Gene-Smoking Interactions Identify Several Novel Blood Pressure Loci in the Framingham Heart Study
Gene-Smoking Interactions Identify Several Novel Blood Pressure Loci in the Framingham Heart Study
复制标题
DOI：
10.1093/ajh/hpt283
复制
发表时间：
2015-03-01
影响因子：
3.2
通讯作者：
Rao, Dabeeru C.
中科院分区：
文献类型：
--
作者：
Sung, Yun J.;de las Fuentes, Lisa;Rao, Dabeeru C.
血压（BP）变异具有遗传因素，其中大部分尚未归因于特定变异。基因发现的一种有前景的策略是分析单核苷酸多态性 (SNP) 与血压相关因素（包括年龄、性别和体重指数 (BMI)）之间的相互作用。教育程度是社会经济地位的标志，对血压和体重指数都有影响。我们利用弗雷明汉心脏研究 (Framingham Heart Study) 家庭中 3,836 名受试者的全基因组数据，研究了 SNP 教育交互作用对血压的影响。 ABEL 套件用于调整年龄、性别、BMI、药物使用和亲属关系，并进行 1 自由度 (df) 和 2 df SNP 教育相互作用测试。PTN 中的 SNP 与没有学士学位的人的收缩压升高（每个小等位基因 5.4 毫米汞柱）相关，但在拥有学士学位的人中与收缩压降低（每个等位基因 1.6 毫米汞柱）相关（2 df；P 2.0810(8))。 TOX2 中的 SNP 与受教育程度不超过高中的人的舒张压升高（DBP；每个小等位基因 4.1mm Hg）相关，但在高中以上受教育的人中 DBP 降低（0.7；1 df；P 3.7410(8)）。还发现了三种暗示性关联：MYO16（脉压：2 df；P 2.8910(7)）、HAS2（DBP：1 df；P 1.4110（7））和 DLEU2（DBP：2 df；P 1.9310（7））。所有 5 个基因均与 BP 相关，包括 PTN 和 TOX2 在血管舒张和血管生成中的作用。PTN 和 TOX2 与 BP 相关。分析 SNPeducation 交互可能会发现新的关联。教育可能是未测量的暴露和改变 SNP 对血压影响的行为的替代品。背景心血管疾病是美国最重要的健康问题之一。血压（BP）变异具有遗传成分，大部分遗传变异仍有待鉴定。基因发现的一种有前景的策略是对单核苷酸多态性 (SNP) 与心血管疾病相关环境因素之间的相互作用进行全基因组分析。方法我们在弗雷明汉心脏研究的 6,889 名参与者的全基因组数据中研究了 SNP 与吸烟相互作用对血压的影响。我们进行了交互效应的标准 1 自由度 (df) 检验以及主要效应和交互效应的联合 2 df 检验。使用了三种吸烟指标：每天吸烟量 (CPD)、吸烟包年数和吸烟状况。 结果我们确定了 7 个显着的血压基因座和 21 个提示性的血压基因座。通过联合 2 df 检验鉴定出显着的 SBP 位点包括：CYB5B 中的 rs12149862 (P = 3.65 x 10(-9))、LRP2 中的 rs2268365 (P = 4.85 x 10(-8))、rs133980 (P = 1.71 x 10(-8)，CPD 和 P = MN1 附近为 1.07 x 10(-8)（含包年），MECOM 中为 rs12634933 (P = 4.05 x 10(-8))。通过 1 df 相互作用分析，使用所有 3 种吸烟测量方法，在 NRXN3 附近的 SNP rs8010717 处确定了 1 个提示性 SBP 位点（对于 CPD，P = 3.27 x 10(-7)；对于包年，P = 1.03 x 10(-7)；对于吸烟状况，P = 1.19 x 10(-7)）。 结论 这些 BP 位点中的几个在生物学上是合理的，为血压调节提供了生理联系。我们的研究表明，SNP-吸烟相互作用可以增强基因发现，并提供对调节血压的新途径和机制的见解。
Blood pressure (BP) variability has a genetic component, most of which has yet to be attributed to specific variants. One promising strategy for gene discovery is analysis of interactions between single-nucleotide polymorphisms (SNPs) and BP-related factors, including age, sex, and body mass index (BMI). Educational attainment, a marker for socioeconomic status, has effects on both BP and BMI.We investigated SNPeducation interaction effects on BP in genome-wide data on 3,836 subjects in families from the Framingham Heart Study. The ABEL suite was used to adjust for age, sex, BMI, medication use, and kinship and to perform 1 degree-of-freedrom (df) and 2 df SNPeducation interaction tests.An SNP in PTN was associated with increased systolic BP (5.4mm Hg per minor allele) in those without a bachelors degree but decreased systolic BP (1.6mm Hg per allele) in those with a bachelors degree (2 df; P 2.0810(8)). An SNP in TOX2 was associated with increased diastolic BP (DBP; 4.1mm Hg per minor allele) in those with no more educational attainment than high school but decreased DBP in those with education past high school (0.7; 1 df; P 3.7410(8)). Three suggestive associations were also found: in MYO16 (pulse pressure: 2 df; P 2.8910(7)), in HAS2 (DBP: 1 df; P 1.4110(7)), and in DLEU2 (DBP: 2 df; P 1.9310(7)). All 5 genes are related to BP, including roles in vasodilation and angiogenesis for PTN and TOX2.PTN and TOX2 are associated with BP. Analyzing SNPeducation interactions may detect novel associations. Education may be a surrogate for unmeasured exposures and behaviors modifying SNP effects on BP.BACKGROUNDCardiovascular diseases are among the most significant health problems in the United States. Blood pressure (BP) variability has a genetic component, and most of the genetic variance remains to be identified. One promising strategy for gene discovery is genome-wide analysis of interactions between single nucleotide polymorphisms (SNPs) and environmental factors related to cardiovascular diseases.METHODSWe investigated SNP-smoking interaction effects on BP in genome-wide data in 6,889 participants from the Framingham Heart Study. We performed the standard 1 degree of freedom (df) test of the interaction effect and the joint 2 df test of main and interaction effects. Three smoking measures were used: cigarettes per day (CPD), pack years of smoking, and smoking status.RESULTSWe identified 7 significant and 21 suggestive BP loci. Identified through the joint 2 df test, significant SBP loci include: rs12149862 (P = 3.65 x 10(-9)) in CYB5B, rs2268365 (P = 4.85 x 10(-8)) in LRP2, rs133980 (P = 1.71 x 10(-8) with CPD and P = 1.07 x 10(-8) with pack-years) near MN1, and rs12634933 (P = 4.05 x 10(-8)) in MECOM. Through 1 df interaction analysis, 1 suggestive SBP locus at SNP rs8010717 near NRXN3 was identified using all 3 smoking measures (P = 3.27 x 10(-7) with CPD, P = 1.03 x 10(-7) with pack-years, and P = 1.19 x 10(-7) with smoking status).CONCLUSIONSSeveral of these BP loci are biologically plausible, providing physiological connection to BP regulation. Our study demonstrates that SNP-smoking interactions can enhance gene discovery and provide insight into novel pathways and mechanisms regulating BP.