Astanand Jugessur, Allen J Wilcox, Jeffrey C Murray, Håkon K Gjessing, Truc Trung Nguyen, Roy M Nilsen, Rolv T Lie
{"title":"评估尼古丁依赖基因对唇裂风险的影响:使用国家登记和生物银行数据的一个例子。","authors":"Astanand Jugessur, Allen J Wilcox, Jeffrey C Murray, Håkon K Gjessing, Truc Trung Nguyen, Roy M Nilsen, Rolv T Lie","doi":"10.5324/nje.v21i2.1500","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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 (<i>GABBR2</i>), dopa decarboxylase (<i>DDC</i>), and cholinergic receptor nicotinic alpha 4 (<i>CHRNA4</i>) are three examples of genes that have previously shown strong associations with nicotine dependence.</p><p><strong>Methods: </strong>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 <i>GABBR2, DDC</i> and <i>CHRNA4</i> 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 <i>GABBR2</i>; rs2060762, rs3757472, rs1451371, rs3735273, and rs921451 in <i>DDC</i>; rs4522666 and rs1044393 in <i>CHRNA4</i>).</p><p><strong>Results: </strong>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 <i>DDC</i> 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 (<i>P</i><sub>trend</sub> = 0.06). No statistically significant associations were detected with <i>GABBR2</i> and <i>CHRNA4</i>.</p><p><strong>Conclusions: </strong>Despite strong associations previously reported between nicotine dependence and variants in <i>GABBR2</i>, <i>DDC</i> and <i>CHRNA4</i>, these genes were poor predictors of maternal first-trimester smoking in our data. The direct association of the <i>DDC</i> 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).</p>","PeriodicalId":35548,"journal":{"name":"Norsk Epidemiologi","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594948/pdf/nihms466654.pdf","citationCount":"4","resultStr":"{\"title\":\"Assessing the impact of nicotine dependence genes on the risk of facial clefts: An example of the use of national registry and biobank data.\",\"authors\":\"Astanand Jugessur, Allen J Wilcox, Jeffrey C Murray, Håkon K Gjessing, Truc Trung Nguyen, Roy M Nilsen, Rolv T Lie\",\"doi\":\"10.5324/nje.v21i2.1500\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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 (<i>GABBR2</i>), dopa decarboxylase (<i>DDC</i>), and cholinergic receptor nicotinic alpha 4 (<i>CHRNA4</i>) are three examples of genes that have previously shown strong associations with nicotine dependence.</p><p><strong>Methods: </strong>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 <i>GABBR2, DDC</i> and <i>CHRNA4</i> 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 <i>GABBR2</i>; rs2060762, rs3757472, rs1451371, rs3735273, and rs921451 in <i>DDC</i>; rs4522666 and rs1044393 in <i>CHRNA4</i>).</p><p><strong>Results: </strong>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 <i>DDC</i> 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 (<i>P</i><sub>trend</sub> = 0.06). No statistically significant associations were detected with <i>GABBR2</i> and <i>CHRNA4</i>.</p><p><strong>Conclusions: </strong>Despite strong associations previously reported between nicotine dependence and variants in <i>GABBR2</i>, <i>DDC</i> and <i>CHRNA4</i>, these genes were poor predictors of maternal first-trimester smoking in our data. The direct association of the <i>DDC</i> 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).</p>\",\"PeriodicalId\":35548,\"journal\":{\"name\":\"Norsk Epidemiologi\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2012-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594948/pdf/nihms466654.pdf\",\"citationCount\":\"4\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Norsk Epidemiologi\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.5324/nje.v21i2.1500\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Norsk Epidemiologi","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.5324/nje.v21i2.1500","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 4
摘要
背景:孕妇在怀孕期间吸烟与后代患面部裂的风险有关,但因果关系尚未确定。母亲吸烟对唇裂的影响可能是通过与尼古丁依赖有关的基因介导的。γ -氨基丁酸B受体2 (GABBR2)、多巴脱羧酶(DDC)和胆碱能受体烟碱α 4 (CHRNA4)是先前显示与尼古丁依赖密切相关的基因的三个例子。方法:我们从挪威(1996-2001)选取377例伴有或不伴有腭裂的唇裂父母三人组和762例对照父母三人组作为样本,研究GABBR2、DDC和CHRNA4基因变异是否与母亲妊娠早期吸烟和唇裂风险相关。我们使用HAPLIN (Gjessing et al. 2006),这是一种专为基于家族的关联测试而设计的统计软件,对这些基因(GABBR2中的rs10985765、rs1435252、rs3780422、rs2779562和rs3750344)中的12个snp进行单倍型分析;DDC中的rs2060762、rs3757472、rs1451371、rs3735273和rs921451;rs4522666和rs1044393在CHRNA4)。结果:当一次分析一个时,几乎没有证据表明12个snp中的任何一个与母亲妊娠早期吸烟有关。然而,在单倍型分析中,DDC中母体G-G-c-G-c单倍型的一个拷贝与吸烟率有关(优势比:1.5;95%置信区间:1.0-2.1)。同样的单倍型也增加了后代分离CL/P的风险,单拷贝时增加1.5倍,双拷贝时增加2.4倍(P趋势= 0.06)。GABBR2和CHRNA4未发现有统计学意义的相关性。结论:尽管先前报道了尼古丁依赖与GABBR2、DDC和CHRNA4变异之间的强烈关联,但在我们的数据中,这些基因不能很好地预测孕妇妊娠早期吸烟。DDC单倍型与CL/P的直接关联表明,该单倍型可能对裂裂有直接影响,也可能通过其他尚未探索的风险行为影响裂裂风险。
Assessing the impact of nicotine dependence genes on the risk of facial clefts: An example of the use of national registry and biobank data.
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 (GABBR2), dopa decarboxylase (DDC), and cholinergic receptor nicotinic alpha 4 (CHRNA4) 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 GABBR2, DDC and CHRNA4 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 GABBR2; rs2060762, rs3757472, rs1451371, rs3735273, and rs921451 in DDC; rs4522666 and rs1044393 in CHRNA4).
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 DDC 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 (Ptrend = 0.06). No statistically significant associations were detected with GABBR2 and CHRNA4.
Conclusions: Despite strong associations previously reported between nicotine dependence and variants in GABBR2, DDC and CHRNA4, these genes were poor predictors of maternal first-trimester smoking in our data. The direct association of the DDC 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).