BACKGROUND Spontaneous preterm birth (SPTB) is the leading cause of neonatal morbidity and mortality. It is a final common pathway for multiple etiologies, some of which are well known while others likely remain to be identified. Despite recent advancements in identifying genetic risk factors, the mechanisms of many SPTBs remain poorly understood due to the phenotypic heterogeneity and complexity. Large family-based studies decrease heterogeneity and improve power to identify genetic causes of SPTB. OBJECTIVE To identify inherited genetic factors in SPTB etiology using large families. STUDY DESIGN Using the Utah Population Database, which links a 4.5 million-person genealogy to state birth certificate and fetal death records, we identified large pedigrees containing multiple women with early SPTB (<34 weeks' gestation) and any SPTB (<37 weeks' gestation). We reviewed birth certificate data to exclude those with maternal and fetal diagnoses associated with iatrogenic preterm birth, resulting in 74 large multiplex pedigrees for early SPTB. Enrolled women with SPTB underwent comprehensive clinical phenotyping with review of primary medical records. Seven pedigrees, each containing at least 3 sampled women with SPTB, were the focus of this genetic study. High-density single-nucleotide polymorphism genotyping was conducted in maternal peripheral blood samples from women in the seven pedigrees. Shared genomic segments analysis was performed to identify genome-wide significant chromosomal regions shared in excess by women with SPTB. RESULTS We identified two genome-wide significant chromosomal regions. In single-pedigree SGS analysis, a 1.75 Mega base region in chromosome 8 (8q24.23) was shared by 5 out of 6 women with SPTB in a single large pedigree (false positive rate=0.028). In duo-pedigree analysis, a 1.05 Mega base region in the same 8q24.23 locus was identified in a second pedigree (false-positive rate [duo]= 0.0019). The intersecting region at the 8q24.23 locus contains FAM135B (family with sequence similarity 135 member B) and KHDRBS3 (KH RNA binding domain containing, signal transduction associated 3) genes, which have previously been implicated in oncogenesis and ovarian cancer, respectively. Duo-pedigree SPTB analysis also identified a second genome-wide significant 67 kilo base locus in chromosome 12 (12q21.1-q21.2) that was shared by all women with SPTB in two independent pedigrees (false-positive rate [duo] =0.01). The intersecting region at the 12q21.1-q21.2 locus contains CAPS2 (calcyphosine 2) and KCNC2 (potassium voltage-gated channel subfamily C member 2) genes, both implicated in vascular-related complications of pregnancy and preterm labor. CONCLUSION Using large SPTB families, we identified shared chromosomal regions (8q24.23 and 12q21.1-q21.2), providing evidence for inherited (segregating) risk loci in SPTB etiology. Further investigation into genes in SPTB etiology, including functional validation may provide avenues for novel therapeutic development and guide efforts for SPTB prevention to prolong pregnancy and improve outcomes.

中文翻译：

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绘制自发性早产的遗传易感性图谱：分析犹他州家谱以查找遗传遗传因素。


背景 自发性早产 （SPTB） 是新生儿发病率和死亡率的主要原因。这是多种病因的最终常见途径，其中一些病因是众所周知的，而另一些可能仍有待确定。尽管最近在鉴定遗传风险因素方面取得了进展，但由于表型异质性和复杂性，许多 SPTB 的机制仍然知之甚少。基于家系的大型研究降低了异质性，提高了识别 SPTB 遗传原因的能力。目的 使用大家庭确定 SPTB 病因中的遗传遗传因素。研究设计 使用犹他州人口数据库，该数据库将 450 万人的家谱与州出生证明和胎儿死亡记录联系起来，我们确定了包含多名早期 SPTB （<34 周妊娠） 和任何 SPTB （<37 妊娠） 妇女的大型家系。我们回顾了出生证明数据，以排除那些与医源性早产相关的母体和胎儿诊断的患者，从而产生了 74 个早期 SPTB 的大型多重家系。入组的 SPTB 女性接受了全面的临床表型分析，并审查了原发性病历。7 个家系，每个家系包含至少 3 名 SPTB 样本女性，是这项遗传研究的重点。对 7 个家系中女性的母体外周血样本进行高密度单核苷酸多态性基因分型。进行共享基因组片段分析，以确定 SPTB 女性患者过度共享的全基因组重要染色体区域。结果 我们确定了两个全基因组的重要染色体区域。在单系 SGS 分析中，在单个大系系中，6 名患有 SPTB 的女性中有 5 名共享 8 号染色体 （8q24.23） 中的 1.75 兆碱基区域（假阳性率 = 0。在双系系分析中，在第二个系系中鉴定出同一 8q24.23 位点中的 1.05 兆碱基区域（假阳性率 [duo] = 0.0019）。8q24.23 基因座的交叉区域包含 FAM135B （序列相似性为 135 成员 B 的家族） 和 KHDRBS3 （包含 KH RNA 结合域，信号转导相关 3） 基因，它们以前分别与肿瘤发生和卵巢癌有关。双系 SPTB 分析还确定了 12 号染色体 （12q21.1-q21.2） 中第二个全基因组显著的 67 kg 碱基位点，该位点在两个独立的家系中被所有患有 SPTB 的女性共享 （假阳性率 [duo] =0.01）。12q21.1-q21.2 基因座的交叉区域包含 CAPS2 （钙膦 2） 和 KCNC2 （钾电压门控通道亚家族 C 成员 2） 基因，两者均与妊娠和早产的血管相关并发症有关。结论 使用大型 SPTB 家族，我们确定了共享的染色体区域 （8q24.23 和 12q21.1-q21.2），为 SPTB 病因中的遗传 （分离） 风险位点提供了证据。进一步研究 SPTB 病因中的基因，包括功能验证，可能为新的治疗方法开发提供途径，并指导 SPTB 预防工作以延长妊娠和改善结果。