As regards LEPR Sun et al showed that the rs

As regards LEPR, Sun et al. showed that the rs1137101-223A > G polymorphism influences the effectiveness of simvastatin on plasma HDL-C levels in CHD patients [35]. In accordance with the results of García-Bermúdez et al., however, no such an association exists between leptin rs2167270 (G > A) polymorphism and the risk of CVDs in rheumatoid arthritis patients [36]. In contrast, in a study conducted by Tang et al., results suggested that LEPR rs1137100-Lys109Arg and rs1137101-A > G polymorphisms serve as susceptibility markers for ischemic stroke in southern Chinese [37]. Furthermore, other studies indicated that rs1137101-A > G polymorphism of the LEPR is associated with hypertension, obesity lipids, and insulin resistance [38, 39]. Two further studies demonstrated individuals who were homozygous for G allele carriers, exhibited higher ligand binding affinity [40, 41]. In j9 to the above-mentioned studies, the present findings indicated that LEPR rs1137101 polymorphism was not associated with the risk of CAD/hypertension. Leptin demonstrates atherogenic effects such as induction of endothelial dysfunction, migration, hypertrophy and proliferation of vascular smooth muscle cells, platelet aggregation, induction of inflammation and oxidative stress, and hence, pathogenesis of hypertension and CAD [42, 43]. The rs7799039-G2548A polymorphism of the leptin gene is one of the most common polymorphisms in all populations which is located at the 5'end of the leptin promoter gene and may exert inhibitory effects on leptin transcription [44]. The rs7799039 polymorphism is close to a SP-1, MER11 and Alu transcription factor binding site that may regulate leptin transcription. Coinciding with the present results, Hinuy et al. did not show any association between leptin rs7799039-G2548A and CAD, contrarily shown formerly for the leptin-tet microsatellite polymorphism among the Italians and Brazilians [45, 46]. In a sense, no significant association was found between leptin gene polymorphism and CAD/hypertension. The discrepancies between the present results and other findings may be due to interactions of rs7799039 polymorphism with other variants in leptin and LEPR genes, gender, sample size, and population ethnicity. Some limitations can be considered in interpretation of the results yielded by the study. Firstly, the population under examination was restricted to the southeast residents of Iran, as a result of which these findings may differ from those of other studies incorporating a broader range of populations. Secondly, by using multinomial regression model analysis, the results were adjusted for each variable to show the reliable statistical power of our association study. Finally, selection of “H+CAD−” group was one of the important limitations as all H+CAD− patients were susceptible to coronary angiography. Accordingly, it was a demanding and taxing task to select hypertensive patients without any critical coronary vessel stenosis, hence the modest sample size. The present study, however, enjoys some strong points as well including the fact that CAD was diagnosed by coronary angiograms while it was confirmed in other studies only through an electrocardiogram or a thallium scan. Furthermore, we analyzed four effective SNPs of APLNR genes, leptin gene receptor and leptin gene in patients with CAD and/or hypertension in different conditions.
Conclusion
Introduction The apelin gene encodes a preproprotein of 77 amino acids that is processed into multiple shorter peptides including apelin-36, apelin-17, apelin-13 and apelin-12 (Tatemoto et al., 1998). Apelin-13 may undergo post-translational modification leading to the formation of a more stable and biologically active pyroglutamyl form, [Pyr1]apelin-13. Apelin acts via the single apelin receptor (APJ) subtype to mediate effects on the cardiovascular system (Reaux et al., 2001, Ishida et al., 2004), fluid homeostasis (O'Carroll and Lolait, 2003), glucose metabolism (Dray et al., 2008), and food intake (Taheri et al., 2002), influencing not only cAMP production but also PKC, PI3K, protein kinase B (Akt), S6 ribosomal protein kinase (p70S6K), ERK (Masri et al., 2002, Masri et al., 2004) and cytoplasmic Ca2+ concentration (Choe et al., 2000). APJ couples to Gi/o in assays measuring extracellular acidification rates (Hosoya et al., 2000) and phosphorylation of ERK and p70S6 kinase (Masri et al., 2002, Masri et al., 2004), and activates ERK1/2 and inhibits adenylate cyclase through Gαi1- and Gαi2-dependent pathways (Masri et al., 2006, Bai et al., 2008). However apelin activation of ERK1/2 is mediated via PKC in HEK293 cells expressing mouse APJ, indicative of coupling to either Go or Gq/11 (Masri et al., 2002). Additionally the beneficial inotropic effect of apelin in vivo is only partially abrogated by pertussis toxin (PTX) and by PKC inhibitors, indicating that some of the actions of APJ could be mediated by Gi/o and/or Gq/11 coupling (Szokodi et al., 2002). Recently it has been shown that mechanical stretch signals via APJ to induce myocardial hypertrophy by a G protein-independent, β-arrestin-dependent pathway (Scimia et al., 2012). Interestingly APJ, when stably expressed in CHO cells, shows ligand bias with endogenous ligands as, for example, apelin-13 preferentially signals to ERK via Gαi2 whereas apelin-36 does so equally well via Gαi1 and Gαi2 (Masri et al., 2006).