Pharmacogenetic Associations of ß1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes).

BACKGROUND AND PURPOSE: Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and ß-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by ß-blocker treatment in patients with a history of stroke. METHODS: Nine hundred and twenty-six participants of the SPS3 trial's (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan-Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41 475 individuals of European and African ancestry in the NINDS (National Institute of Neurological Disorders and Stroke) SiGN (Stroke Genetics Network). RESULTS: MACE was higher in carriers of the Gly49 allele than in those with the Ser49Ser genotype (10.5% versus 5.4%, log-rank P=0.005). Gly49 carrier status was associated with MACE (hazard ratio, 1.62; 95% confidence interval, 1.00-2.68) and ischemic stroke (hazard ratio, 1.81; 95% confidence interval, 1.01-3.23) in SPS3 and with small artery ischemic stroke (odds ratio, 1.14; 95% confidence interval, 1.03-1.26) in SiGN. In SPS3, ß-blocker-treated Gly49 carriers had increased MACE versus non-ß-blocker-treated individuals and noncarriers (hazard ratio, 2.03; 95% confidence interval, 1.20-3.45). No associations were observed with the Arg389Gly polymorphism. CONCLUSION: Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among ß-blocker-treated individuals. Further research is needed to define ß-blocker benefit among ischemic stroke patients by ADRB1 genotype. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Gene-environment interactions and obesity traits among postmenopausal African-American and Hispanic women in the Women's Health Initiative SHARe Study.

Genome-wide association studies (GWAS) of obesity measures have identified associations with single nucleotide polymorphisms (SNPs). However, no large-scale evaluation of gene-environment interactions has been performed. We conducted a search of gene-environment (G × E) interactions in post-menopausal African-American and Hispanic women from the Women's Health Initiative SNP Health Association Resource GWAS study. Single SNP linear regression on body mass index (BMI) and waist-to-hip circumference ratio (WHR) adjusted for multidimensional-scaling-derived axes of ancestry and age was run in race-stratified data with 871,512 SNPs available from African-Americans (N = 8,203) and 786,776 SNPs from Hispanics (N = 3,484). Tests of G × E interaction at all SNPs for recreational physical activity (m h/week), dietary energy intake (kcal/day), alcohol intake (categorical), cigarette smoking years, and cigarette smoking (ever vs. never) were run in African-Americans and Hispanics adjusted for ancestry and age at interview, followed by meta-analysis of G × E interaction terms. The strongest evidence for concordant G × E interactions in African-Americans and Hispanics was for smoking and marker rs10133840 (Q statistic P = 0.70, beta = -0.01, P = 3.81 × 10(-7)) with BMI as the outcome. The strongest evidence for G × E interaction within a cohort was in African-Americans with WHR as outcome for dietary energy intake and rs9557704 (SNP × kcal = -0.04, P = 2.17 × 10(-7)). No results exceeded the Bonferroni-corrected statistical significance threshold.

Sibling composition and children's anthropometric indicators of nutritional status: evidence from native Amazonians in Bolivia.

BACKGROUND: Siblings compete for parental resources. Little is known about how sibling composition (older sisters, older brothers, younger sisters, younger brothers) might affect child anthropometric indicators of nutritional status. AIM: This study evaluates the associations between sibling composition and child anthropometry using panel data from a native Amazonian society (Tsimane'). METHODS: Anthropometry of ~168 girls and 169 boys aged 2-9 years were measured annually during 2002-2007 (2360 observations). Children's weight-for-height Z-score (WHZ), mid-upper arm circumference (MUAC), mid-upper arm muscle area (AMA) and triceps skin-fold thickness (TST) were regressed separately against all of the sibling composition variables while controlling for child's age and survey year. Multivariate panel linear regressions were used with individual, village, survey year and village-year fixed-effects, clustering by household. RESULTS: Among girls, an additional older brother was associated with a 1.4% decrease in MUAC (p < 0.01) and a 4.3% decrease in AMA (p < 0.01); an additional younger sister was associated with a 6.3% decrease in TST (p < 0.01). The association between sibling composition and arm anthropometry was robust to various model specifications. CONCLUSION: Older brothers and younger sisters were negatively associated with arm measures in girls. This finding may help improve policy interventions that aim to address children's nutritional health and long-term well-being.

