评估尼古丁依赖基因对面部裂隙风险的影响：利用国家登记处和生物样本库数据的一个实例。

Assessing the impact of nicotine dependence genes on the risk of facial clefts: An example of the use of national registry and biobank data.

作者信息

Jugessur Astanand, Wilcox Allen J, Murray Jeffrey C, Gjessing Håkon K, Nguyen Truc Trung, Nilsen Roy M, Lie Rolv T

机构信息

Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway ; Craniofacial Research, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.

Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, Durham, North Carolina, USA.

出版信息

Nor Epidemiol. 2012;21(2):241-250. doi: 10.5324/nje.v21i2.1500.

DOI:10.5324/nje.v21i2.1500

PMID:26451072

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4594948/

Abstract

BACKGROUND

Maternal smoking during pregnancy has been associated with risk of facial clefts in offspring, but causation has not yet been established. It is possible that the effect of maternal smoking on facial clefts is mediated through genes that are involved in nicotine dependence. Gamma-aminobutyric acid B receptor 2 (), dopa decarboxylase (), and cholinergic receptor nicotinic alpha 4 () are three examples of genes that have previously shown strong associations with nicotine dependence.

METHODS

We used a population-based sample of 377 case-parent trios of cleft lip with or without cleft palate (CL/P) and 762 control-parent trios from Norway (1996-2001) to investigate whether variants in and are associated with maternal first-trimester smoking and with clefting risk. We used HAPLIN (Gjessing et al. 2006), a statistical software tailored for family-based association tests, to perform haplotype-based analyses on 12 SNPs in these genes (rs10985765, rs1435252, rs3780422, rs2779562, and rs3750344 in ; rs2060762, rs3757472, rs1451371, rs3735273, and rs921451 in ; rs4522666 and rs1044393 in ).

RESULTS

When analyzed one at a time, there was little evidence of association between any of the 12 SNPs and maternal first-trimester smoking. In haplotype analyses, however, one copy of the maternal G-G-c-G-c haplotype in was linked with smoking prevalence (odds ratio: 1.5; 95% confidence interval: 1.0-2.1). This same haplotype also increased the risk of isolated CL/P in offspring by 1.5-fold with one copy and 2.4-fold with two copies ( = 0.06). No statistically significant associations were detected with and .

CONCLUSIONS

Despite strong associations previously reported between nicotine dependence and variants in , and , these genes were poor predictors of maternal first-trimester smoking in our data. The direct association of the haplotype with CL/P suggests that this haplotype may either have direct effects on clefts or it may influence clefting risks through other yet unexplored risk behavior(s).

摘要

背景

孕期母亲吸烟与后代患唇腭裂的风险相关，但因果关系尚未确立。母亲吸烟对唇腭裂的影响可能是通过参与尼古丁依赖的基因介导的。γ-氨基丁酸B受体2（GABBR2）、多巴脱羧酶（DDC）和烟碱型胆碱能受体α4（CHRNA4）是先前已显示与尼古丁依赖有强关联的三个基因实例。

方法

我们使用了来自挪威（1996 - 2001年）的377例唇裂伴或不伴腭裂（CL/P）病例 - 父母三联体和762例对照 - 父母三联体的基于人群的样本，以研究GABBR2和CHRNA4中的变异是否与母亲孕早期吸烟及唇腭裂风险相关。我们使用HAPLIN（Gjessing等人，2006年），一种为基于家系的关联测试量身定制的统计软件，对这些基因中的12个单核苷酸多态性（SNP）进行单倍型分析（GABBR2中的rs10985765、rs1435252、rs3780422、rs2779562和rs3750344；CHRNA4中的rs2060762、rs3757472、rs1451371、rs3735273和rs921451；DDC中的rs4522666和rs1044393）。

结果

逐个分析时，几乎没有证据表明这12个SNP中的任何一个与母亲孕早期吸烟有关联。然而，在单倍型分析中，母亲GABBR2基因中的G - G - c - G - c单倍型的一个拷贝与吸烟流行率相关（优势比：1.5；95%置信区间：1.0 - 2.1）。这个相同的单倍型也使后代孤立性CL/P的风险增加1.5倍（一个拷贝）和2.4倍（两个拷贝）（P = 0.06）。未检测到与DDC和CHRNA4有统计学显著关联。