Heme oxygenase-1 promoter polymorphisms and risk of spina bifida
Heme oxygenase-1 promoter polymorphisms and risk of spina bifida
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DOI：
10.1002/bdra.23343
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发表时间：
2015-09-01
影响因子：
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通讯作者：
Shaw, Gary M.
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文献类型：
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作者：
Fujioka, Kazumichi;Yang, Wei;Shaw, Gary M.
脊柱裂是神经管畸形（neural tube defects，NTDs）中最常见的一种。NTD的病因是多因素的，氧化应激被认为在NTD的发展中起关键作用。血红素加氧酶（HO）是血红素降解的限速酶，具有多种保护作用，包括介导抗氧化过程，使其成为理想的研究对象。诱导型HO异构体（HO-1）具有两种功能性遗传多态性：（GT）（n）二核苷酸重复序列和A（-413）T SNP（rs 2071746），这两种多态性均可影响其启动子活性。然而，没有研究调查HO-1基因多态性和NTD风险之间的可能关联。研究方法：该病例对照研究包括152例脊柱裂病例（均为脊髓脊膜膨出）和148例正常对照，这些病例均来自加州出生缺陷监测项目，反映了1990年至1999年期间的出生情况。采用聚合酶链反应和扩增片段长度多态性/限制性片段长度多态性方法，从存档的新生儿血斑中提取基因组DNA，确定遗传多态性。比较两种HO-1基因启动子多态性在病例组和对照组中的基因型和单倍型频率。结果如下：对于（GT）n二核苷酸重复长度和A（-413）T SNP，在等位基因频率或基因型上没有发现显著差异，在HO-1多态性之间观察到连锁不平衡（D：0.833）;然而，单倍型分析并没有显示脊柱裂的总体或种族/种族风险增加。结论：虽然HO-1多态性与脊柱裂风险之间没有发现关联，但我们推测HO-1低表达和暴露于已知环境氧化应激源（低叶酸状态或糖尿病）的联合作用可能会压倒抗氧化防御并增加NTD的风险，并需要进一步研究。出生缺陷研究（A部分）103：741-746，2015年。(c)2015年威利期刊公司
BackgroundSpina bifida is the most common form of neural tube defects (NTDs). Etiologies of NTDs are multifactorial, and oxidative stress is believed to play a key role in NTD development. Heme oxygenase (HO), the rate-limiting enzyme in heme degradation, has multiple protective properties including mediating antioxidant processes, making it an ideal candidate for study. The inducible HO isoform (HO-1) has two functional genetic polymorphisms: (GT)(n) dinucleotide repeats and A(-413)T SNP (rs2071746), both of which can affect its promoter activity. However, no study has investigated a possible association between HO-1 genetic polymorphisms and risk of NTDs. Methods: This case-control study included 152 spina bifida cases (all myelomeningoceles) and 148 nonmalformed controls obtained from the California Birth Defects Monitoring Program reflecting births during 1990 to 1999. Genetic polymorphisms were determined by polymerase chain reaction and amplified fragment length polymorphisms/restriction fragment length polymorphisms using genomic DNA extracted from archived newborn blood spots. Genotype and haplotype frequencies of two HO-1 promoter polymorphisms between cases and controls were compared. Results: For (GT)n dinucleotide repeat lengths and the A(-413)T SNP, no significant differences in allele frequencies or genotypes were found. Linkage disequilibrium was observed between the HO-1 polymorphisms (D: 0.833); however, haplotype analyses did not show increased risk of spina bifida overall or by race/ethnicity. Conclusion: Although, an association was not found between HO-1 polymorphisms and risk of spina bifida, we speculate that the combined effect of low HO-1 expression and exposures to known environmental oxidative stressors (low folate status or diabetes), may overwhelm antioxidant defenses and increase risk of NTDs and warrants further study. Birth Defects Research (Part A) 103:741-746, 2015. (c) 2015 Wiley Periodicals, Inc.