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

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.