Association of ACE2 Polymorphisms and Derived Haplotypes with Obesity and Hyperlipidemia in Female Spanish Adolescents

Background In the cardiovascular (CV) system, overactivation of the angiotensin converting enzyme (ACE) may trigger deleterious responses derived from angiotensin (Ang)-II, which can be attenuated by stimulation of ACE2 and subsequent Ang-(1-7) metabolite. However, ACE2 exhibits a high degree of genetic polymorphism that may affect its structure and stability, interfering with these cardioprotective actions. Methodology: Five ACE2-single nucleotide polymorphisms (SNP); rs4646188, rs2158083, rs233575, rs879922, and rs2074192, previously related with CV risk factors, were analyzed in a general population of adolescents and tested for potential associations with anthropometric and plasma parameters. Results Girls (n=461) exhibited lower rates of overweight and obesity, blood pressure, and glycemia than boys (n=412), though increased plasma lipids. The triglycerides (TG)/HDL-C ratio was, however, lower in females. Interestingly, only in girls, the occurrence of overweight/obesity was associated with the SNPs rs879922 [OR 1.67 (1.02-2.75)], rs233575 [OR 1.98 (1.21- 3.22)] and rs2158083 [OR 1.67 (1.04-2.68)]. Also, their highest levels of TG were linked to rs879922, rs233575, and rs2158083, and the highest TG/HDL-C ratio was assocated with rs879922 and rs233575. The upper levels of TC and LDL-C was associated with rs2074192 and rs2158083. Furthermore, the established cut-off level for TG ≥ 90 mg/dl was related with rs879922 [OR 1.78 (1.06-2.96)], rs2158083 [OR 1.75 (1.08-2.82)], and rs233575 [OR 1.62 (1.00 -2.61)]. The cut-off level for TC ≥ 170 mg/dl was associated with rs2074192 [OR 1.54 (1.04-2.28) and rs2158083 [OR 1.53 (1.04-2.25)]. In addition, the haplotype (C-G-C) derived from rs879922-rs2158083-rs233575 was related with higher prevalence of overweight/obesity and TG elevation. Conclusion The expression and activity of ACE2 may be essential for CV homeostasis. Interestingly, ACE2-SNPs rs879922, rs233575, rs2158083 and rs2074192, and haplotype (C-G-C) of the three former could induce vulnerability to obesity and hyperlipidemia in women. Thus, these SNPs might be used as predictive biomarkers for CV diseases and as molecular targets for CV therapy.