Department of Pediatrics, Institute of Clinical Medicine, University of Oulu, Oulu, Finland.
PLoS One. 2012;7(12):e51378. doi: 10.1371/journal.pone.0051378. Epub 2012 Dec 5.
Preterm birth is the major cause of neonatal mortality and morbidity. In many cases, it has severe life-long consequences for the health and neurological development of the newborn child. More than 50% of all preterm births are spontaneous, and currently there is no effective prevention. Several studies suggest that genetic factors play a role in spontaneous preterm birth (SPTB). However, its genetic background is insufficiently characterized. The aim of the present study was to perform a linkage analysis of X chromosomal markers in SPTB in large northern Finnish families with recurrent SPTBs. We found a significant linkage signal (HLOD = 3.72) on chromosome locus Xq13.1 when the studied phenotype was being born preterm. There were no significant linkage signals when the studied phenotype was giving preterm deliveries. Two functional candidate genes, those encoding the androgen receptor (AR) and the interleukin-2 receptor gamma subunit (IL2RG), located near this locus were analyzed as candidates for SPTB in subsequent case-control association analyses. Nine single-nucleotide polymorphisms (SNPs) within these genes and an AR exon-1 CAG repeat, which was previously demonstrated to be functionally significant, were analyzed in mothers with preterm delivery (n = 272) and their offspring (n = 269), and in mothers with exclusively term deliveries (n = 201) and their offspring (n = 199), all originating from northern Finland. A replication study population consisting of individuals born preterm (n = 111) and term (n = 197) from southern Finland was also analyzed. Long AR CAG repeats (≥ 26) were overrepresented and short repeats (≤ 19) underrepresented in individuals born preterm compared to those born at term. Thus, our linkage and association results emphasize the role of the fetal genome in genetic predisposition to SPTB and implicate AR as a potential novel fetal susceptibility gene for SPTB.
早产是新生儿死亡和发病的主要原因。在许多情况下，它会对新生儿的健康和神经发育产生严重的终身影响。超过 50%的早产是自发性的，目前还没有有效的预防方法。有几项研究表明，遗传因素在自发性早产（SPTB）中起作用。然而，其遗传背景尚未得到充分描述。本研究的目的是在具有复发性自发性早产（SPTB）的大型芬兰北部家庭中，对 X 染色体标记进行连锁分析。我们在研究的表型为早产时，在 X 染色体 q13.1 位点发现了一个显著的连锁信号（HLOD = 3.72）。当研究的表型为早产分娩时，没有显著的连锁信号。位于该位点附近的两个功能候选基因，即雄激素受体（AR）和白细胞介素-2 受体γ亚基（IL2RG）的编码基因，被分析为随后的病例对照关联分析中 SPTB 的候选基因。在具有早产分娩的母亲（n = 272）及其后代（n = 269）以及仅具有足月分娩的母亲（n = 201）及其后代（n = 199）中，分析了这两个基因内的 9 个单核苷酸多态性（SNP）和先前证明具有功能意义的 AR 外显子 1 CAG 重复。所有这些母亲和孩子均来自芬兰北部。还对来自芬兰南部的 111 名早产和 197 名足月出生的个体的复制研究人群进行了分析。与足月出生的个体相比，早产出生的个体中长 AR CAG 重复（≥26）的比例过高，而短重复（≤19）的比例过低。因此，我们的连锁和关联结果强调了胎儿基因组在自发性早产遗传易感性中的作用，并暗示 AR 可能是自发性早产的一个潜在新的胎儿易感基因。
