Weese-Mayer Debra E, Zhou Lili, Berry-Kravis Elizabeth M, Maher Brion S, Silvestri Jean M, Marazita Mary L
Department of Pediatrics, Rush Children's Hospital at Rush-Presbyterian-St. Luke's Medical Center, Rush University, 1653 West Congress Parkway, Chicago, IL 60612, USA.
Am J Med Genet A. 2003 Oct 15;122A(3):238-45. doi: 10.1002/ajmg.a.20427.
Serotonergic receptor binding in the arcuate nucleus, n. raphé obscurus, and other medullary regions is decreased in sudden infant death syndrome (SIDS) cases. Further, an insertion/deletion polymorphism in the promoter region of the serotonin transporter protein (5-HTT) gene has recently been associated with risk of SIDS. This polymorphism differentially regulates 5-HTT expression, with the long allele (L), the SIDS-associated allele, being a more effective promoter than the short allele (S). To further elucidate the role of the 5-HTT gene in SIDS, we investigated the 5-HTT intron 2 polymorphism, which also differentially regulates 5-HTT expression with the 12 repeat allele being the more effective promoter. In a cohort of 90 SIDS cases (44 African-American and 46 Caucasian) and gender/ethnicity-matched controls, significant positive associations were found between SIDS and the intron 2 genotype distribution (P-value = 0.041) among African-American SIDS vs. African-American controls, specifically with the 12/12 genotype (P-value = 0.03), and with the 12 repeat allele (P-value=0.018). The frequency of the 12/12 genotype and 12-repeat allele was significantly different (P < 0.001) between the African-American and Caucasian SIDS cases. Furthermore, the promoter and intron 2 loci were in significant linkage disequilibrium, and the L-12 haplotype was significantly associated with SIDS in the African-American (P = 0.002) but not Caucasian (P = 0.117) subgroups. These results indicate a relationship between SIDS and the 12-repeat allele of the intron 2 variable number tandem repeat of the 5-HTT gene in African-Americans, and a significant role of the haplotype containing the 12-repeat allele and the promoter L-allele in defining SIDS risk in African-Americans. These data, if confirmed in larger studies, may begin to explain the differences in SIDS incidence by ethnicity, suggest a role for levels of 5-HTT expression in generation of SIDS susceptibility, and provide an important tool for identifying at-risk individuals and estimating the risk of recurrence.
在婴儿猝死综合征（SIDS）病例中，弓状核、中缝隐核及其他延髓区域的5-羟色胺能受体结合减少。此外，血清素转运蛋白（5-HTT）基因启动子区域的插入/缺失多态性最近与SIDS风险相关。这种多态性差异调节5-HTT表达，其中长等位基因（L），即与SIDS相关的等位基因，是比短等位基因（S）更有效的启动子。为了进一步阐明5-HTT基因在SIDS中的作用，我们研究了5-HTT内含子2多态性，其也通过12次重复等位基因作为更有效的启动子来差异调节5-HTT表达。在一个由90例SIDS病例（44名非裔美国人、46名白种人）以及性别/种族匹配的对照组成的队列中，在非裔美国人SIDS病例与非裔美国人对照之间，发现SIDS与内含子2基因型分布存在显著正相关（P值 = 0.041），特别是与12/12基因型（P值 = 0.03）以及12次重复等位基因（P值 = 0.018）。非裔美国人和白种人SIDS病例之间，12/12基因型和12次重复等位基因的频率存在显著差异（P < 0.001）。此外，启动子和内含子2位点处于显著连锁不平衡状态，并且L - 12单倍型在非裔美国人亚组中与SIDS显著相关（P = 0.002），但在白种人亚组中不相关（P = 0.117）。这些结果表明非裔美国人中SIDS与5-HTT基因内含子2可变数目串联重复的12次重复等位基因之间存在关联，并且包含12次重复等位基因和启动子L等位基因的单倍型在定义非裔美国人的SIDS风险中起重要作用。如果在更大规模的研究中得到证实，这些数据可能开始解释SIDS发病率的种族差异，提示5-HTT表达水平在SIDS易感性产生中的作用，并为识别高危个体和估计复发风险提供重要工具。
