Genetic variation in the renin–angiotensin–aldosterone system is associated with cardiovascular risk factors and early mortality in established coronary heart disease

Abstract

This study examined renin-angiotensin-aldosterone (RAAS) system gene variants for associations with cardiovascular risk factors and outcomes in coronary heart disease. Coronary disease patients (n ¼ 1186) were genotyped for 21 single-nucleotide polymorphisms (SNPs) within angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin-II type-1 receptor (AGTR1) and aldosterone synthase (CYP11B2). Associations with all-cause mortality and cardiovascular readmissions were assessed over a median of 3.0 years. The AGT M235T 'T' allele was associated with a younger age of clinical coronary disease onset (P ¼ 0.006), and the AGT rs2478545 minor allele was associated with lower circulating natriuretic peptides (P ¼ 0.0001-P ¼ 0.001) and E/E 1 (P ¼ 0.018). Minor alleles of AGT SNPs rs1926723 and rs11122576 were associated with more frequent history of renal disease (Pp0.04) and type-2 diabetes (Pp0.02), higher body mass index (Pp0.02) and greater mortality (Pp0.007). AGT rs11568054 minor allele carriers had more frequent history of renal disease (P ¼ 0.04) and higher plasma creatinine (P ¼ 0.033). AGT rs6687360 minor allele carriers exhibited worse survival (P ¼ 0.02). ACE rs4267385 was associated with older clinical coronary disease onset (P ¼ 0.008) and hypertension (P ¼ 0.013) onset, increased plasma creatinine (P ¼ 0.01), yet greater mortality (P ¼ 0.044). Less history of hypertension was observed with the AGTR1 rs12685977 minor allele (P ¼ 0.039). Genetic variation within the RAAS was associated with cardiovascular risk factors and accordingly poorer survival.

The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure

“…The RAS has been the target of active research interest since the discovery of renin more than 100 years ago (Tigerstedt R & PG., 1898), reflecting its importance in the pathogenesis of hypertension and other cardiovascular diseases (Ellis, et al, 2012; Hsueh & Wyne, 2011; Re, 2004; Te Riet, van Esch, Roks, van den Meiracker, & Danser, 2015; Vijayaraghavan & Deedwania, 2011). In the traditional view of the systemic RAS, active renin is generated by the removal of a prosegment from prorenin, a precursor of renin, in the juxtaglomerular cells of the kidney.…”

The effects of angiotensinogen gene polymorphisms on cardiovascular disease outcomes during antihypertensive treatment in the GenHAT study

“…A recent study found a significant association of the minor allele of rs11122576 with CHD mortality in a cohort of 1186 CHD participants mostly of European ancestry-after 3-years of follow-up. The minor allele of rs1122576 was also associated with of higher risk of renal disease, type 2 diabetes, and higher body mass index in that study (Ellis et al, 2013). Similarly to the CHD results, there were more marginally significant associations among African Americans compared to Caucasians for the HF outcome, however none were close to statistical significance.…”

Prognostic Significance of Met235/235thr Polymorphisms of Gene Agt for Development of Cardiovascular Disorders in Professional Sportsmen

“…Связь 235Тhr поли-морфизма гена AGT с неблагоприятным исходом ИМ в молодом возрасте отмечена в работах Elis KL, et al [5], Hara M, et al [6].…”

“…В дополнение к этому Hara M, et al, наблюдая на протяжении 5 лет за пациентами, перенесшими ИМ (n=3149), пришли к выводу, что лица с Т235Т мутантным гомозигот-ным генотипом имеют более низкий процент выжи-ваемости в сравнении с нормальным М235М гено-типом. Подтверждением ассоциации 235Т полимор-физма и Т235Т генотипа гена AGT с АГ в детском возрасте являются экспериментальные данные, полученные автором [7] в лонгитюдном исследова-нии на протяжении 35 лет (1977-2012) с участием 507 человек [5][6][7]. примечания: p -достоверность различий для контроля и больных ССЗ (р1), спортсменов и больных ССЗ (p2), контроля и спортсменов (p3), OR1 -относитель-ный риск (для генотипов), OR2 -относительный риск (для аллелей).…”

“…В условиях интенсивных физиче-ских нагрузок носительство типированных SNP и генотипов у спортсменов, независимо от их этни-ческой принадлежности, предрас полагает к повы-шенному риску БСК. Поэтому представляется целе-сообразным рекомендовать исследование М235T гена AGT при целенаправленном отборе в спорт высших достижений [3][4][5][6][7][8][15][16][17].…”