Assessing public and private sector contributions in reproductive health financing and utilization for six sub-Saharan African countries.

The present study provides evidence to support enhanced attention to reproductive health and comprehensive measures to increase access to quality reproductive health services. We compare and contrast the financing and utilization of reproductive health services in six sub-Saharan African countries using data from National Health Accounts and Demographic and Health Surveys. Spending on reproductive health in 2006 ranged from US$4 per woman of reproductive age in Ethiopia to US$17 in Uganda. These are below the necessary level for assuring adequate services given that an internationally recommended spending level for family planning alone was US$16 for 2006. Moreover, reproductive health spending shows signs of decline in tandem with insufficient improvement in service utilization. Public providers played a predominant role in antenatal and delivery care for institutional births, but home deliveries with unqualified attendants dominated. The private sector was a major supplier of condoms, oral pills and IUDs. Private clinics, pharmacies and drug vendors were important sources of STI treatment. The findings highlight the need to commit greatly increased funding for reproductive health services as well as more policy attention to the contribution of public, private and informal providers and the role of collaboration among them to expand access to services for under-served populations.

Short but catching up: statural growth among native Amazonian Bolivian children.

The ubiquity and consequences of childhood growth stunting (<-2 SD in height-for-age Z score, HAZ) in rural areas of low-income nations has galvanized research into the reversibility of stunting, but the shortage of panel data has hindered progress. Using panel data from a native Amazonian society of foragers-farmers in Bolivia (Tsimane'), we estimate rates of catch-up growth for stunted children. One hundred forty-six girls and 158 boys 2 < or = age < or = 7 were measured annually during 2002-2006. Annual Delta height in cm and in HAZ were regressed separately against baseline stunting and control variables related to attributes of the child, mother, household, and village. Children stunted at baseline had catch-up growth rates 0.11 SD/year higher than their nonstunted age and sex peers, with a higher rate among children farther from towns. The rate of catch up did not differ by the child's sex. A 10% rise in household income and an additional younger sibling lowered by 0.16 SD/year and 0.53 SD/year the rate of growth. Results were weaker when measuring Delta height in cm rather than in HAZ. Possible reasons for catch-up growth include (a) omitted variable bias, (b) parental reallocation of resources to redress growth faltering, particularly if parents perceive the benefits of redressing growth faltering for child school achievement, and (c) developmental plasticity during this period when growth rates are most rapid and linear growth trajectories have not yet canalized.

Individual wealth rank, community wealth inequality, and self-reported adult poor health: a test of hypotheses with panel data (2002-2006) from native Amazonians, Bolivia.

Growing evidence suggests that economic inequality in a community harms the health of a person. Using panel data from a small-scale, preindustrial rural society, we test whether individual wealth rank and village wealth inequality affects self-reported poor health in a foraging-farming native Amazonian society. A person's wealth rank was negatively but weakly associated with self-reported morbidity. Each step up/year in the village wealth hierarchy reduced total self-reported days ill by 0.4 percent. The Gini coefficient of village wealth inequality bore a positive association with self-reported poor health that was large in size, but not statistically significant. We found small village wealth inequality, and evidence that individual economic rank did not change. The modest effects may have to do with having used subjective rather than objective measures of health, having small village wealth inequality, and with the possibly true modest effect of a person's wealth rank on health in a small-scale, kin-based society. Finally, we also found that an increase in mean individual wealth by village was related to worse self-reported health. As the Tsimane' integrate into the market economy, their possibilities of wealth accumulation rise, which may affect their well-being. Our work contributes to recent efforts in biocultural anthropology to link the study of social inequalities, human biology, and human-environment interactions.

