Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head.
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ABSTRACT:
SUBMITTER: Sakamoto Y
PROVIDER: S-EPMC5678103 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
Publications
Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head.
Sakamoto Yuma Y Yamamoto Takuaki T Sugano Nobuhiko N Takahashi Daisuke D Watanabe Toshiyuki T Atsumi Takashi T Nakamura Junichi J Hasegawa Yukiharu Y Akashi Koichi K Narita Ichiei I Miyamoto Takeshi T Takeuchi Tsutomu T Ikari Katsunori K Amano Koichi K Fujie Atsuhiro A Kubo Toshikazu T Tada Yoshifumi Y Kaneuji Ayumi A Nakamura Hiroaki H Miyamura Tomoya T Kabata Tamon T Yamaji Ken K Okawa Takahiro T Sudo Akihiro A Ohzono Kenji K Tanaka Yoshiya Y Yasunaga Yuji Y Matsuda Shuichi S Imai Yuuki Y Akiyama Masato M Kubo Michiaki M Kamatani Yoichiro Y Iwamoto Yukihide Y Ikegawa Shiro S
Scientific reports 20171108 1
Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibi ...[more]
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Project description:Osteonecrosis of the femoral head (ONFH) is a multifactorial disease and is associated with genetic predisposition, and exposure to certain risk factors. In particular, idiopathic ONFH in twins and the clustering of cases in families have indicated that genetic factors are involved. However, the majority of cases of ONFH are sporadic and various studies have demonstrated that differences in the study design and/or the ethnic groups analyzed leads to different results. The present study performed one of the first genome‑wide association studies to identify genetic loci that may increase the risk of idiopathic ONFH. In total, 217 patients with idiopathic ONFH and 217 control samples, without ONFH, were genotyped using Axiom™ chips. Following quality control, 509,886 single‑nucleotide polymorphisms (SNPs) were included in the association analysis to identify genetic variants that may influence susceptibility to idiopathic ONFH. The lowest P‑value identified by the current study was for an association with rs220324 (P=3.57x10‑7), an SNP that is located near to the uromodulin‑like 1 gene region on chromosome 21q22.3, although none of the SNPs reached the traditional genome‑wide significance level of 5x10‑8. However, the DnaJ heat shock protein family (Hsp40) member C6 (DNAJC6) locus, a region between 65.37 and 65.67 Mb located on chromosome 1p31.3, harbored a cluster of SNPs that were associated with idiopathic ONFH at a significance level of P<1x10‑5. Four variants, rs10493374, rs12032616, rs17127529 and rs6679032, with marginal associations were located in and around the DNAJC6 locus and were in strong linkage disequilibrium with each other. In conclusion, the current study did not identify any SNPs that were associated with idiopathic ONFH at a genome‑wide significance level, however, the results suggest that future studies should investigate the effects of SNPs in the DNAJC6 gene on the idiopathic ONFH risk.
| S-EPMC5364851 | biostudies-literature
Project description:Objectives Urinary microRNAs (miRNAs) have shown great diagnostic and prognostic values for multiple diseases. The profile of urinary miRNAs in patients with idiopathic osteonecrosis of femoral head (ONFH) is currently unclear. Methods We first randomly chose ten patients with each Association Research Circulation Osseous (ARCO) stage (I, II, III and IV) and ten healthy participants from the entire cohorts for initial screening. The miRNA polymerase chain reaction (PCR) array was then performed to identify the differentially abundant miRNAs in urine of these participants. We then verified the findings in the entire cohort. Clinical features including age, gender, bone mass index (BMI), lesion size and stages were recorded. We then analysed the association between the level of urinary miRNAs and clinical features. Results Our data indicated that there were 13 differentially abundant miRNAs among all groups. Urinary miR-150 demonstrated the highest diagnostic value among all candidates. Urinary miR-185 and miR-133a increased by ARCO staging. The levels of urinary miR-4824 abruptly decreased after femoral head collapse (ARCO stage III and IV). Urinary miR-144 was the only marker that correlated with lesion size. Conclusions The levels of urinary miRNAs are valuable biomarkers for idiopathic ONFH. Given the noninvasive nature of this test, it is potentially useful for diagnosis and monitoring of idiopathic ONFH progression. The translational potential of this article This article gives novel methods for ONFH diagnosis and progression monitoring in a convenient and non-invasive way.
