaps of Lumbar Disc Degeneration With Height, Body Mass Index, and Bone Mineral Density.

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