The M235T single nucleotide polymorphism in the angiotensinogen gene is associated with coronary artery calcium in patients with a family history of coronary artery disease

Parag H. Joshi, Hongyan Xu, Renee LeStrange, Nancy Flockhart, Ben Kirkland, Gustavo Vazquez, Zhen Qian, Abhinav Sharma, Idean Marvasty, Kunal Bhatt, Charles Brown, Sarah Rinehart, Joseph Miller, Szilard Voros

Research output: Contribution to journalArticle

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Abstract

Little is known about the contribution of genetics and lipoprotein subclasses to the development of coronary artery calcification (CAC) in asymptomatic, first-degree relatives of patients with CAD. We evaluated 100 asymptomatic, non-smoking, lipid-lowering therapy-naïve, first-degree relatives of patients with obstructive CAD through testing for 27 biomarkers, 15 single nucleotide polymorphisms in 12 candidate genes, and CAC and compared them to matched controls without family history. We compared prevalence of CAC in those with and without family history and biomarkers between those with and without CAC. Mean age was 41.6 ± 9 years; 58% were female. Significantly more subjects with family history had non-zero CAC (median Agatston: 13, range 1-1107) compared to those without family history (median Agatston: 43; range 1-345) (21% vs. 9%; p = 0.028). Among subjects with family history, in subjects with positive vs. negative CAC, multivariable analysis showed significantly lower HDL-2A (999 ± 333 vs. 1262 ± 397 nmol/L) and higher frequency of a substitution of threonine for methionine at codon 235 in the angiotensinogen gene (AGT M235T) (75% vs. 54%; p < 0.05; odds ratio of 2.6 for CAC). Population attributable risk of one copy of the risk allele at the AGT locus was 16%, highest of any variable tested. In conclusion, in this population of healthy, low-risk subjects with a family history of CAD, the AGT M235T variant was the most significant predictor of CAC independent of blood pressure, raising the possibility of an alternative biological pathway.

Original languageEnglish (US)
Pages (from-to)433-439
Number of pages7
JournalAtherosclerosis
Volume226
Issue number2
DOIs
StatePublished - Feb 1 2013

Fingerprint

Angiotensinogen
Single Nucleotide Polymorphism
Coronary Artery Disease
Coronary Vessels
Calcium
Genes
Biomarkers
Threonine
Codon
Methionine
Population
Lipoproteins
Alleles
Odds Ratio
Blood Pressure
Lipids

Keywords

  • Angiotensinogen
  • Candidate genes
  • Coronary artery calcification
  • Family history

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

The M235T single nucleotide polymorphism in the angiotensinogen gene is associated with coronary artery calcium in patients with a family history of coronary artery disease. / Joshi, Parag H.; Xu, Hongyan; LeStrange, Renee; Flockhart, Nancy; Kirkland, Ben; Vazquez, Gustavo; Qian, Zhen; Sharma, Abhinav; Marvasty, Idean; Bhatt, Kunal; Brown, Charles; Rinehart, Sarah; Miller, Joseph; Voros, Szilard.

In: Atherosclerosis, Vol. 226, No. 2, 01.02.2013, p. 433-439.

Research output: Contribution to journalArticle

Joshi, PH, Xu, H, LeStrange, R, Flockhart, N, Kirkland, B, Vazquez, G, Qian, Z, Sharma, A, Marvasty, I, Bhatt, K, Brown, C, Rinehart, S, Miller, J & Voros, S 2013, 'The M235T single nucleotide polymorphism in the angiotensinogen gene is associated with coronary artery calcium in patients with a family history of coronary artery disease', Atherosclerosis, vol. 226, no. 2, pp. 433-439. https://doi.org/10.1016/j.atherosclerosis.2012.10.039
Joshi, Parag H. ; Xu, Hongyan ; LeStrange, Renee ; Flockhart, Nancy ; Kirkland, Ben ; Vazquez, Gustavo ; Qian, Zhen ; Sharma, Abhinav ; Marvasty, Idean ; Bhatt, Kunal ; Brown, Charles ; Rinehart, Sarah ; Miller, Joseph ; Voros, Szilard. / The M235T single nucleotide polymorphism in the angiotensinogen gene is associated with coronary artery calcium in patients with a family history of coronary artery disease. In: Atherosclerosis. 2013 ; Vol. 226, No. 2. pp. 433-439.
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abstract = "Little is known about the contribution of genetics and lipoprotein subclasses to the development of coronary artery calcification (CAC) in asymptomatic, first-degree relatives of patients with CAD. We evaluated 100 asymptomatic, non-smoking, lipid-lowering therapy-na{\"i}ve, first-degree relatives of patients with obstructive CAD through testing for 27 biomarkers, 15 single nucleotide polymorphisms in 12 candidate genes, and CAC and compared them to matched controls without family history. We compared prevalence of CAC in those with and without family history and biomarkers between those with and without CAC. Mean age was 41.6 ± 9 years; 58{\%} were female. Significantly more subjects with family history had non-zero CAC (median Agatston: 13, range 1-1107) compared to those without family history (median Agatston: 43; range 1-345) (21{\%} vs. 9{\%}; p = 0.028). Among subjects with family history, in subjects with positive vs. negative CAC, multivariable analysis showed significantly lower HDL-2A (999 ± 333 vs. 1262 ± 397 nmol/L) and higher frequency of a substitution of threonine for methionine at codon 235 in the angiotensinogen gene (AGT M235T) (75{\%} vs. 54{\%}; p < 0.05; odds ratio of 2.6 for CAC). Population attributable risk of one copy of the risk allele at the AGT locus was 16{\%}, highest of any variable tested. In conclusion, in this population of healthy, low-risk subjects with a family history of CAD, the AGT M235T variant was the most significant predictor of CAC independent of blood pressure, raising the possibility of an alternative biological pathway.",
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AU - Marvasty, Idean

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AU - Miller, Joseph

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AB - Little is known about the contribution of genetics and lipoprotein subclasses to the development of coronary artery calcification (CAC) in asymptomatic, first-degree relatives of patients with CAD. We evaluated 100 asymptomatic, non-smoking, lipid-lowering therapy-naïve, first-degree relatives of patients with obstructive CAD through testing for 27 biomarkers, 15 single nucleotide polymorphisms in 12 candidate genes, and CAC and compared them to matched controls without family history. We compared prevalence of CAC in those with and without family history and biomarkers between those with and without CAC. Mean age was 41.6 ± 9 years; 58% were female. Significantly more subjects with family history had non-zero CAC (median Agatston: 13, range 1-1107) compared to those without family history (median Agatston: 43; range 1-345) (21% vs. 9%; p = 0.028). Among subjects with family history, in subjects with positive vs. negative CAC, multivariable analysis showed significantly lower HDL-2A (999 ± 333 vs. 1262 ± 397 nmol/L) and higher frequency of a substitution of threonine for methionine at codon 235 in the angiotensinogen gene (AGT M235T) (75% vs. 54%; p < 0.05; odds ratio of 2.6 for CAC). Population attributable risk of one copy of the risk allele at the AGT locus was 16%, highest of any variable tested. In conclusion, in this population of healthy, low-risk subjects with a family history of CAD, the AGT M235T variant was the most significant predictor of CAC independent of blood pressure, raising the possibility of an alternative biological pathway.

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