| S-EPMC7773953 | biostudies-literature
Project description:ObjectiveThis study aims to identify novel candidate genes associated with osteonecrosis of the femoral head (ONFH).MethodsA transcriptome-wide association study (TWAS) was performed by integrating the genome-wide association study dataset of osteonecrosis (ON) in the UK Biobank with pre-computed mRNA expression reference weights of muscle skeleton (MS) and blood. The ON-associated genes identified by TWAS were further subjected to gene ontology (GO) analysis by the DAVID tool. Finally, a trans-omics comparative analysis of TWAS and genome-wide mRNA expression profiling was conducted to identify the common genes and the GO terms shared by both DNA-level TWAS and mRNA-level expression profile for ONFH.ResultsTWAS totally identified 564 genes that were with P TWAS value <0.05 for MS and blood, such as CBX1 (P TWAS = 0.0001 for MS), SRPK2 (P TWAS = 0.0002 for blood), and MYO5A (P TWAS = 0.0005 for blood). After comparing the genes detected by TWAS with the differentially expressed genes identified by mRNA expression profiling, we detected 59 overlapped genes, such as STEAP4 [P TWAS = 0.0270, FC (fold change)mRNA = 7.03], RABEP1 (P TWAS = 0.010, FCmRNA = 2.22), and MORC3 (P TWAS = 0.0053, FCmRNA = 2.92). The GO analysis of TWAS-identified genes discovered 53 GO terms for ON. Further comparing the GO results of TWAS and mRNA expression profiling identified four overlapped GO terms, including cysteine-type endopeptidase activity (P TWAS = 0.0006, P mRNA = 0.0227), extracellular space (P TWAS = 0.0342, P mRNA = 0.0012), protein binding (P TWAS = 0.0112, P mRNA = 0.0106), and ATP binding (P TWAS = 0.0464, P mRNA = 0.0033).ConclusionSeveral ONFH-associated genes and GO terms were identified by integrating TWAS and mRNA expression profiling. It provides novel clues to reveal the pathogenesis of ONFH.
| S-EPMC8215574 | biostudies-literature
Project description:The purpose of this study was to investigate the relationship between Paraoxonase-1 (PON1) gene rs662, rs854555 polymorphisms and osteonecrosis of the femoral head (ONFH) in Han population, northern China.Polymerase chain reaction-restriction fragment length polymorphism was used to determine genotypes of PON1 polymorphisms in 84 patients with ONFH and 96 healthy persons. χ test was used to compare distribution differences of genotype, allele, and haplotype between the case and control groups. The odds ratio (OR) and 95% confidence interval (CI) were calculated to reveal the effects of PON1 polymorphisms on risk of ONFH, and the results were adjusted using logistic regression analysis. The linkage disequilibrium and haplotype analysis were performed with haploview software.That people carrying AA genotype of rs662 were easier to be attacked by ONFH than GG genotype carriers (OR = 2.53, 95% CI = 1.05-6.07, P = .038). Meanwhile, the frequency of A allele in the case group was significantly higher than the controls and it was a risk factor for ONFH (OR = 1.56, 95% CI = 1.03-2.38, P = .038). The A-A haplotype frequency of rs854555-rs662 in PON1 was significantly correlated to the increased susceptibility to ONFH (OR = 2.74, 95% CI = 1.28-5.84).The rs662 polymorphism in PON1 may be associated with ONFH susceptibility, but not rs854555 in Han population, northern China. Additionally, haplotype is also a nonignorable risk factor.
