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. 2014 Mar;27(3):431-44.
doi: 10.1093/ajh/hpt283. Epub 2014 Jan 28.

Gene-education interactions identify novel blood pressure loci in the Framingham Heart Study

Jacob Basson  1 , Yun Ju Sung, Karen Schwander, Rezart Kume, Jeannette Simino, Lisa de las Fuentes, Dabeeru Rao
Affiliations

Gene-education interactions identify novel blood pressure loci in the Framingham Heart Study

Jacob Basson et al. Am J Hypertens. 2014 Mar.

Erratum in

  • Am J Hypertens. 2014 Nov;27(11):1432

Abstract

Background: 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.

Methods: We investigated SNP-education 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 SNP-education interaction tests.

Results: An SNP in PTN was associated with increased systolic BP (5.4mm Hg per minor allele) in those without a bachelor's degree but decreased systolic BP (1.6mm Hg per allele) in those with a bachelor's degree (2 df; P = 2.08 × 10(-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 = 3.74 × 10(-8)). Three suggestive associations were also found: in MYO16 (pulse pressure: 2 df; P = 2.89 × 10(-7)), in HAS2 (DBP: 1 df; P = 1.41 × 10(-7)), and in DLEU2 (DBP: 2 df; P = 1.93 × 10(-7)). All 5 genes are related to BP, including roles in vasodilation and angiogenesis for PTN and TOX2.

Conclusions: PTN and TOX2 are associated with BP. Analyzing SNP-education interactions may detect novel associations. Education may be a surrogate for unmeasured exposures and behaviors modifying SNP effects on BP.

Keywords: GWAS; blood pressure; educational attainment; gene–education interaction; hypertension; interaction..

