Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.
Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.
复制标题
DOI：
10.1371/journal.pgen.1007394
复制
发表时间：
2018-07
期刊：
影响因子：
4.5
通讯作者：
Muglia LJ
中科院分区：
文献类型：
--
作者：
Huusko JM;Karjalainen MK;Graham BE;Zhang G;Farrow EG;Miller NA;Jacobsson B;Eidem HR;Murray JC;Bedell B;Breheny P;Brown NW;Bødker FL;Litterman NK;Jiang PP;Russell L;Hinds DA;Hu Y;23andMe Research Team;Rokas A;Teramo K;Christensen K;Williams SM;Rämet M;Kingsmore SF;Ryckman KK;Hallman M;Muglia LJ
早产是婴儿发病和死亡的主要原因。遗传和环境因素在早产的易感性中起作用，但尽管进行了许多研究，早产的遗传基础在很大程度上仍然未知。我们的目的是确定罕见的，可能是有害的，核苷酸变异的母亲与复发性自发性早产（SPTB）的家庭。来自17名至少早产一名婴儿的芬兰母亲的DNA样本进行了全外显子组测序。所有的母亲都是北方芬兰血统，来自七个多元化的家庭。欧洲起源的其他复制样本包括93个丹麦姐妹对（和两个姐妹黑社会），所有早产的历史。分析罕见外显子变异（频率<1%）以鉴定可能影响SPTB易感性的基因和途径。我们发现了罕见的，可能具有破坏性的基因变异，这些变异是多个受影响个体所共有的。糖皮质激素受体信号传导途径是最显著的（p<1.7e-8），在一个由10位芬兰母亲组成的亚组中，每一位母亲都有2-4个SPTB。这种途径在丹麦姐妹对中复制。该途径中的一个基因，热休克蛋白家族A（Hsp 70）成员1样（HSPA 1 L），包含两个可能具有破坏性的错义等位基因，这些基因在四个不同的芬兰家庭中发现。在一项由一般欧洲血统母亲组成的大型早产全基因组关联研究（GWAS）中，其中一种变体（rs34620296）在病例中的频率高于对照组（0.0025 vs. 0.0010，p = 0.002）。复制样本中的姐妹对也共享罕见的，可能具有破坏性的HSPA 1 L变体。此外，计算机模拟分析预测rs34620296产生的额外磷酸化位点可能会影响分子伴侣活性或HSPA 1 L蛋白稳定性。最后，体外功能实验表明HSPA 1 L活性与蜕膜化之间存在联系。总之，在多个复发性SPTB家族中观察到HSPA 1 L的罕见、可能具有破坏性的变异。早产是婴儿死亡的主要原因，早产还与以后生活中的严重疾病有关。遗传和环境风险因素在早产的易感性中起作用。尽管有许多研究，早产的遗传基础仍然很难定义。我们调查了自发性早产（SPTB）母亲中罕见的、可能与风险相关的核苷酸变异的存在。第一组有反复早产家族史的母亲来自芬兰北方。还研究了另一组欧洲血统的母亲（姐妹对，都早产）。全外显子组测序在几个受SPTB影响的家族中鉴定出多种罕见的、可能具有破坏性的HSPA 1 L变体，并且该基因与糖皮质激素受体信号通路相关。大型GWAS数据集进一步支持了SPTB中HSPA 1 L变体之一的潜在参与。此外，该变体改变蛋白质翻译后修饰潜力，因此可能影响蛋白质稳定性及其作为分子伴侣的功能。
Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2–4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB. Preterm birth is the leading cause of infant mortality, and prematurity is further associated with serious morbidities in later life. Genetic and environmental risk factors play a role in the susceptibility to preterm birth. Despite numerous studies, the genetic basis for preterm birth remains poorly defined. We investigated the presence of rare, possibly risk associated nucleotide variants in mothers with spontaneous preterm births (SPTB). The first set of mothers with family history of recurrent preterm births was of northern Finnish origin. An additional set of mothers (sister pairs, both giving birth preterm) of European origin was also studied. Whole exome sequencing identified multiple rare, likely damaging HSPA1L variants in several families affected by SPTB, and this gene was associated with the glucocorticoid receptor signaling pathway. Potential involvement of one of the HSPA1L variants in SPTB was further supported by large GWAS dataset. In addition, this variant alters protein post-translational modification potential, and thus may affect protein stability and its function as a chaperone.
登录
查看更多内容
影响因子：
30.8
作者：
Marchini, Jonathan;Howie, Bryan;Donnelly, Peter
通讯作者：
Donnelly, Peter
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
3.4
作者：
Brocchieri L;Conway de Macario E;Macario AJ
通讯作者：
Macario AJ
影响因子：
13.8
作者：
Kadmiel M;Cidlowski JA
通讯作者：
Cidlowski JA
影响因子：
24.1
作者：
通讯作者：
--