Combination Antihypertensive Therapy Prescribing and Blood Pressure Control in a Real-World Setting.

BACKGROUND: Specific combinations of two drug classes are recommended in a variety of clinical situations in the management of hypertension. These preferred combinations are based on complimentary blood pressure (BP) lowering mechanisms or benefit for a concomitant disease. METHODS: Using electronic health records (EHRs) data from 27,579 ambulatory hypertensive patients, we investigated antihypertensive therapy prescribing patterns and associations of preferred two drug classes with BP control. RESULTS: Overall, BP control, defined as BP <140/90 mm Hg, was 65% among treated patients. Preferred dual antihypertensive therapy was prescribed in 55% of patients with uncomplicated hypertension, 49% of patients with diabetes, and 47% of patients with a history of myocardial infarction (MI); these prescribing frequencies of preferred combinations were not explained by worse BP control on those combinations. In fact, we found suggestive evidence of association between prescribing of preferred two drug classes and improved BP control among post-MI (OR: 1.21, 95% CI: 0.99-1.48, P = 0.061) and uncomplicated hypertensive (OR: 1.11, 95% CI: 0.98-1.26, P = 0.089) patients. CONCLUSIONS: Prescribing of guideline-recommended antihypertensive drug classes for concomitant diseases is suboptimal and prescribing of preferred/optimized drug class combinations was moderate. We did not find a clear association between the use of optimized drug class combinations and greater BP control. Overall, using EHR data, we identified potential opportunities for re-examining prescribing practices with implications for clinical decision support and healthcare improvement at the community and health system-wide levels.

Antihypertensive therapy prescribing patterns and correlates of blood pressure control among hypertensive patients with chronic kidney disease.

We used electronic health records (EHRs) data from 5658 ambulatory chronic kidney disease (CKD) patients with hypertension and prescribed antihypertensive therapy to examine antihypertensive drug prescribing patterns, blood pressure (BP) control, and risk factors for resistant hypertension (RHTN) in a real-world setting. Two-thirds of CKD patients and three-fourths of those with proteinuria were prescribed guideline-recommended renoprotective agents including an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin receptor blocker (ARB); however, one-third were not prescribed an ACEI or ARB. CKD patients, particularly those with stages 1-2 CKD, who were prescribed regimens including beta-blocker (BB) + diuretic or ACEI/ARB + BB + diuretic were more likely to have controlled BP (<140/90 mm Hg) compared to those prescribed other combinations. Risk factors for RHTN included African American race and major comorbidities. Clinicians may use these findings to tailor antihypertensive therapy to the needs of each patient, including providing CKD stage-specific treatment, and better identify CKD patients at risk of RHTN.

Genetic Variants Influencing Plasma Renin Activity in Hypertensive Patients From the PEAR Study (Pharmacogenomic Evaluation of Antihypertensive Responses).

BACKGROUND: Plasma renin is an important regulator of blood pressure (BP). Plasma renin activity (PRA) has been shown to correlate with variability in BP response to antihypertensive agents. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with baseline PRA using data from the PEAR study (Pharmacogenomic Evaluation of Antihypertensive Responses). METHODS: Multiple linear regression analysis was performed in 461 whites and 297 blacks using an additive model, adjusting for age, sex, and ancestry-specific principal components. Top SNPs were prioritized by testing the expected direction of association for BP response to atenolol and hydrochlorothiazide. Top regions from the BP response prioritization were tested for functional evidence through differences in gene expression by genotype using RNA sequencing data. Regions with functional evidence were assessed for replication with baseline PRA in an independent study (PEAR-2). RESULTS: Our top SNP rs3784921 was in the SNN-TXNDC11 gene region. The G allele of rs3784921 was associated with higher baseline PRA (ß=0.47; P=2.09×10-6) and smaller systolic BP reduction in response to hydrochlorothiazide (ß=2.97; 1-sided P=0.006). In addition, TXNDC11 expression differed by rs3784921 genotype (P=0.007), and rs1802409, a proxy SNP for rs3784921 (r2=0.98-1.00), replicated in PEAR-2 (ß=0.15; 1-sided P=0.038). Additional SNPs associated with baseline PRA that passed BP response prioritization were in/near the genes CHD9, XIRP2, and GHR. CONCLUSIONS: We identified multiple regions associated with baseline PRA that were prioritized through BP response signals to 2 mechanistically different antihypertensive drugs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.

