Genetic biomarkers related to hemarthrosis, inflammation, and cartilage structure in pediatric patients with hemophilic arthropathy

Abstract

BackgroundThe pathophysiology of hemophilic arthropathy is complex and not completely understood. In this study, we aimed to identify biomarkers that can affect the hemophilic arthropathy severity.MethodsFifty patients were analyzed for biomarker frequencies; in 37 patients, articular symptoms were evaluated based on the physical joint examination score, and in 18, it was based on magnetic resonance imaging. Eight polymorphisms, namely FV 1691G>A, FII 20210G>A, MTHFR 677C>T and 1298A>C, TNFα‐308G>A and ‐238G>A, ACAN VNTR, and IL1RN*2‐VNTR were identified.ResultsPatients with the MTHFR 677TT genotype showed a higher number of affected joints (1.83 ± 0.9 vs. 0.55 ± 0.7 for CC; p = .023), whereas those with the MTHFR 1298AC genotype exhibited higher effusion according to two radiologists (0.90 ± 0.31/1.20 ± 0.63 vs. 0.38 ± 0.52/0.50 ± 0.53 for AA genotype; p = .043/0.036, respectively). In addition, patients with the TNFα‐308GA genotype had more subchondral cysts (0.75 ± 0.95 vs. 0.07 ± 0.26 for GG genotype; p = .041).ConclusionsThe distribution of risk genotypes for MTHFR and TNFα‐308GA suggests their association with clinical parameters of hemophilic arthropathy. Cohort studies are essential to verify these associations.

Asymptomatic Joint Bleeding and Joint Health in Hemophilia: A Review of Variables, Methods, and Biomarkers

“… 29 A small study reported that patients with the MTHFR variants MTHFR 677TT or MTHFR 1298AC had a higher number of affected joints or a higher degree of effusion, respectively, compared to patients with other genotypes. 30 Furthermore, this study also found a positive association between genetic biomarkers related to inflammation and number of subchondral cysts.…”

“… 30 Furthermore, this study also found a positive association between genetic biomarkers related to inflammation and number of subchondral cysts.…”

“…Several studies have correlated gene mutations with joint outcomes in patients with hemophilia (Table 2). [24][25][26][27][28][29][30] An investigation conducted in 14 hemophilia treatment centers in the United States found that a total of 613 single nucleotide polymorphism (SNP) markers were significantly correlated with ROM scores on at least two joint pairs. 24 This study also identified multiple inflammatory-or immunerelated genes that were associated with arthropathy; SNPs in the NOD2 (associated with musculoskeletal manifestations in inflammatory bowel disease) and TLR10 (role in pathogen recognition and activation of innate immunity) genes were potentially strongly associated with arthropathy, but only a small number of patients carried the variant alleles.…”

Hemophilic arthropathy: Current knowledge and future perspectives

“…Lopez‐Jimenez et al . have reported that carriers of the TNFα‐308G>A variant have a larger number of subchondral cysts, 17 platelet aggregation, 18 and the innate immune response pathways that play a fundamental role in pathogen recognition and the activation of innate immunity such as nucleotide‐binding oligomerization domain‐containing protein 2, and toll‐like receptor 10 . 19 …”

“…However, as patients with the same mutation often have different bleeding phenotypes, other genetic factors such as inherited thrombophilia may also be involved. 16 Genetic susceptibility to more rapid joint damage progression also involves gene polymorphisms associated with an increased expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF)α. Lopez-Jimenez et al have reported that carriers of the TNFα-308G>A variant have a larger number of subchondral cysts, 17 platelet aggregation, 18 and the innate immune response pathways that play a fundamental role in pathogen recognition and the activation of innate immunity such as nucleotide-binding oligomerization domain-containing protein 2, and toll-like receptor 10 . 19…”