GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.

Family History of Developmental Dysplasia of the Hip is a Risk Factor for the Progression of Hip Osteoarthritis.

BACKGROUND: Developmental dysplasia of the hip (DDH) is considered to have genetic predisposition and presents many intrafamilial occurrences. However, there is no report that evaluates the effect of DDH family history on the progression after the onset of hip osteoarthritis (OA). METHODS: Medical interviews about detailed clinical information including family history were conducted on 298 consecutive patients who had undergone surgery for OA due to DDH. Clinical or radiographic items that are associated with the severity of DDH (total hip arthroplasty [THA], involvement of bilateral DDH, onset age of hip pain, and three radiological indices of DDH: center-edge angle, sharp angle, and acetabular roof obliquity) were collected and evaluated in multivariate analyses for their associations with DDH family history in a qualitative or quantitative manner. Survival time analyses for THA as the endpoint was also performed to evaluate the effects of DDH family history on the progression of OA. RESULTS: The DDH family history showed significant associations with bilateral involvement of DDH (odds ratio = 2.09 [95% confidence interval {CI} 1.05 to 4.16]; P = .037), early onset of hip pain (P = .0065), and radiological severity of DDH (P = .016). The DDH family history showed a significant association with undergoing THA (odds ratio = 2.25 [95% CI 1.09 to 4.66]; P = .029), further supported by the Cox regression analyses (hazards ratio = 1.56 [95% CI 1.15 to 2.11]; P = .0044). CONCLUSION: A DDH family history is a risk factor for the progression of hip OA. Stronger genetic predisposition to DDH leads to faster onset and progression of hip OA.

Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects.

Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.

Identification of a Functional Susceptibility Variant for Adolescent Idiopathic Scoliosis that Upregulates Early Growth Response 1 (EGR1)-Mediated UNCX Expression.

Adolescent idiopathic scoliosis (AIS) is a serious health problem affecting 3% of live births all over the world. Many loci associated with AIS have been identified by previous genome wide association studies, but their biological implication remains mostly unclear. In this study, we evaluated the AIS-associated variants in the 7p22.3 locus by combining in silico, in vitro, and in vivo analyses. rs78148157 was located in an enhancer of UNCX, a homeobox gene and its risk allele upregulated the UNCX expression. A transcription factor, early growth response 1 (EGR1), transactivated the rs78148157-located enhancer and showed a higher binding affinity for the risk allele of rs78148157. Furthermore, zebrafish larvae with UNCX messenger RNA (mRNA) injection developed body curvature and defective neurogenesis in a dose-dependent manner. rs78148157 confers the genetic susceptibility to AIS by enhancing the EGR1-regulated UNCX expression. © 2022 American Society for Bone and Mineral Research (ASBMR).

Anterior superior iliac spine is not always reliable as a pelvic reference axis. -3D study of pelvic axis.

BACKGROUND: This study aims to evaluate the accuracy of the axis connecting both anterior superior iliac spines (ASIS axis) as the absolute pelvic axis. No study has ever verified the accuracy of ASIS axis particularly on the AP pelvic radiograph, which cannot be specified on it. METHODS: Sixty patients who underwent total knee arthroplasty and fifty patients with femoral neck fracture were recruited as subjects without hip deformities and their CT scan data were collected. We defined the line through both center of femoral heads as absolute reference axis of pelvis three-dimensionally. On the coronal plane, the errors between the femoral head axis and the axes through six pelvic landmarks in total, including ASIS were analyzed. On the axial plane, the errors of the lines through four landmarks were analyzed in the same way. Finally, on the coronal images, the mediolateral diameter of the obturator foramen and the mediolateral distance between the midline of the sacrum and the pelvic cavity were measured to evaluate bilateral symmetry of the pelvis. RESULTS: The errors tended to be smaller as the axes were closer to the femoral head axis (axes connecting bilateral superior aspects of the acetabulum and the teardrops) and the ASIS axis errors were moderate. The obturator foramen based on the ASIS axis was more asymmetrical than the femoral head axis. CONCLUSION: Adjusting the pelvic tilt and rotation, surgeons should not always rely on the ASIS and refer to appropriate, close to the hip joint references in each case.

Contemporary indications for first-time revision surgery after primary cementless total hip arthroplasty with emphasis on early failures.

BACKGROUND: To clarify contemporary indications for first-time revision surgery after primary cementless total hip arthroplasty (THA) for addressing potential issues with cementless THA. METHODS: Data for 101 consecutive hips in 94 patients who underwent primary cementless THA at our institution and subsequently underwent first-time revision surgery were retrospectively reviewed. Baseline characteristics, indications for first-time revision surgery, and time from the primary THA to first-time revision surgery were evaluated. RESULTS: The overall mean time to first-time revision surgery was 10.3 years (range, 0-33 years). The indications for first-time revision surgery were polyethylene wear and osteolysis in 33 hips, aseptic loosening in 25 hips, infection in 17 hips, periprosthetic fracture in 13 hips, instability in 8 hips, and component failure (liner dissociation or stem fracture) in 5 hips. Thirty-seven hips (37%) had undergone first-time revision surgery within 5 years of primary THA, of which the most common indications were infection and periprosthetic fracture. CONCLUSION: The current results suggested that reducing the number of early failures seems to be essential form improving THA outcomes.