Haplotype association analysis of AGT variants with hypertension-related traits: The HyperGEN study

C. Charles Gu, Yen Pei C Chang, Steven Hunt, Karen Schwander, Donna Arnett, Luc Djousse, Gerardo Heiss, Al Oberman, Jean Marc Lalouel, Mike Province, Aravinda Chakravarti, D. C. Rao

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Objective: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. Methods: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. Results: In Blacks, two SNPs in exon 5 and 3′ UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p = 0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p = 0.009) and gripSBP emerged in Whites. Conclusion: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.

Original languageEnglish
Pages (from-to)164-176
Number of pages13
JournalHuman Heredity
Volume60
Issue number3
DOIs
Publication statusPublished - 2005
Externally publishedYes

Fingerprint

Angiotensinogen
Haplotypes
Single Nucleotide Polymorphism
Blood Pressure
Hypertension
Body Mass Index
Nucleic Acid Regulatory Sequences
5' Untranslated Regions
3' Untranslated Regions
Renin-Angiotensin System
Exons
Phenotype
Genes

Keywords

  • AGT
  • Blood pressure reactivity
  • BMI
  • Genetic interaction
  • Haplotype analysis
  • Hypertension
  • Intermediate phenotype

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Gu, C. C., Chang, Y. P. C., Hunt, S., Schwander, K., Arnett, D., Djousse, L., ... Rao, D. C. (2005). Haplotype association analysis of AGT variants with hypertension-related traits: The HyperGEN study. Human Heredity, 60(3), 164-176. https://doi.org/10.1159/000090118

Haplotype association analysis of AGT variants with hypertension-related traits : The HyperGEN study. / Gu, C. Charles; Chang, Yen Pei C; Hunt, Steven; Schwander, Karen; Arnett, Donna; Djousse, Luc; Heiss, Gerardo; Oberman, Al; Lalouel, Jean Marc; Province, Mike; Chakravarti, Aravinda; Rao, D. C.

In: Human Heredity, Vol. 60, No. 3, 2005, p. 164-176.

Research output: Contribution to journalArticle

Gu, CC, Chang, YPC, Hunt, S, Schwander, K, Arnett, D, Djousse, L, Heiss, G, Oberman, A, Lalouel, JM, Province, M, Chakravarti, A & Rao, DC 2005, 'Haplotype association analysis of AGT variants with hypertension-related traits: The HyperGEN study', Human Heredity, vol. 60, no. 3, pp. 164-176. https://doi.org/10.1159/000090118
Gu, C. Charles ; Chang, Yen Pei C ; Hunt, Steven ; Schwander, Karen ; Arnett, Donna ; Djousse, Luc ; Heiss, Gerardo ; Oberman, Al ; Lalouel, Jean Marc ; Province, Mike ; Chakravarti, Aravinda ; Rao, D. C. / Haplotype association analysis of AGT variants with hypertension-related traits : The HyperGEN study. In: Human Heredity. 2005 ; Vol. 60, No. 3. pp. 164-176.
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AU - Gu, C. Charles

AU - Chang, Yen Pei C

AU - Hunt, Steven

AU - Schwander, Karen

AU - Arnett, Donna

AU - Djousse, Luc

AU - Heiss, Gerardo

AU - Oberman, Al

AU - Lalouel, Jean Marc

AU - Province, Mike

AU - Chakravarti, Aravinda

AU - Rao, D. C.

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N2 - Objective: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. Methods: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. Results: In Blacks, two SNPs in exon 5 and 3′ UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p = 0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p = 0.009) and gripSBP emerged in Whites. Conclusion: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.

AB - Objective: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. Methods: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. Results: In Blacks, two SNPs in exon 5 and 3′ UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p = 0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p = 0.009) and gripSBP emerged in Whites. Conclusion: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.

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KW - Intermediate phenotype

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