| S-EPMC5662370 | biostudies-literature
Project description:ObjectiveIschemic osteonecrosis of the femoral head (ONFH) in piglets results in an ischemic injury to the immature articular cartilage. The molecular changes in the articular cartilage in response to ONFH have not been investigated using a transcriptomic approach. The purpose of this study was to perform a genome-wide transcriptomic analysis to identify genes that are upregulated in the immature articular cartilage following ONFH.MethodsONFH was induced in the right femoral head of 6-week old piglets. The unoperated femoral head was used as the normal control. At 24 hours (acute ischemic-hypoxic injury), 2 weeks (avascular necrosis in the femoral head) and 4 weeks (early repair) after surgery (n = 4 piglets/time point), RNA was isolated from the articular cartilage of the femoral head. A microarray analysis was performed using Affymetrix Porcine GeneChip Array. An enrichment analysis and functional clustering of the genes upregulated due to ONFH were performed using DAVID and STRING software, respectively. The increased expression of selected genes was confirmed by a real-time qRTPCR analysis.ResultsInduction of ONFH resulted in the upregulation of 383 genes at 24 hours, 122 genes at 2 weeks and 124 genes at 4 weeks compared to the normal controls. At 24 hours, the genes involved in oxidoreductive, cell-survival, and angiogenic responses were significantly enriched among the upregulated genes. These genes were involved in HIF-1, PI3K-Akt, and MAPK signaling pathways. At 2 weeks, secretory and signaling proteins involved in angiogenic and inflammatory responses, PI3K-Akt and matrix-remodeling pathways were significantly enriched. At 4 weeks, genes that represent inflammatory cytokines and chemokine signaling pathways were significantly enriched. Several index genes (genes that are upregulated at more than one time point following ONFH and are known to be important in various biological processes) including HIF-1A, VEGFA, IL-6, IL6R, IL-8, CCL2, FGF2, TGFB2, MMP1, MMP3, ITGA5, FN and Col6A1 were upregulated in the immature articular cartilage following ONFH. A qRTPCR analysis of selected genes confirmed the upregulated expression observed in the microarray analysis.ConclusionImmature articular cartilage responds to ONFH by the upregulation of genes involved in hypoxic stress response, angiogenesis, matrix remodeling and inflammation. This study provides novel insights into the multi-faceted role of immature articular cartilage, with inflammation as a key component, following ONFH in piglets.
| S-EPMC4821627 | biostudies-literature
Project description:BackgroundAlcohol-induced osteonecrosis of femoral head (ONFH) is a complex disease and genetic factors are one of the causes. The purpose of this study is to investigate the effects of RETN (resistin; OMIM: 605565) and LDLR (low density lipoprotein receptor; OMIM: 606945) polymorphisms on the risk of alcohol-induced ONFH in Chinese Han population.MethodsA case-control study including 201 patients and 201 controls was designed. Seven single nucleotide polymorphisms (SNPs) in RETN gene and four SNPs in LDLR gene were genotyped using Agena MassARRAY platform. In allele model and genetic model, chi-square test and logistic regression were used to study the associations between these SNPs and ONFH susceptibility. In addition, the relationships between these SNPs, clinical phenotypes, and blood lipid level with one-way analysis of variance were analyzed.ResultsIn the allele model, rs7408174 and rs3745369 in RETN were associated with increased risk of alcohol-induced ONFH, whereas rs34861192 and rs3219175 in RETN showed reduced risk of alcohol-induced ONFH. In the genetic model, rs7408174 was associated with increased risk of alcohol-induced ONFH in dominant model and log-additive model. Rs3745369 showed an increased risk in codominant model, recessive model, and log-additive model. Rs34861192 showed a decreased risk in codominant model, dominant model, and log-additive model, and rs3219175 showed a decreased risk in dominant model and log-additive model. The rs3745368 in RETN was associated with the clinical stage of the disease.ConclusionThese results suggest that RETN genetic polymorphisms are associated with the susceptibility of alcohol-induced ONFH in Chinese Han population.