Multisite Investigation of Outcomes With Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

OBJECTIVES: This multicenter pragmatic investigation assessed outcomes following clinical implementation of CYP2C19 genotype-guided antiplatelet therapy after percutaneous coronary intervention (PCI). BACKGROUND: CYP2C19 loss-of-function alleles impair clopidogrel effectiveness after PCI. METHODS: After clinical genotyping, each institution recommended alternative antiplatelet therapy (prasugrel, ticagrelor) in PCI patients with a loss-of-function allele. Major adverse cardiovascular events (defined as myocardial infarction, stroke, or death) within 12 months of PCI were compared between patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy. Risk was also compared between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy. Cox regression was performed, adjusting for group differences with inverse probability of treatment weights. RESULTS: Among 1,815 patients, 572 (31.5%) had a loss-of-function allele. The risk for major adverse cardiovascular events was significantly higher in patients with a loss-of-function allele prescribed clopidogrel versus alternative therapy (23.4 vs. 8.7 per 100 patient-years; adjusted hazard ratio: 2.26; 95% confidence interval: 1.18 to 4.32; p = 0.013). Similar results were observed among 1,210 patients with acute coronary syndromes at the time of PCI (adjusted hazard ratio: 2.87; 95% confidence interval: 1.35 to 6.09; p = 0.013). There was no difference in major adverse cardiovascular events between patients without a loss-of-function allele and loss-of-function allele carriers prescribed alternative therapy (adjusted hazard ratio: 1.14; 95% confidence interval: 0.69 to 1.88; p = 0.60). CONCLUSIONS: These data from real-world observations demonstrate a higher risk for cardiovascular events in patients with a CYP2C19 loss-of-function allele if clopidogrel versus alternative therapy is prescribed. A future randomized study of genotype-guided antiplatelet therapy may be of value.

Genetic Variants Associated With Uncontrolled Blood Pressure on Thiazide Diuretic/ß-Blocker Combination Therapy in the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) and INVEST (International Verapamil-SR Trandolapril Study) Trials.

BACKGROUND: The majority of hypertensive individuals require combination antihypertensive therapy to achieve adequate blood pressure (BP) control. This study aimed to identify genetic variants associated with uncontrolled BP on combination therapy with a thiazide diuretic and a ß-blocker. METHODS AND RESULTS: A genome-wide association study of uncontrolled BP on combination therapy was conducted among 314 white participants of the PEAR (Pharmacogenomic Evaluation of Antihypertensive Responses) trial. Multivariable logistic regression analysis was used. Genetic variants meeting a suggestive level of significance (P<1.0E-05) were tested for replication in an external cohort, INVEST (International Verapamil-SR Trandolapril study). We also examined genome-wide variant associations with systolic and diastolic BP response on combination therapy and tested for replication. We discovered a single nucleotide polymorphism, the rs261316 major allele, at chromosome 15 in the gene ALDH1A2 associated with an increased odds of having uncontrolled BP on combination therapy (odds ratio: 2.56, 95% confidence interval, 1.69-3.88, P=8.64E-06). This single nucleotide polymorphism replicated (odds ratio: 1.86, 95% confidence interval, 1.35-2.57, P=0.001) and approached genome-wide significance in the meta-analysis between discovery and replication cohorts (odds ratio: 2.16, 95% confidence interval, 1.63-2.86, P=8.60E-08). Other genes in the region surrounding rs261316 (ALDH1A2) include AQP9 and LIPC. CONCLUSIONS: A single nucleotide polymorphism in the gene ALDH1A2 may be associated with uncontrolled BP following treatment with a thiazide diuretic/ß-blocker combination. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00246519.

