O'Loughlin Jennifer, Sylvestre Marie-Pierre, Labbe Aurélie, Low Nancy C, Roy-Gagnon Marie-Hélène, Dugas Erika N, Karp Igor, Engert James C
Centre de recherche CHUM, Montreal, Quebec, Canada; Department of Social and Preventive Medicine, University of Montreal, Montreal, Quebec, Canada; Institut national de santé publique du Québec, Montreal, Quebec, Canada.
Centre de recherche CHUM, Montreal, Quebec, Canada; Department of Social and Preventive Medicine, University of Montreal, Montreal, Quebec, Canada.
PLoS One. 2014 Dec 29;9(12):e115716. doi: 10.1371/journal.pone.0115716. eCollection 2014.
While the heritability of cigarette smoking and nicotine dependence (ND) is well-documented, the contribution of specific genetic variants to specific phenotypes has not been closely examined. The objectives of this study were to test the associations between 321 tagging single-nucleotide polymorphisms (SNPs) that capture common genetic variation in 24 genes, and early smoking and ND phenotypes in novice adolescent smokers, and to assess if genetic predictors differ across these phenotypes.
In a prospective study of 1294 adolescents aged 12-13 years recruited from ten Montreal-area secondary schools, 544 participants who had smoked at least once during the 7-8 year follow-up provided DNA. 321 single-nucleotide polymorphisms (SNPs) in 24 candidate genes were tested for an association with number of cigarettes smoked in the past 3 months, and with five ND phenotypes (a modified version of the Fagerstrom Tolerance Questionnaire, the ICD-10 and three clusters of ND symptoms representing withdrawal symptoms, use of nicotine for self-medication, and a general ND/craving symptom indicator).
The pattern of SNP-gene associations differed across phenotypes. Sixteen SNPs in seven genes (ANKK1, CHRNA7, DDC, DRD2, COMT, OPRM1, SLC6A3 (also known as DAT1)) were associated with at least one phenotype with a p-value <0.01 using linear mixed models. After permutation and FDR adjustment, none of the associations remained statistically significant, although the p-values for the association between rs557748 in OPRM1 and the ND/craving and self-medication phenotypes were both 0.076.
Because the genetic predictors differ, specific cigarette smoking and ND phenotypes should be distinguished in genetic studies in adolescents. Fifteen of the 16 top-ranked SNPs identified in this study were from loci involved in dopaminergic pathways (ANKK1/DRD2, DDC, COMT, OPRM1, and SLC6A3).
Dopaminergic pathways may be salient during early smoking and the development of ND.
虽然吸烟和尼古丁依赖（ND）的遗传力已有充分记录，但特定基因变异对特定表型的贡献尚未得到仔细研究。本研究的目的是测试321个标签单核苷酸多态性（SNP）与24个基因中的常见遗传变异、青少年新手吸烟者的早期吸烟和ND表型之间的关联，并评估这些表型的遗传预测因子是否不同。
在一项对从蒙特利尔地区十所中学招募的1294名12 - 13岁青少年进行的前瞻性研究中，544名在7 - 8年随访期间至少吸烟一次的参与者提供了DNA。测试了24个候选基因中的321个单核苷酸多态性（SNP）与过去3个月吸烟数量以及五种ND表型（Fagerstrom耐受性问卷的修改版、ICD - 10以及代表戒断症状、自我用药使用尼古丁和一般ND/渴望症状指标的三组ND症状）之间的关联。
SNP - 基因关联模式因表型而异。使用线性混合模型，七个基因（ANKK1、CHRNA7、DDC、DRD2、COMT、OPRM1、SLC6A3（也称为DAT1））中的16个SNP与至少一种表型相关，p值<0.01。经过排列和FDR调整后，尽管OPRM1中rs557748与ND/渴望和自我用药表型之间关联的p值均为0.076，但没有一个关联仍具有统计学意义。
由于遗传预测因子不同，在青少年的遗传研究中应区分特定的吸烟和ND表型。本研究中确定的16个排名靠前的SNP中有15个来自参与多巴胺能途径（ANKK1/DRD2、DDC、COMT、OPRM1和SLC6A3）的基因座。
多巴胺能途径在早期吸烟和ND的发展过程中可能很突出。
