University of California-San Diego School of Medicine, La Jolla, CA, USA.
Am J Med Genet A. 2013 Apr;161A(4):702-10. doi: 10.1002/ajmg.a.35775. Epub 2013 Feb 26.
Small intestinal atresia (SIA) is a rare congenital occlusion of the small intestine. SIA development, particularly in the jejunum and ileum, has been associated with in utero disruption of vascular supply. However, the number of studies of the vascular hypothesis is limited. This study considers the vascular hypothesis by exploring risks associated with 32 SNPs of genes involved in vascular processes of homocysteine metabolism, coagulation, cell-cell interactions, inflammatory response, and blood pressure regulation. A total of 206 SIA cases were ascertained by the California Birth Defects Monitoring Program, and 573 infants with no major congenital anomalies by their first birthday were selected as controls. Genomic DNA was genotyped for 32 SNPs involving the following genes: MTHFR, F2, F5, F7, SERPINE1, FGB, ITGA2, ITGB3, SELE, ICAM1, MMP3, TNF, LTA, NOS3, AGTR1, AGT, NPPA, ADD1, SCNN1A, GNB3, and ADRB2. Risks were estimated as odds ratios, adjusted for maternal age and race, with 95% confidence intervals. Cases were considered collectively and by subgroups based on atresia location (duodenal/jejunum/ileum). Three SNPs had reduced risk: SERPINE1 11053 T/G, MMP3 (-1171) A6/A5, and ADRB2 gln27glu. Two had increased risk: ITGA2 873 G/A and NPPA 2238 T/C. No intestinal subphenotypes showed a unique pattern of SNP associations. The association of two SNPs with increased risk lends some, albeit limited, support to vascular impairment as a possible mechanism leading to SIA. These results also identify genes meriting further exploration in SIA studies. Hence, this study makes an important contribution by exploring the long-held but not well-investigated vascular hypothesis.
小肠闭锁（SIA）是一种罕见的先天性小肠闭锁。SIA 的发展，特别是在空肠和回肠，与血管供应中断有关。然而，关于血管假说的研究数量有限。本研究通过探讨与同型半胱氨酸代谢、凝血、细胞-细胞相互作用、炎症反应和血压调节等血管过程相关的 32 个单核苷酸多态性（SNP）的风险，来考虑血管假说。通过加利福尼亚出生缺陷监测计划确定了 206 例 SIA 病例，并选择了 573 名无重大先天畸形的婴儿作为对照。对涉及以下基因的 32 个 SNP 进行了全基因组 DNA 基因分型：MTHFR、F2、F5、F7、SERPINE1、FGB、ITGA2、ITGB3、SELE、ICAM1、MMP3、TNF、LTA、NOS3、AGTR1、AGT、NPPA、ADD1、SCNN1A、GNB3 和 ADRB2。使用优势比（OR）估计风险，并调整了母亲年龄和种族，置信区间为 95%。根据闭锁位置（十二指肠/空肠/回肠）对病例进行了综合和亚组分析。有 3 个 SNP 显示出较低的风险：SERPINE1 11053 T/G、MMP3（-1171）A6/A5 和 ADRB2 gln27glu。有 2 个 SNP 显示出较高的风险：ITGA2 873 G/A 和 NPPA 2238 T/C。没有肠道亚型表现出独特的 SNP 关联模式。两个 SNP 与风险增加相关，这为血管损伤作为导致 SIA 的可能机制提供了一些支持，尽管支持有限。这些结果还确定了一些值得在 SIA 研究中进一步探索的基因。因此，本研究通过探索长期存在但研究不足的血管假说，做出了重要贡献。
