Witkin Steven S, Vardhana Santosh, Yih Melissa, Doh Kunihiko, Bongiovanni Ann Marie, Gerber Stefan
Division of Immunology and Infectious Diseases, Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, 525 E. 68th Street, Box 35, New York, NY 10021, USA.
Am J Obstet Gynecol. 2003 Nov;189(5):1413-7. doi: 10.1067/s0002-9378(03)00630-6.
Preterm labor in experimental models is initiated by intra-amniotic interleukin-1beta (IL-1beta) and inhibited by interleukin-1 receptor antagonist (IL-1ra). The IL-1ra gene is polymorphic and the different alleles are associated with variations in IL-1beta and IL-1ra production. The relationship among the IL-1ra genotype of the fetus, concentrations of IL-1beta and IL-1ra in second-trimester amniotic fluid, and pregnancy outcome was determined.
Amniotic fluids from 291 consecutive women with singleton pregnancies, obtained at 15 to 17 weeks' gestation, were tested for IL-1beta and IL-1ra concentrations by enzyme-linked immunosorbent assay. DNA from fetal cells was analyzed for a length polymorphism in intron 2 of the IL-1ra gene by polymerase chain reaction. Pregnancy outcomes were obtained after completion of testing.
The distribution of fetal IL-1ra genotypes was similar to that found in other populations: 50.9% (148) were homozygous for allele 1 (IL1RN1), 39.5% (115) were IL1RN1/allele 2 (IL1RN2) heterozygotes, 6.9% (20) were IL1RN2 homozygotes, whereas 2.7% (8) had combinations of other alleles. Fetal possession of IL1RN2 was associated with a greater than 50% increase in midtrimester intra-amniotic IL-1beta levels (P=.006) and a smaller increase in IL-1ra levels (P=.01) compared with fetuses who were IL1RN1 homozygotes. Despite the low sample size, IL1RN2 homozygosity, but not midtrimester intraamniotic levels of IL-1beta and IL-1ra, was related to an increased rate of preterm birth (P<.0001). In the 11 pregnancies that were subsequently terminated because of major malformations, there was a decreased frequency of IL1RN1 homozygosity (P=.04). Birth weight was unrelated to IL-1ra genotype.
Possession by the fetus of the IL1RN2 allele is associated with enhanced intraamniotic IL-1beta production. Induction of an intra-amniotic proinflammatory immune response might be more likely to lead to preterm labor in fetuses carrying the IL1RN2 allele.
实验模型中的早产由羊膜腔内白细胞介素-1β（IL-1β）引发，而白细胞介素-1受体拮抗剂（IL-1ra）可抑制早产。IL-1ra基因具有多态性，不同等位基因与IL-1β和IL-1ra产生的变化相关。确定了胎儿的IL-1ra基因型、孕中期羊水IL-1β和IL-1ra浓度与妊娠结局之间的关系。
对291例连续单胎妊娠妇女在妊娠15至17周时获取的羊水进行酶联免疫吸附测定，检测IL-1β和IL-1ra浓度。通过聚合酶链反应分析胎儿细胞DNA中IL-1ra基因内含子2的长度多态性。检测完成后获取妊娠结局。
胎儿IL-1ra基因型的分布与其他人群相似：50.9%（148例）为等位基因1（IL1RN1）纯合子，39.5%（115例）为IL1RN1/等位基因2（IL1RN2）杂合子，6.9%（20例）为IL1RN2纯合子，而2.7%（8例）具有其他等位基因组合。与IL1RN1纯合子胎儿相比，胎儿携带IL1RN2与孕中期羊膜腔内IL-1β水平升高超过50%相关（P = 0.006），而IL-1ra水平升高幅度较小（P = 0.01）。尽管样本量较小，但IL1RN2纯合性而非孕中期羊膜腔内IL-1β和IL-1ra水平与早产率增加相关（P < 0.0001）。在随后因严重畸形而终止的11例妊娠中，IL1RN1纯合子的频率降低（P = 0.04）。出生体重与IL-1ra基因型无关。
胎儿携带IL1RN2等位基因与羊膜腔内IL-1β产生增加相关。羊膜腔内促炎免疫反应的诱导更有可能导致携带IL1RN2等位基因的胎儿早产。