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Figures

Figure 1.
Figure 1.
QQ plots for selected combinations of blood pressure phenotype, education covariable, and interaction test. (a) QQ plot for joint 2 degrees-of-freedom (df) test of single nucleotide polymorphism (SNP) main effect and interaction of SNP with a dichotomous variable distinguishing those without a bachelor’s degree from those with a bachelor’s degree (Comp_BA) for systolic blood pressure (SBP). (b) QQ plot for 1 df test of interaction of SNP with a dichotomous variable distinguishing those with no more than high school education from those with at least some college (Comp_HS+) for diastolic blood pressure (DBP). (c) QQ plot for 1 df test of SNP-Comp_HS+ interaction for pulse pressure (PP). (d) QQ plot for 2 df test of SNP main effect and SNP-Comp_BA interactions for DBP.
Figure 1.
Figure 1.
QQ plots for selected combinations of blood pressure phenotype, education covariable, and interaction test. (a) QQ plot for joint 2 degrees-of-freedom (df) test of single nucleotide polymorphism (SNP) main effect and interaction of SNP with a dichotomous variable distinguishing those without a bachelor’s degree from those with a bachelor’s degree (Comp_BA) for systolic blood pressure (SBP). (b) QQ plot for 1 df test of interaction of SNP with a dichotomous variable distinguishing those with no more than high school education from those with at least some college (Comp_HS+) for diastolic blood pressure (DBP). (c) QQ plot for 1 df test of SNP-Comp_HS+ interaction for pulse pressure (PP). (d) QQ plot for 2 df test of SNP main effect and SNP-Comp_BA interactions for DBP.
Figure 1.
Figure 1.
QQ plots for selected combinations of blood pressure phenotype, education covariable, and interaction test. (a) QQ plot for joint 2 degrees-of-freedom (df) test of single nucleotide polymorphism (SNP) main effect and interaction of SNP with a dichotomous variable distinguishing those without a bachelor’s degree from those with a bachelor’s degree (Comp_BA) for systolic blood pressure (SBP). (b) QQ plot for 1 df test of interaction of SNP with a dichotomous variable distinguishing those with no more than high school education from those with at least some college (Comp_HS+) for diastolic blood pressure (DBP). (c) QQ plot for 1 df test of SNP-Comp_HS+ interaction for pulse pressure (PP). (d) QQ plot for 2 df test of SNP main effect and SNP-Comp_BA interactions for DBP.
Figure 1.
Figure 1.
QQ plots for selected combinations of blood pressure phenotype, education covariable, and interaction test. (a) QQ plot for joint 2 degrees-of-freedom (df) test of single nucleotide polymorphism (SNP) main effect and interaction of SNP with a dichotomous variable distinguishing those without a bachelor’s degree from those with a bachelor’s degree (Comp_BA) for systolic blood pressure (SBP). (b) QQ plot for 1 df test of interaction of SNP with a dichotomous variable distinguishing those with no more than high school education from those with at least some college (Comp_HS+) for diastolic blood pressure (DBP). (c) QQ plot for 1 df test of SNP-Comp_HS+ interaction for pulse pressure (PP). (d) QQ plot for 2 df test of SNP main effect and SNP-Comp_BA interactions for DBP.
Figure 2.
Figure 2.
Manhattan plots for selected combinations of blood pressure phenotype, education covariable, and interaction test. (a) Manhattan plot of the joint 2 degrees-of-freedom (df) test of the singlue nucleotide polymorphism (SNP) main effect and interaction of SNP with a dichotomous variable distinguishing those without a bachelor’s degree from those with a bachelor’s degree (Comp_BA) for systolic blood pressure (SBP). The –log10(P value) is plotted by genomic position. One novel locus reaching significance is located on chromosome 7 (PTN). (b) Manhattan plot of the 1 df test of interaction of SNP with a dichotomous variable distinguishing those with no more than high school education from those with at least some college (Comp_HS+) for diastolic blood pressure (DBP). The –log10(P value) is plotted by genomic position. One novel locus reaching significance is located on chromosome 20 (TOX2), and a suggestive locus is located on chromosome 8 (HAS2). (c) Manhattan plot of joint 1 df test of the SNP main effect and SNP-Comp_HS+ interaction for pulse pressure (PP). The –log10(P value) is plotted by genomic position. A suggestive locus is located on chromosome 13 (MYO16). (d) Manhattan plot of joint 2 df test of the SNP main effect and SNP-Comp_BA interaction for DBP. The –log10(P value) is plotted by genomic position. A suggestive locus is located on chromosome 13 (DLEU2).
Figure 2.
Figure 2.
Manhattan plots for selected combinations of blood pressure phenotype, education covariable, and interaction test. (a) Manhattan plot of the joint 2 degrees-of-freedom (df) test of the singlue nucleotide polymorphism (SNP) main effect and interaction of SNP with a dichotomous variable distinguishing those without a bachelor’s degree from those with a bachelor’s degree (Comp_BA) for systolic blood pressure (SBP). The –log10(P value) is plotted by genomic position. One novel locus reaching significance is located on chromosome 7 (PTN). (b) Manhattan plot of the 1 df test of interaction of SNP with a dichotomous variable distinguishing those with no more than high school education from those with at least some college (Comp_HS+) for diastolic blood pressure (DBP). The –log10(P value) is plotted by genomic position. One novel locus reaching significance is located on chromosome 20 (TOX2), and a suggestive locus is located on chromosome 8 (HAS2). (c) Manhattan plot of joint 1 df test of the SNP main effect and SNP-Comp_HS+ interaction for pulse pressure (PP). The –log10(P value) is plotted by genomic position. A suggestive locus is located on chromosome 13 (MYO16). (d) Manhattan plot of joint 2 df test of the SNP main effect and SNP-Comp_BA interaction for DBP. The –log10(P value) is plotted by genomic position. A suggestive locus is located on chromosome 13 (DLEU2).
Figure 2.
Figure 2.
Manhattan plots for selected combinations of blood pressure phenotype, education covariable, and interaction test. (a) Manhattan plot of the joint 2 degrees-of-freedom (df) test of the singlue nucleotide polymorphism (SNP) main effect and interaction of SNP with a dichotomous variable distinguishing those without a bachelor’s degree from those with a bachelor’s degree (Comp_BA) for systolic blood pressure (SBP). The –log10(P value) is plotted by genomic position. One novel locus reaching significance is located on chromosome 7 (PTN). (b) Manhattan plot of the 1 df test of interaction of SNP with a dichotomous variable distinguishing those with no more than high school education from those with at least some college (Comp_HS+) for diastolic blood pressure (DBP). The –log10(P value) is plotted by genomic position. One novel locus reaching significance is located on chromosome 20 (TOX2), and a suggestive locus is located on chromosome 8 (HAS2). (c) Manhattan plot of joint 1 df test of the SNP main effect and SNP-Comp_HS+ interaction for pulse pressure (PP). The –log10(P value) is plotted by genomic position. A suggestive locus is located on chromosome 13 (MYO16). (d) Manhattan plot of joint 2 df test of the SNP main effect and SNP-Comp_BA interaction for DBP. The –log10(P value) is plotted by genomic position. A suggestive locus is located on chromosome 13 (DLEU2).
Figure 2.
Figure 2.
Manhattan plots for selected combinations of blood pressure phenotype, education covariable, and interaction test. (a) Manhattan plot of the joint 2 degrees-of-freedom (df) test of the singlue nucleotide polymorphism (SNP) main effect and interaction of SNP with a dichotomous variable distinguishing those without a bachelor’s degree from those with a bachelor’s degree (Comp_BA) for systolic blood pressure (SBP). The –log10(P value) is plotted by genomic position. One novel locus reaching significance is located on chromosome 7 (PTN). (b) Manhattan plot of the 1 df test of interaction of SNP with a dichotomous variable distinguishing those with no more than high school education from those with at least some college (Comp_HS+) for diastolic blood pressure (DBP). The –log10(P value) is plotted by genomic position. One novel locus reaching significance is located on chromosome 20 (TOX2), and a suggestive locus is located on chromosome 8 (HAS2). (c) Manhattan plot of joint 1 df test of the SNP main effect and SNP-Comp_HS+ interaction for pulse pressure (PP). The –log10(P value) is plotted by genomic position. A suggestive locus is located on chromosome 13 (MYO16). (d) Manhattan plot of joint 2 df test of the SNP main effect and SNP-Comp_BA interaction for DBP. The –log10(P value) is plotted by genomic position. A suggestive locus is located on chromosome 13 (DLEU2).
Figure 3.
Figure 3.
Mean blood pressure by minor allele count (MAC) for selected combinations of blood pressure phenotype and SNP. (a) Mean systolic blood pressure (SBP) by PTN genotype and a dichotomous variable distinguishing those without a bachelor’s degree from those with a bachelor’s degree (Comp_BA). (b) Mean diastolic blood pressure (DBP) by TOX2 genotype and a dichotomous variable distinguishing those with no more than high school education from those with at least some college (Comp_HS+).
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