Sibling composition during childhood and adult blood pressure among native Amazonians in Bolivia.

Sibling configuration, including birth order, or the number, age, and sex of siblings is associated with parental resource allocation between children and is thus associated with a person's well-being. Little is known about the association between specific types of siblings and adult health outcomes. Here we test several hypotheses about sibling composition (number of older brothers, older sisters, younger sisters, younger brothers) and adult blood pressure in a foraging-farming society of native Amazonians in Bolivia (Tsimane'). We collected data in 2007 from 374 adults (16-60years of age) from 196 households in 13 villages. Household random-effects multiple regressions were run using systolic (SBP) or diastolic blood pressure (DBP) as outcomes; covariates included the four sibling categories and control variables (e.g., sex, age, education, body mass index [BMI]). Mean SBP and DBP were 114 (SD=14) and 66 (SD=11)mmHg. The prevalence of hypertension was 5.08%. Having an additional younger brother bore a small (3.3-5.9%) positive association with both SBP and DBP, with the effect weakening as people aged. Having an additional younger sister was associated with a small (3.8%) increase in SBP among women, with the magnitude shrinking as people aged. In a large family, the number of younger brothers may exert an impact on an individual's blood pressure.

Why no adult stunting penalty or height premium? Estimates from native Amazonians in Bolivia.

Among adults of industrial nations, growth stunting (<-2 SD height Z score) is associated with worse indicators of adult well-being (e.g., income). Does adult stunting also inflict private costs in traditional societies? Adult stunting penalties or height premiums might only emerge when traditional societies modernize. Here we estimate the association between adult stunting and indicators of adult well-being using data from a panel study in progress among the Tsimane', a foraging-farming society of native Amazonians in Bolivia. Subjects included 248 women and 255 men >or=age 22 measured annually during 5 consecutive years (2002-2006). Nine outcomes (wealth, monetary income, illness, access to credit, mirth, schooling, math skills, plant knowledge, forest clearance) were regressed separately against a stunting dummy variable and a wide range of control variables. We found no significant association between any of the indicators of own well-being and adult stunting. Additional analysis showed that stunting bore an association only with poorer mid-arm muscle area. Height premiums and stunting penalties, though evident and marked in modern societies, might not be common in all traditional societies.

Human's cognitive ability to assess facial cues from photographs: a study of sexual selection in the Bolivian Amazon.

BACKGROUND: Evolutionary theory suggests that natural selection favors the evolution of cognitive abilities which allow humans to use facial cues to assess traits of others. The use of facial and somatic cues by humans has been studied mainly in western industrialized countries, leaving unanswered whether results are valid across cultures. METHODOLOGY/PRINCIPAL FINDINGS: Our objectives were to test (i) if previous finding about raters' ability to get accurate information about an individual by looking at his facial photograph held in low-income non western rural societies and (ii) whether women and men differ in this ability. To answer the questions we did a study during July-August 2007 among the Tsimane', a native Amazonian society of foragers-farmers in Bolivia. We asked 40 females and 40 males 16-25 years of age to rate four traits in 93 facial photographs of other Tsimane' males. The four traits were based on sexual selection theory, and included health, dominance, knowledge, and sociability. The rating scale for each trait ranged from one (least) to four (most). The average rating for each trait was calculated for each individual in the photograph and regressed against objective measures of the trait from the person in the photograph. We found that (i) female Tsimane' raters were able to assess facial cues related to health, dominance, and knowledge and (ii) male Tsimane' raters were able to assess facial cues related to dominance, knowledge, and sociability. CONCLUSIONS/SIGNIFICANCE: Our results support the existence of a human ability to identify objective traits from facial cues, as suggested by evolutionary theory.