Genome-wide association analyses suggested a novel mechanism for smoking behavior regulated by IL15.
Genome-wide association analyses suggested a novel mechanism for smoking behavior regulated by IL15.
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DOI：
10.1038/mp.2009.3
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发表时间：
2009-07
影响因子：
11
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中科院分区：
文献类型：
--
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吸烟是美国主要的可预防的死亡原因。虽然吸烟行为具有重要的遗传决定作用，但吸烟行为背后的特定基因和相关机制在很大程度上是未知的。在这里，我们对840名白人（包括417名男性和423名女性）的吸烟行为进行了全基因组关联研究，其中我们检查了1380，000个SNP。我们发现，IL 15基因上游的9个SNP簇与男性吸烟状况相关，其中最显著的SNP rs 4956302达到了全基因组显著性的p值（8.80×10−8）。另一个SNP rs 17354547在多个物种中高度保守，p值为5.65×10−5。从上述9个SNP中选择这两个SNP以及另外两个SNP（rs 1402812和rs 4956396），用于在包含1，251名受试者（包括412名男性和839名女性）的非洲裔美国人样本中进行复制。SNP rs 17354547在复制样本的男性亚组中成功复制;它与吸烟量（SQ），吸烟指数（HSI）和Fagerstrom尼古丁依赖性检验（FTND）相关，p值分别为0.031，0.0046和0.019。此外，由rs 17354547、rs 1402812和rs 4956396形成的单倍型也与SQ、HSI和FTND相关，p值分别为0.039、0.0093和0.0093。为了进一步证实我们的发现，我们对来自1，731个家庭的7，623名高加索人的心脏研究样本中的9个SNP进行了计算机模拟复制研究，其中3，491名受试者为男性，4，132名为女性。同样，观察到男性特异性与吸烟状况的关联，其中9个SNP中的7个在男性中达到显著p值（p<0.05），2个在男性中达到边缘显著p值（p<0.10）。9个SNPs中的几个，包括跨物种高度保守的一个，rs 17354547，位于潜在的转录因子结合位点，这表明转录调节作为这些SNPs的可能功能。通过这种功能，SNP可以调节IL 15的基因表达，IL 15是调节免疫功能的关键细胞因子。由于免疫系统长期以来一直被认为会影响药物成瘾行为，我们的研究结果表明，吸烟成瘾的一种新机制涉及通过IL 15途径进行免疫调节。
Cigarette smoking is the leading preventable cause of death in the US. Although smoking behavior has a significant genetic determination, the specific genes and associated mechanisms underlying smoking behavior are largely unknown. Here, we performed a genome-wide association study on smoking behavior in 840 Caucasians, including 417 males and 423 females, in which we examined ∼380,000 SNPs. We found that a cluster of nine SNPs upstream from the IL15 gene were associated with smoking status in males, with the most significant SNP, rs4956302, achieving a p value (8.80×10−8) of genome-wide significance. Another SNP, rs17354547, that is highly conserved across multiple species, achieved a p value of 5.65×10−5. These two SNPs, together with two additional SNPs (rs1402812 and rs4956396) were selected from the above nine SNPs for replication in an African-American sample containing 1,251 subjects, including 412 males and 839 females. The SNP rs17354547 was successfully replicated in the male subgroup of the replication sample; it was associated with smoking quantity (SQ), the Heaviness of Smoking Index (HSI) and the Fagerstrom Test for Nicotine Dependence (FTND), with p values of 0.031, 0.0046 and 0.019, respectively. In addition, a haplotype formed by rs17354547, rs1402812 and rs4956396 was also associated with SQ, HSI and FTND, achieving p values of 0.039, 0.0093 and 0.0093, respectively. To further confirm our findings, we performed an in silico replication study of the nine SNPs in a Framingham Heart Study sample containing 7,623 Caucasians from 1,731 families, among which, 3,491 subjects are males and 4,132 are females. Again, male-specific association with smoking status was observed, for which seven of the nine SNPs achieved significant p values (p<0.05) and two achieved marginally significant p values (p<0.10) in males. Several of the nine SNPs, including the highly conserved one across species, rs17354547, are located at potential transcription factor binding sites, suggesting transcription regulation as a possible function for these SNPs. Through this function, the SNPs may modulate gene expression of IL15, a key cytokine regulating immune function. As the immune system has long been recognized to influence drug addiction behavior, our association findings suggest a novel mechanism for smoking addiction involving immune modulation via the IL15 pathway.
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影响因子：
56.9
作者：
Cheng, J;Kapranov, P;Gingeras, TR
通讯作者：
Gingeras, TR
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DAFNY, N;PELLIS, NR
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HIRSCHMAN, JE;DURBIN, KJ;WINSTON, F
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