Pharmacogenomic Genome-Wide Meta-Analysis of Blood Pressure Response to ß-Blockers in Hypertensive African Americans.

African Americans suffer a higher prevalence of hypertension compared with other racial/ethnic groups. In this study, we performed a pharmacogenomic genome-wide association study of blood pressure (BP) response to ß-blockers in African Americans with uncomplicated hypertension. Genome-wide meta-analysis was performed in 318 African American hypertensive participants in the 2 Pharmacogenomic Evaluation of Antihypertensive Responses studies: 150 treated with atenolol monotherapy and 168 treated with metoprolol monotherapy. The analysis adjusted for age, sex, baseline BP and principal components for ancestry. Genome-wide significant variants with P<5×10(-8) and suggestive variants with P<5×10(-7) were evaluated in an additional cohort of 141 African Americans treated with the addition of atenolol to hydrochlorothiazide treatment. The validated variants were then meta-analyzed in these 3 groups of African Americans. Two variants discovered in the monotherapy meta-analysis were validated in the add-on therapy. African American participants heterozygous for SLC25A31 rs201279313 deletion versus wild-type genotype had better diastolic BP response to atenolol monotherapy, metoprolol monotherapy, and atenolol add-on therapy: -9.3 versus -4.6, -9.6 versus -4.8, and -9.7 versus -6.4 mm Hg, respectively (3-group meta-analysis P=2.5×10(-8), ß=-4.42 mm Hg per variant allele). Similarly, LRRC15 rs11313667 was validated for systolic BP response to ß-blocker therapy with 3-group meta-analysis P=7.2×10(-8) and ß=-3.65 mm Hg per variant allele. In this first pharmacogenomic genome-wide meta-analysis of BP response to ß-blockers in African Americans, we identified novel variants that may provide valuable information for personalized antihypertensive treatment in this group.

PTPRD gene associated with blood pressure response to atenolol and resistant hypertension.

OBJECTIVE: The aim of this study is to identify single-nucleotide polymorphisms (SNPs) influencing blood pressure (BP) response to the ß-blocker atenolol. METHODS: Genome-wide association analysis of BP response to atenolol monotherapy was performed in 233 white participants with uncomplicated hypertension in the pharmacogenomic evaluation of antihypertensive responses study. Forty-two polymorphisms with P less than 10 for association with either diastolic or systolic response to atenolol monotherapy were validated in four independent groups of hypertensive individuals (total n = 2114). RESULTS: In whites, two polymorphisms near the gene PTPRD (rs12346562 and rs1104514) were associated with DBP response to atenolol (P = 3.2 × 10 and P = 5.9 × 10, respectively) with directionally opposite association for response to hydrochlorothiazide in another group of 228 whites (P = 0.0018 and P = 0.00012). A different polymorphism (rs10739150) near PTPRD was associated with response to atenolol in 150 black hypertensive individuals (P = 8.25 × 10). rs12346562 had a similar trend in association with response to bisoprolol (a different ß-blocker) in 207 Finnish men in the genetics of drug responsiveness in essential hypertension study. In addition, an intronic single-nucleotide polymorphism (rs4742610) in the PTPRD gene was associated with resistant hypertension in whites and Hispanics in the international verapamil SR trandolapril study (meta-analysis P = 3.2 × 10). CONCLUSION: PTPRD was identified as a novel locus potentially associated with BP response to atenolol and resistant hypertension in multiple ethnic groups.

Hindbrain oxytocin receptors contribute to the effects of circulating oxytocin on food intake in male rats.

Oxytocin (OT)-elicited hypophagia has been linked to neural activity in the nucleus of the solitary tract (NTS). Because plasma OT levels increase after a meal, we hypothesized that circulating OT acts at both peripheral and hindbrain OT receptors (OTRs) to limit food intake. To initially determine whether circulating OT inhibits food intake by acting at hindbrain OTRs, we pretreated rats with an OTR antagonist administered into the fourth ventricle (4V) followed by either central or systemic OT administration. Administration of the OTR antagonist into the 4V blocked anorexia induced by either 4V or i.p. injection of OT. However, blockade of peripheral OTRs also weakened the anorectic response to ip OT. Our data suggest a predominant role for hindbrain OTRs in the hypophagic response to peripheral OT administration. To elucidate central mechanisms of OT hypophagia, we tested whether OT activates NTS catecholaminergic neurons. OT (ip) increased the number of NTS cells expressing c-Fos, of which 10%-15% were catecholaminergic. Furthermore, electrophysiological studies in mice revealed that OT stimulated 47% (8 of 17) of NTS catecholamine neurons through a presynaptic mechanism. However, OT-elicited hypophagia did not appear to require activation of α1-adrenoceptors, and blockade of glucagon-like peptide-1 receptors similarly did not attenuate anorexia induced by OT. These findings demonstrate that OT elicits satiety through both central and peripheral OTRs and that although catecholamine neurons are a downstream target of OT signaling in the NTS, the hypophagic effect is mediated independently of α1-adrenoceptor signaling.

Assessments for measuring patient-centered cultural sensitivity in community-based primary care clinics.

OBJECTIVE: To develop and test the reliability of three race/ethnicity-specific forms of the pilot Tucker-Culturally Sensitive Health Care Inventory (T-CUSHCI) for use by patients at community-based primary care centers to evaluate the level of patient-centered cultural sensitivity perceived in the health care that they experience. METHODS: This research involved two studies using independent samples of primary care patients. In study 1, mostly low-income African-American, Hispanic and non-Hispanic white American patients (N=221) rated the importance of specific provider and office staff behaviors and attitudes, and center policies and physical environment characteristics that were earlier identified in previous focus groups as characteristics of patient-centered culturally sensitive healthcare. In study 2, three pilot race/ethnicity-specific T-CUSHCI patient forms were constructed from the items rated as at least important in study 1. Mostly low-income African-American and non-Hispanic white American patients (N=180) provided data to determine the reliability of the T-CUSHCI patient form for their racial/ethnic group. RESULTS: The pilot T-CUSHCI-African-American patient form and the pilot T-CUSHCI-non-Hispanic white American patient form were found to have Cronbach's alpha coefficients ranging from 0.71-0.96 and six-month test-retest and split-half reliabilities ranging from 0.92-0.99. CONCLUSION: The pilot T-CUSHCI patient forms (one each for African Americans, Hispanics and non-Hispanic whites) should be further tested using a national sample of patients. In the interim, these inventory forms can be used as clinical tools to obtain patient feedback for providing "individualized" patient-centered culturally sensitive healthcare.