Modi Bhavi P, Parikh Hardik I, Teves Maria E, Kulkarni Rewa, Liyu Jiang, Romero Roberto, York Timothy P, Strauss Jerome F
Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA.
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA.
BMC Med Genet. 2018 Oct 5;19(1):181. doi: 10.1186/s12881-018-0696-4.
Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm birth, a complication that is more common in African Americans. Attempts to identify genetic loci associated with preterm birth using genome-wide association studies (GWAS) have only been successful with large numbers of cases and controls, and there has yet to be a convincing genetic association to explain racial/ethnic disparities. Indeed, the search for ancestry-specific variants associated with preterm birth has led to the conclusion that spontaneous preterm birth could be the consequence of multiple rare variants. The hypothesis that preterm birth is due to rare genetic variants that would go undetected in standard GWAS has been explored in the present study. The detection and validation of these rare variants present challenges because of the low allele frequency. However, some success in the identification of fetal loci/genes associated with preterm birth using whole genome sequencing and whole exome sequencing (WES) has recently been reported. While encouraging, this is currently an expensive technology, and methods to leverage the sequencing data to quickly identify and cost-effectively validate variants are needed.
We developed a WES data analysis strategy based on neonatal genomic DNA from PPROM cases and term controls that was unencumbered by preselection of candidate genes, and capable of identifying variants in African Americans worthy of focused evaluation to establish statistically significant associations.
We describe this approach and the identification of damaging nonsense variants of African ancestry in the DEFB1 and MBL2 genes that encode anti-microbial proteins that presumably defend the fetal membranes from infectious agents. Our approach also enabled us to rule out a likely contribution of a predicted damaging nonsense variant in the METTL7B gene.
Our findings support the notion that multiple rare population-specific variants in the fetal genome contribute to preterm birth associated with PPROM.
胎膜早破（PPROM）是早产的主要可识别原因，早产是一种在非裔美国人中更为常见的并发症。试图通过全基因组关联研究（GWAS）来识别与早产相关的基因座，只有在大量病例和对照的情况下才取得成功，并且尚未有令人信服的基因关联来解释种族/族裔差异。事实上，对与早产相关的特定祖先变体的搜索得出结论，自发性早产可能是多种罕见变体的结果。本研究探讨了早产是由于在标准GWAS中未被检测到的罕见基因变体这一假设。由于等位基因频率低，这些罕见变体的检测和验证面临挑战。然而，最近有报道称，使用全基因组测序和全外显子组测序（WES）在识别与早产相关的胎儿基因座/基因方面取得了一些成功。虽然令人鼓舞，但这目前是一项昂贵的技术，需要利用测序数据快速识别并以具有成本效益的方式验证变体的方法。
我们基于PPROM病例和足月对照的新生儿基因组DNA开发了一种WES数据分析策略，该策略不受候选基因预选的限制，并且能够识别非裔美国人中值得重点评估以建立统计学显著关联的变体。
我们描述了这种方法以及在编码抗菌蛋白的DEFB1和MBL2基因中鉴定出具有非洲血统的有害无义变体，这些抗菌蛋白可能保护胎膜免受感染因子的侵害。我们的方法还使我们能够排除METTL7B基因中一个预测的有害无义变体的可能贡献。
我们的研究结果支持这样一种观点，即胎儿基因组中的多种罕见人群特异性变体导致了与PPROM相关的早产。
