Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment
Abstract
:1. Introduction
2. Materials and Methods
2.1. Subjects
2.2. Whole-Exome Sequencing (WES)
2.3. AFF Network Construction (AFFNET)
3. Results
3.1. Variant Selection
3.2. AFF Network Analysis with Candidate Genes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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With AFF N = 12 | No AFF N = 4 | p-Value | |
---|---|---|---|
Mean age (years ± SD) | 74.5 ± 6.1 | 79 ± 7.2 | NS |
BMI ± SD | 29.7 ± 4.6 | 25.3 ± 3.3 | NS |
Time on BP (Years ± SD) | 9.1 ± 4.4 | 9 ± 2.7 | NS |
Denosumab (n) | 2 | 1 | NS |
Corticosteroid treatment (n) | 6 | 0 | <0.05 |
AFF Bilateral (n) | 3 | - | - |
Previous OP fractures (n) | 8 | 2 | NS |
Genes with Rare Variants in Two AFF Cases | Genes with Rare Variants in More Than two AFF Cases | ||||
---|---|---|---|---|---|
Two Different Variants | One Variant | ||||
Gene Name | Gene Name | Gene Name | Gene Name | Gene Name | Number of Variants and (Carriers) |
AASS | DNAH10 | PSD3 | ACADL | C8orf46 | 1 (3) |
ABCA10 | DNAH12 | PTH1R | C1orf87 | CHRNG | 3 (3) |
ABCA4 | DNAH6 | PYHIN1 | CD1A | DAAM2 | 3 (3, one homoz) |
ABL2 | DYSF | R3HDML | CITED4 | DNAH14 | 4 (4) |
ADAMTS12 | EFHB | RET | GBA | DNAH2 | 3 (3) |
ANAPC11 | EP400 | RMDN1 | IQSEC3 | DNAH9 | 3 (3) |
ANK3 | ERCC5 | RNF157 | NSMAF | FSIP2 | 3 (3) |
ANKRD40 | FAT4 | RNF34 | PPP2R1B | HLA-DRB1 | 2 (4) |
ARHGEF18 | FBLN7 | RTEL1 | SERPINB2 | HRASLS | 1 (3) |
ARID1B | FLJ00418 | SCN9A | SPTBN1 | IGFLR1 | 2 (2, one homoz) |
ASH1L | GBP3 | 5-Sep | SYDE1 | KRT10 | 1 (5) |
ATAD2 | GPX4 | SH3BP2 | TNFRSF25 | LAMA1 | 3 (3) |
ATP10B | HK3 | SHROOM4 | TRAPPC2L | LRP5 | 4 (3) |
BIN1 | HPS6 | SIRT5 | TRIM32 | MRPS12 | 1 (3) |
C10orf54 | IGFN1 | SLC26A9 | NEB | 4 (4) | |
C12orf42 | IGSF10 | SLC2A7 | OBSCN | 5 (5) | |
C14orf159 | IGSF22 | SLC34A3 | TCOF1 | 3 (4) | |
C17orf107 | KLHL33 | SLC52A2 | TNXB | 3 (3) | |
C6 | LLGL1 | SPTBN5 | TTN | 8 (8) | |
C9orf84 | MEX3D | SRCAP | UTRN | 3 (3) | |
CA9 | MKS1 | TAF15 | VEGFB | 1 (3) | |
CDC42BPG | MMP20 | TENM4 | ZC3H3 | 3 (3) | |
CERKL | MSLNL | TJP3 | |||
CHAMP1 | NOD2 | TMEM143 | |||
CLCN2 | NUP153 | TNRC6B | |||
CRYBA1 | OPLAH | TOPORS | |||
CTSE | PACSIN2 | TSFM | |||
CUL7 | PARD6B | TTC14 | |||
CYYR1 | PCDHAC1 | ZNF34 | |||
DAB2IP | PDE4DIP | ZNF646 | |||
DAW1 | PISD | ZNF729 | |||
DHX34 | PLA2G4D | ZSCAN32 |
Gene ID | Number of Carriers | Function | Bone Association | Bibliography Source |
---|---|---|---|---|
CUL7 | 2 | A core component of the 3 M complex required to regulate microtubule dynamics and genome integrity | Mutations in this gene produce the 3 m syndrome, which causes skeletal abnormalities | Genecards |
Daam2 | 3 | Involved in the canonical Wnt signaling, a pathway critical for bone formation and repair | SNPs in this gene are associated with estimated bone mineral density (eBMD). Daam2 knockout mouse showed decreased bone strength | Musculoskeletal Knowledge Portal, Morris et al., 2019 [24] |
DNAH10 | 2 | Found in cilia and flagella; ATPase activity and microtubule motor activity | SNPs in this gene are associated with waist-hip ratio and eBMD. | Musculoskeletal Knowledge Portal |
