van de Putte Romy, Wijers Charlotte H W, de Blaauw Ivo, Marcelis Carlo L M, Sloots Cornelius E J, Brooks Alice S, Broens Paul M A, Roeleveld Nel, van der Zanden Loes F M, van Rooij Iris A L M
Department for Health Evidence (133), Radboud Institute for Health Sciences, Radboud University Medical Center (Radboudumc), P.O. Box 9101, 6500 HB Nijmegen, the Netherlands
Department for Health Evidence (133), Radboud Institute for Health Sciences, Radboud University Medical Center (Radboudumc), P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.
Hum Reprod. 2017 Feb;32(2):299-306. doi: 10.1093/humrep/dew327. Epub 2017 Jan 5.
Are anorectal malformations (ARMs) associated with previous miscarriages or single nucleotide polymorphisms (SNPs) in the Bone Morphogenetic Protein 4 (BMP4) and GLI family zinc finger 2 (GLI2) genes?
The SNP rs3738880 in GLI2 and miscarriages were associated with ARM, especially in patients with multiple congenital anomalies (MCA).
ARM are one of the most common birth defects of the gastrointestinal tract. The etiology is likely to be multifactorial, involving both environmental and genetic factors. SNPs in BMP4 and GLI2 genes were associated with ARM in non-Caucasian populations. During a patient information day, several mothers of ARM patients reported their concerns about previous miscarriages.
STUDY DESIGN, SIZE, DURATION: A case-control study was performed among 427 ARM patients and 663 population-based controls.
PARTICIPANTS/MATERIALS, SETTING, METHODS: We examined the associations of ARM with SNPs in GLI2 and BMP4 using DNA samples of the children and associations with previous miscarriages using parental questionnaires. In addition, gene-gene and gene-environment interaction analyses were performed.
The SNP rs3738880 in GLI2 was associated with ARM, especially in patients with MCA (homozygous GG-genotype: odds ratio (OR): 2.1; 95% CI: 1.2, 3.7). We identified previous miscarriages as a new risk factor for ARM, especially when occurring in the pregnancy directly preceding the index pregnancy and in patients with MCA (OR: 2.1; 95% CI: 1.3, 3.5). No association with rs17563 in BMP4, nor gene-gene or gene-environment interactions were found.
LIMITATIONS, REASONS FOR CAUTION: The possibility of recall errors for previous miscarriage, but we expect these errors to be limited, as a miscarriage is a major life event. In addition, potential misclassification regarding miscarriages and stillbirth, but sensitivity analyses showed that this did not influence our results.
This study showed associations of ARM with rs3738880 in GLI2 and with previous miscarriages. Both associations were stronger in patients with MCA, showing the importance of stratifying the analyses by patients with isolated ARM or MCA.
STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Radboudumc. The authors have no conflict of interest to disclose.
肛门直肠畸形（ARM）是否与既往流产或骨形态发生蛋白4（BMP4）和GLI家族锌指蛋白2（GLI2）基因中的单核苷酸多态性（SNP）有关？
GLI2基因中的SNP rs3738880和流产与ARM有关，尤其是在患有多种先天性异常（MCA）的患者中。
ARM是胃肠道最常见的出生缺陷之一。其病因可能是多因素的，涉及环境和遗传因素。BMP4和GLI2基因中的SNP在非白种人群中与ARM有关。在一次患者信息日活动中，几位ARM患者的母亲报告了她们对既往流产的担忧。
研究设计、规模、持续时间：对427例ARM患者和663例基于人群的对照进行了病例对照研究。
参与者/材料、环境、方法：我们使用儿童的DNA样本检查了ARM与GLI2和BMP4中SNP的关联，并使用父母问卷检查了与既往流产的关联。此外，还进行了基因-基因和基因-环境相互作用分析。
GLI2基因中的SNP rs3738880与ARM有关，尤其是在患有MCA的患者中（纯合GG基因型：比值比（OR）：2.1；95%置信区间：1.2，3.7）。我们将既往流产确定为ARM的一个新危险因素，尤其是在本次索引妊娠前直接发生的妊娠中以及患有MCA的患者中（OR：2.1；95%置信区间：1.3，3.5）。未发现与BMP4中的rs17563有关联，也未发现基因-基因或基因-环境相互作用。
局限性、谨慎原因：既往流产存在回忆错误的可能性，但我们预计这些错误有限，因为流产是一件重大的生活事件。此外，流产和死产可能存在潜在的错误分类，但敏感性分析表明这并未影响我们的结果。
本研究表明ARM与GLI2中的rs3738880以及既往流产有关。这两种关联在患有MCA的患者中更强，表明按孤立性ARM或MCA患者进行分层分析的重要性。
研究资金/利益冲突：本研究由拉德堡大学医学中心资助。作者无利益冲突需要披露。
