Anti-ADRA1A monoclonal antibody

Background: Adrenergic gene polymorphisms are associated with cardiovascular and metabolic phenotypes. We investigated the influence of adrenergic gene polymorphisms on cardiovascular risk in women with suspected myocardial ischemia. Methods: We genotyped 628 women referred for coronary angiography for eight polymorphisms in the alpha(1A)-, beta(1)-, beta(2)- and beta(3)-adrenergic receptors (ADRA1A, ADRB1, ADRB2, ADRB3, respectively), and their signaling proteins, G-protein beta 3 subunit (GNB3) and G-protein alpha subunit (GNAS). We compared the incidence of death, myocardial infarction, stroke, or heart failure between genotype groups in all women and women without obstructive coronary stenoses. Results: After a median of 5.8 years of follow-up, 115 women had an event. Patients with the ADRB1 Gly389 polymorphism were at higher risk for the composite outcome due to higher rates of myocardial infarction ( adjusted hazard ratio [HR] 3.63, 95% confidence interval [ 95% CI] 1.17-11.28; Gly/Gly vs. Arg/Arg HR 4.14, 95% CI 0.88-19.6). The risk associated with ADRB1 Gly389 was limited to those without obstructive CAD (n = 400, P-interaction = 0.03), albeit marginally significant in this subset ( HR 1.71, 95% CI 0.91-3.19). Additionally, women without obstructive CAD carrying the ADRB3 Arg64 variant were at higher risk for the composite endpoint ( HR 2.10, 95% CI 1.05-4.24) due to subtle increases in risk for all of the individual endpoints. No genetic associations were present in women with obstructive CAD. Conclusion: In this exploratory analysis, common coding polymorphisms in the beta(1)- and beta(3)-adrenergic receptors increased cardiovascular risk in women referred for diagnostic angiography, and could improve risk assessment, particularly for women without evidence of obstructive CAD. Trial Registration: ClinicalTrials. gov NCT00000554.

The response of blood pressure to thiazide diuretics (TZDs) differs among individuals. The prediction of the anti hypertensive effect of TZDs is important for realizing individualized therapy in the management of hypertension. The aim of this study was to identify the single nucleotide polymorphisms (SNPs) susceptible to the anti hypertensive effect of TZDs, particularly focusing on genes related to water-electrolyte absorption in the kidney. Seventy-six outpatients (mean age, 65.4 +/- 9.0 years) with essential hypertension (EHT) taking TZDs were retrospectively assessed. We defined as responders (R) those whose mean blood pressure was lowered by more than 5 mmHg after the use of TZDs. Forty-eight SNPs in 17 genes (ADD1, GNB3, TSC [SLC12A3], MLR [NR3C2], NCX1 [SLC8A1], WNK1, WNK4, AGT, ACE, AT1 [AGTR1], CYP11B2, ADRB1, ADRB2, ADRB3, ADRA1A, ADRA1B, ADRA2A) were genotyped in the 76 patients. The SNPs in TSC, MLR, NCX1, WNK1, and WNK4 were identified by direct sequencing and those with minor frequencies of greater than 5% were genotyped in this study. The comparison of polymorphism prevalence between R and non-responders (NR) showed significant differences in TSC C1784T (C allele vs. T allele, odds ratio (OR)=3.81, p= 0.016, confidence interval (CI): 1.25-11.63) and ADRB3 T727C(Trp64Arg) (T allele vs. C allele, OR = 4.59, p = 0.005, CI: 1.54-13.68). The blood pressure (BP) in patients homozygous for the major alleles of both TSC C1784T and ADRB3 T727C were significantly reduced by TZD treatment; however, the BID in those homozygous for the minor allele and heterozygous (TSC C1784T. TT+CT; ADRB3 T727C: CC+CT) for both SNPs were not significantly changed after TZD treatment. Both newly detected TSC C1784T and ADRB3 T727C are gene polymorphisms susceptible to the anti hypertensive effect of TZDs in patients with EHT. Thus, the prediction of BP reduction by TZDs may be possible by evaluating these two SNPs.