Role of single nucleotide polymorphism rs2383206 on coronary artery disease risk among Saudi Population: a case-control study.

OBJECTIVE: We aim to investigate the relationship between genetic variation and biological function on a genomic scale, focusing on identifying genes responsible for complex diseases using single nucleotide polymorphisms. Specifically, the study explores the association between the rs2383206 gene located on chromosome 9p21.3 and the development of coronary artery disease (CAD) in a specific Saudi population. PATIENTS AND METHODS: This case-control study was conducted between September 2013 and May 2015 at King Abdullah Medical City (KAMC) and Al-Noor Specialist Hospital targeting the Saudi Population residing in the western region of Saudi Arabia. The study enrolled 315 cases with documented CAD and 205 controls with normal coronary arteries on coronary angiography. Genomic DNA was extracted from peripheral blood samples of both groups, and genotyping of rs2383206 was performed using the tetra-primer amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) method. RESULTS: In this study, the prevalence of the GG genotype in rs2383206 was found to be higher in patients with CAD than in controls, with an odds ratio of 1.997 [95% confidence interval (CI): 1.176-3.394, p = 0.007]. Additionally, individuals with the GG genotype who had sedentary lifestyles, hyperlipidemia, and smoked were found to be at a higher risk for developing CAD (p = 0.003, 0.009, and 0.003, respectively). The G allele also increased the risk of CAD with an odds ratio of 1.413 (95% CI: 1.099-1.817; p = 0.004). CONCLUSIONS: In conclusion, this study demonstrated a significant association between the rs2383206 variant located on chromosome 9p21 and the development of CAD. The findings of this study provide valuable insights into the genetic susceptibility to CAD and highlight the potential of this variant as a target for future functional studies.

Comparison of non-invasive vs invasive blood pressure measurement in neonates undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.

OBJECTIVE: To evaluate the accuracy of blood pressure (BP) measured non-invasively (NIBP) compared with invasive arterial BP (IABP) measured by umbilical arterial catheter in neonates undergoing therapeutic hypothermia (TH) for hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: We conducted a retrospective study of neonates with gestational age (GA)⩾35 weeks with HIE who received TH. Paired NIBP and IABP measurements were obtained during TH and during normothermia. RESULT: We collected 897 paired measurements from 40 infants, which included 623 pairs during TH and 274 pairs during normothermia. The mean±s.d. differences in BP measured by NIBP compared with IABP in mmHg were -0.2±8.8 (P=0.505) for systolic BP (SBP), -4.5±8.3 (P<0.001) for diastolic BP (DBP) and -5.1±7.5 (P<0.001) for mean BP (MBP) during TH; and -1.3±9.2 (P=0.016) for SBP, -7.5±7.8 (P<0.001) for DBP and -7.3±6.8 (P<0.001) for MBP during normothermia. Overall 466/623 (74.8%), 324/623 (52.0%) and 363/623 (58.3%) of NIBP measurements of SBP, DBP and MBP, respectively, were clinically acceptable (defined as difference ⩽15% of IABP reading) during TH; and 202/274 (73.7%), 118/274 (43.1%) and 148/274 (54.0%), were clinically acceptable during normothermia. CONCLUSION: In term or near-term neonates with HIE, NIBP measurements are a robust method to determine SBP; however, DBP and MBP are underestimated. Determination of hypotension using the MBP measured non-invasively should be interpreted with caution.

Milrinone attenuates thromboxane receptor-mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes.

BACKGROUND AND PURPOSE: Neonatal pulmonary hypertension (PPHN) is characterized by pulmonary vasoconstriction, due in part to dysregulation of the thromboxane prostanoid (TP) receptor. Hypoxia induces TP receptor-mediated hyperresponsiveness, whereas serine phosphorylation mediates desensitization of TP receptors. We hypothesized that prostacyclin (IP) receptor activity induces TP receptor phosphorylation and decreases ligand affinity; that TP receptor sensitization in hypoxic myocytes is due to IP receptor inactivation; and that this would be reversible by the cAMP-specific phosphodiesterase inhibitor milrinone. EXPERIMENTAL APPROACH: We examined functional regulation of TP receptors by serine phosphorylation and effects of IP receptor stimulation and protein kinase A (PKA) activity on TP receptor sensitivity in myocytes from neonatal porcine resistance pulmonary arteries after 72 h hypoxia in vitro. Ca(2+) response curves to U46619 (TP receptor agonist) were determined in hypoxic and normoxic myocytes incubated with or without iloprost (IP receptor agonist), forskolin (adenylyl cyclase activator), H8 (PKA inhibitor) or milrinone. TP and IP receptor saturation binding kinetics were measured in presence of iloprost or 8-bromo-cAMP. KEY RESULTS: Ligand affinity for TP receptors was normalized in vitro by IP receptor signalling intermediates. However, IP receptor affinity was compromised in hypoxic myocytes, decreasing cAMP production. Milrinone normalized TP receptor sensitivity in hypoxic myocytes by restoring PKA-mediated regulatory TP receptor phosphorylation. CONCLUSIONS AND IMPLICATIONS: TP receptor sensitivity and EC(50) for TP receptor agonists was regulated by PKA, as TP receptor serine phosphorylation by PKA down-regulated Ca(2+) mobilization. Hypoxia decreased IP receptor activity and cAMP generation, inducing TP receptor hyperresponsiveness, which was reversed by milrinone.