Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus

Abstract

Introduction Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. Methods We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in-silico analyses. Results The Japanese GWAS identified four significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 (OR = 1.99, P-value = 1.1 × 10−9), TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10−8) and MYO16 (OR = 3.91, P-value = 4.9 × 10−10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. Conclusions We identified three novel susceptibility loci for S-ONFH in SLE.

The 330 risk loci known for systemic lupus erythematosus (SLE): a review

“…Furthermore, some results have not yet been replicated even within the same study. For example, rs2714333 (RREB1), which is significant in a sample of Japanese with an alleged OR = 3.11 (p = 10 −08 ), did not show even a trend in the same direction from a meta-analysis of a larger EAS sample set (p = 0.18) (32). The examples of rs933717 and rs2714333 appear to be potentially spurious putative associations with SLE, highlighting the caution needed for alleged association results with large effect sizes (OR > 3) reported in a single study.…”

“…Study ascertainment differences may accentuate the heterogeneity intrinsic to lupus in ways that differentially concentrate the genetics important for subsets with respect to clinical findings or sex. An example is the rare variant rs529561493 (MAF = 0.0004) at 1q32.1 in RASSF5 that was associated (OR = 3.66) with SLE in SLE patients with steroidassociated osteonecrosis of the femoral head compared with healthy controls but not reported in other studies that included patients with more broad SLE spectrum (32). Some studies (20) include only females while most include both sexes.…”

Bone marrow mesenchymal stem cells‐derived exosomes mediate nuclear receptor coactivator‐3 expression in osteoblasts by delivering miR‐532‐5p to influence osteonecrosis of the femoral head development

“…Osteonecrosis of the femoral head (ONFH) is a kind of necrosis of the femoral head and bone marrow caused by ischemia (Suetsugu et al, 2021). At present, the incidence of ONFH is increasing year by year worldwide, and there are 8.12 million ONFH patients in China alone (D. Zhao et al, 2020).…”

Population-specific reference panel improves imputation quality and enhances locus discovery and fine-mapping

“…and systemic lupus erythematosus(40,41) MATERIAL AND METHODS Biobank Japan (BBJ) Project. All individuals participating in this study were collected through the BBJ Project, which is a multi-institutional hospital-based registry.…”