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

Hiroyuki Suetsugu, Kwangwoo Kim, Takuaki Yamamoto, So Young Bang, Yuma Sakamoto, Jung Min Shin, Nobuhiko Sugano, Ji Soong Kim, Masaya Mukai, Yeon Kyung Lee, Koichiro Ohmura, Dae Jin Park, Daisuke Takahashi, Ga Young Ahn, Kohei Karino, Young Chang Kwon, Tomoya Miyamura, Jihye Kim, Junichi Nakamura, Goro MotomuraTakeshi Kuroda, Hiroaki Niiro, Takeshi Miyamoto, Tsutomu Takeuchi, Katsunori Ikari, Koichi Amano, Yoshifumi Tada, Ken Yamaji, Masato Shimizu, Takashi Atsumi, Taisuke Seki, Yoshiya Tanaka, Toshikazu Kubo, Ryo Hisada, Tomokazu Yoshioka, Mihoko Yamazaki, Tamon Kabata, Tomomichi Kajino, Yoichi Ohta, Takahiro Okawa, Yohei Naito, Ayumi Kaneuji, Yuji Yasunaga, Kenji Ohzono, Kohei Tomizuka, Masaru Koido, Koichi Matsuda, Yukinori Okada, Akari Suzuki, Bong Jo Kim, Yuta Kochi, Hye Soon Lee, Shiro Ikegawa, Sang Cheol Bae, Chikashi Terao

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Abstract

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. 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. The Japanese GWAS identified 4 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 [odds ratio (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. We identified three novel susceptibility loci for S-ONFH in SLE.

Original languageEnglish
Pages (from-to)1082-1095
Number of pages14
JournalHuman Molecular Genetics
Volume31
Issue number7
DOIs
StatePublished - 1 Apr 2022
Externally publishedYes

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