Sonehara Kyuto, Yano Yoshitaka, Naito Tatsuhiko, Goto Shinobu, Yoshihara Hiroyuki, Otani Takahiro, Ozawa Fumiko, Kitaori Tamao, Matsuda Koichi, Nishiyama Takashi, Okada Yukinori, Sugiura-Ogasawara Mayumi
Department of Genome Informatics, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Suita, Japan.
Nat Commun. 2024 Jul 17;15(1):5744. doi: 10.1038/s41467-024-49993-5.
Recurrent pregnancy loss (RPL) is a major reproductive health issue with multifactorial causes, affecting 2.6% of all pregnancies worldwide. Nearly half of the RPL cases lack clinically identifiable causes (e.g., antiphospholipid syndrome, uterine anomalies, and parental chromosomal abnormalities), referred to as unexplained RPL (uRPL). Here, we perform a genome-wide association study focusing on uRPL in 1,728 cases and 24,315 female controls of Japanese ancestry. We detect significant associations in the major histocompatibility complex (MHC) region at 6p21 (lead variant=rs9263738; P = 1.4 × 10; odds ratio [OR] = 1.51 [95% CI: 1.33-1.72]; risk allele frequency = 0.871). The MHC associations are fine-mapped to the classical HLA alleles, HLA-C12:02, HLA-B52:01, and HLA-DRB1*15:02 (P = 1.1 × 10, 1.5 × 10, and 1.2 × 10, respectively), which constitute a population-specific common long-range haplotype with a protective effect (P = 2.8 × 10; OR = 0.65 [95% CI: 0.57-0.75]; haplotype frequency=0.108). Genome-wide copy-number variation (CNV) calling demonstrates rare predicted loss-of-function (pLoF) variants of the cadherin-11 gene (CDH11) conferring the risk of uRPL (P = 1.3 × 10; OR = 3.29 [95% CI: 1.78-5.76]). Our study highlights the importance of reproductive immunology and rare variants in the uRPL etiology.
复发性流产（RPL）是一个具有多因素病因的主要生殖健康问题，影响着全球2.6%的妊娠。近一半的RPL病例缺乏临床可识别的病因（如抗磷脂综合征、子宫异常和父母染色体异常），被称为不明原因复发性流产（uRPL）。在此，我们针对1728例uRPL病例和24315名日本血统女性对照进行了全基因组关联研究。我们在6p21的主要组织相容性复合体（MHC）区域检测到显著关联（领先变异体=rs9263738；P = 1.4×10；优势比[OR]=1.51[95%置信区间：1.33 - 1.72]；风险等位基因频率 = 0.871）。MHC关联被精细定位到经典的HLA等位基因，即HLA - C12:02、HLA - B52:01和HLA - DRB1*15:02（P分别为1.1×10、1.5×10和1.2×10），它们构成了一种具有保护作用的群体特异性常见长程单倍型（P = 2.8×10；OR = 0.65[95%置信区间：0.57 - 0.75]；单倍型频率 = 0.108）。全基因组拷贝数变异（CNV）分析表明，钙黏蛋白11基因（CDH11）的罕见预测功能丧失（pLoF）变异赋予了uRPL风险（P = 1.3×10；OR = 3.29[95%置信区间：1.78 - 5.76]）。我们的研究强调了生殖免疫学和罕见变异在uRPL病因学中的重要性。