DNAH12 | 2 | ATPase activity and microtubule motor activity | SNPs in this gene are associated with waist-hip ratio and eBMD | Musculoskeletal Knowledge Portal |
LAMA1 | 3 | A major component of the basal membrane which has been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, and signaling | Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components. | Genecards |
LRP5 | 4 | A co-receptor with Frizzled protein family members for transducing signals by Wnt proteins | It plays a key role in skeletal homeostasis and many bone density related diseases are caused by mutations in this gene | Genecards |
MEX3D | 2 | RNA binding protein, may be involved in post-transcriptional regulatory mechanisms | Found mutated in three sisters with AFF | Roca-Ayats N, et al. 2018 [12] |
PTH1R | 2 | A receptor for parathyroid hormone (PTH) and for parathyroid hormone-like hormone (PTHLH). | Involved in the Hedgehog and PTH signaling pathways in bone and cartilage development | Genecards |
SLC34A3 | 2 | Involved in the transporting phosphate into cells via sodium cotransport in the renal brush border membrane, and contributes to the maintenance of inorganic phosphate concentration in the kidney | Mutations in this gene are associated with hereditary hypophosphatemic rickets with hypercalciuria. | Genecards |
SPTBN1 | 2 | Spectrin is an actin crosslinking and molecular scaffold protein that links the plasma membrane to the actin cytoskeleton, and functions in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles | SNPs in this gene are associated with eBMD and total body BMD | Musculoskeletal Knowledge Portal |
TNRC6B | 2 | Involved in cellular senescence, innate or adaptive immune system, Wnt signaling, and calcium modulating pathways | SNPs in this gene are mainly associated with lean mass. One SNP was also associated with lower lumbar spine BMD and increased risk of fractures | Karasik D, et al. 2019 [27] |
TNXB | 3 | A member of the tenascin family of extracellular matrix glycoproteins | Mutations in this gene are associated with the Ehlers-Danlos Syndrome | Genecards |
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Garcia-Giralt, N.; Roca-Ayats, N.; Abril, J.F.; Martinez-Gil, N.; Ovejero, D.; Castañeda, S.; Nogues, X.; Grinberg, D.; Balcells, S.; Rabionet, R. Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment. Genes 2022, 13, 146. https://doi.org/10.3390/genes13010146
Garcia-Giralt N, Roca-Ayats N, Abril JF, Martinez-Gil N, Ovejero D, Castañeda S, Nogues X, Grinberg D, Balcells S, Rabionet R. Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment. Genes. 2022; 13(1):146. https://doi.org/10.3390/genes13010146
Chicago/Turabian StyleGarcia-Giralt, Natalia, Neus Roca-Ayats, Josep F Abril, Nuria Martinez-Gil, Diana Ovejero, Santos Castañeda, Xavier Nogues, Daniel Grinberg, Susanna Balcells, and Raquel Rabionet. 2022. "Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment" Genes 13, no. 1: 146. https://doi.org/10.3390/genes13010146
APA StyleGarcia-Giralt, N., Roca-Ayats, N., Abril, J. F., Martinez-Gil, N., Ovejero, D., Castañeda, S., Nogues, X., Grinberg, D., Balcells, S., & Rabionet, R. (2022). Gene Network of Susceptibility to Atypical Femoral Fractures Related to Bisphosphonate Treatment. Genes, 13(1), 146. https://doi.org/10.3390/genes13010146