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Project description:Poor femoral neck bone geometry at the femur is an important risk factor for hip fracture. We conducted a genome-wide association study (GWAS) of femoral neck bone geometry, examining approximately 379,000 eligible single-nucleotide polymorphisms (SNPs) in 1000 Caucasians. A common genetic variant, rs7430431 in the receptor transporting protein 3 (RTP3) gene, was identified in strong association with the buckling ratio (BR, P = 1.6 x 10(-7)), an index of bone structural instability, and with femoral cortical thickness (CT, P = 1.9 x 10(-6)). The RTP3 gene is located in 3p21.31, a region that we found to be linked with CT (LOD = 2.19, P = 6.0 x 10(-4)) in 3998 individuals from 434 pedigrees. The replication analyses in 1488 independent Caucasians and 2118 Chinese confirmed the association of rs7430431 to BR and CT (combined P = 7.0 x 10(-3) for BR and P = 1.4 x 10(-2) for CT). In addition, 350 hip fracture patients and 350 healthy control individuals were genotyped to assess the association of the RTP3 gene with the risk of hip fracture. Significant association between a nearby common SNP, rs10514713 of the RTP3 gene, and hip fracture (P = 1.0 x 10(-3)) was found. Our observations suggest that RTP3 may be a novel candidate gene for femoral neck bone geometry.
| S-EPMC3153387 | biostudies-literature
Project description:We observed 21 prominent protein spots that differed between the two groups. Three of these proteins were upregulated and the rest 18 proteins were downregulated in patients with steroid-induced ONFH. The spots determined in the steroid-induced ONFH and health control groups were replicable.The spot no. 21 corresponding to an upregulated protein in patients with steroid-induced ONFH was identified as SAA.
2022-02-15 | PXD028318 | Pride
Project description:This study aimed to analyze the correlation of the plasminogen activator inhibitor (PAI-1) gene polymorphisms (rs6092 and rs7242) with susceptibility of osteonecrosis of the femoral head (ONFH).This case-control study included 106 ONFH patients and 151 healthy controls. PAI-1 polymorphisms were genotyped by polymerase chain reaction (PCR) with direct sequencing. The genotype distribution of polymorphism in the control group was checked with the status of Hardy-Weinberg equilibrium (HWE). The χ test was applied to compare the genotypes of polymorphisms between the case and control groups. The association intensity between PAI-1 polymorphisms and ONFH risk was estimated by odds ratios (ORs) and 95% confidence intervals (95% CI). The linkage disequilibrium of PAI-1 polymorphisms was analyzed by Haploview.We found that the genotypes and alleles of PAI-1 rs6092 and rs7242 polymorphisms had no obvious association with the risk of ONFH (P >.05). But the strong linkage disequilibrium existed between rs6092 and rs7242 polymorphisms and haplotype G-T was significantly associated with the decreased risk of ONFH occurrence (OR = 0.666, 95%CI = 0.445-0.998).PAI-1 rs6092 and rs7242 polymorphisms are not associated with ONFH development, but haplotype G-T may be a protective factor of ONFH.
| S-EPMC5662335 | biostudies-literature
Project description:Osteonecrosis of the femoral head is a disabling condition affecting young patients and treatment of the disease in these patients is variable. We retrospectively reviewed 39 patients (43 hips) in whom a modified transtrochanteric rotational osteotomy was performed for osteonecrosis. The minimum followup was 24 months (mean, 36.6 months; range, 24-52 months). The mean patient age was 34.3 years (range, 20-51 years). Based on the ARCO classification, 17 hips were classified as Stage II and 26 as Stage III. We performed rotational osteotomy alone in 15 cases, in combination with simple bone grafting in three, and in combination with muscle-pedicle-bone grafting in 25. Sixteen of 17 ARCO Stage II cases and 24 of 26 ARCO Stage III cases had no progression of collapse or lesion size; three hips progressively collapsed. Of the 40 hips without progression the Harris hip score improved from a mean 70 to 92 points at final followup, as did the range of motion of the hip. Modified transtrochanteric rotational osteotomy is an effective method for delaying the progression of collapse in the treatment of selected cases of osteonecrosis of the femoral head.
| S-EPMC2311485 | biostudies-other