non-Hispanic Cohorts Research Articles

Abstract LB-246: Evaluating the role of admixture in cancer therapy via in vitro drug response and multivariate genome-wide associations

Abstract It is well established that the majority of drugs/doses to combat diseases and disorders do not exhibit uniform effects for individuals. Indeed, the relationship between ethnicity, admixture or genetic ancestry and drug response is not fully understood. To explore this relationship, we used the lymphoblastoid cell line model to investigate dose-dependent drug response across a broad group of chemotherapeutic drugs spanning 7 drug families including nucleosides, tyrosine kinase inhibitors and DNA alkylating agents. Cell lines from 589 individuals were tested at 6 different concentrations for 28 chemotherapeutic drugs. Moreover, dose-dependent cytotoxic effects were measured for each drug with samples from two distinct cohorts: Hispanic and non-Hispanic/Caucasian. Genome-wide and phenotypic data from these individuals were used in univariate (IC50) and multivariate analyses to explore the relationship between ethnicity and drug response. Both univariate and multivariate models indicated that the majority of drugs tested showed highly significant correlations between self-reported ethnicity and drug responses. The software package ADMIXTURE was used to estimate genetic ancestry per individual. Using these estimates in lieu of self-reported ethnicity, we found highly significant correlations between percent admixture and drug response for the majority of drugs tested. Genome wide association analyses were carried out on each drug for each cohort independently as well as the combined data. From the association analyses, we were able to generate a number of interesting hypotheses on the role of particular genetic variants in variability of drug responses. 10 out of 28 drugs indicated significant associations in the Hispanic cohort. For the combined association analysis, 9 drugs had significant associations. Among the association findings, for the Hispanic cohort analysis, we were able to recapitulate previous association analysis work (in non-Hispanic/Caucasian) showing the role of variants in the gene, MGMT, and the susceptibility to temozolomide treatment. Remarkably, we were able to confirm the association result independently in a Hispanic and non-Hispanic cohort linking temozolomde response in Lymphoblastoid cells to variants in MGMT. To further understand the biological significance or the clinical impact of all of the association results, additional studies involving gene suppression techniques (e.g., knockdown models) and/or clinical trial gene candidate studies are warranted. Citation Format: John Jack, Tammy M. Havener, Howard L. McLeod, Alison A. Motsinger-Reif, Matthew Foster. Evaluating the role of admixture in cancer therapy via in vitro drug response and multivariate genome-wide associations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-246. doi:10.1158/1538-7445.AM2015-LB-246

Abstract 194: Differential Prevalence of Loss/Gain of Function Alleles Affecting Response to Clopidogrel in the Hmong Underscores the Importance of Genotyping Unique Subpopulations as a Means to Address Existing Health Disparities

Introduction: Standard of care for Acute Coronary Syndromes (ACS) includes dual antiplatelet therapy (e.g. aspirin and clopidogrel). CYP2C19 loss of function (*2, *3) or gain of function (*17) alleles are associated with clopidogrel’s bioactivation, antiplatelet effectiveness and clinical outcomes leading to the development of Clinical Pharmacogenomic Implementation Consortium (CPIC) guidelines. Currently the prevalence of CYP2C19 variants in the Hmong - a unique Asian population numbering over 60,000 in Minnesota - is unknown. Given that they are experiencing a surge in CVD, including ACS, we sought to compare their Minor Allele Frequencies (MAFs) for CYP2C19 *2, *3, and *17 with White Non-Hispanic and Han-Chinese. We evaluated the prevalence of *2 (rs4244285) or *3 (rs4986893), or *17 (rs12248560) alleles between the Hmong and those observed in 1) White Non-Hispanics and 2) Han-Chinese. To achieve this, DNA from Hmong was genotyped for the relevant Single Nucleotide Polymorphisms (SNPs) and compared to published (PMID: 21716271) MAFs for White Non-Hispanic and Han-Chinese cohorts Methods: Salivary DNA from 235 Hmong residing in either Minnesota or Wisconsin was genotyped for relevant SNPs by Sequenom iPlex Gold assay. MAFs between groups were compared by Chi-Square or Fisher’s exact test. A Bonferroni corrected significance level of 0.017 was considered statistically significant. Results: Hmong MAFs were higher for *2 (37%, p=0.0001) but lower for *17 (0.2%, p=0.0001) compared to the White Non-Hispanic cohort (13% and 23% respectively). Hmong MAFs were higher for *2 (37%, p=0.0001) but lower for *3 (0.2%, p=0.0001) compared to the Han-Chinese cohort (25% and 3%, respectively). Conclusions: Hmong have a higher prevalence of the loss of function allele, *2, compared to both reference cohorts. Hmong also have significantly different MAFs for both loss of function alleles, *2 and *3, compared to the Han-Chinese cohort. Both conclusions suggest that drug selection cannot be guided by race alone. Our data further underscores the importance of genotyping unique sub-populations as a means to mitigate existing health disparities in the availability of data which facilitate optimal drug selection.

Risk factors for mild cognitive impairment among Mexican Americans

BackgroundAlthough a great deal of literature has focused on risk factors for mild cognitive impairment (MCI), little published work examines risk for MCI among Mexican Americans. MethodsData from 1628 participants (non-Hispanic n = 1002; Mexican American n = 626) were analyzed from two ongoing studies of cognitive aging and Alzheimer's disease, Project FRONTIER (Facing Rural Obstacles to health Now Through Intervention, Education & Research) and TARCC (Texas Alzheimer's Research & Care Consortium). ResultsWhen looking at the full cohorts (non-Hispanic and Mexican American), age, education, Apolipoprotein E (APOE) ε4 status and gender were consistently related to MCI diagnosis across the two cohorts. However, when split by ethnicity, advancing age was the only significant risk factor for MCI among Mexican Americans across both cohorts. ConclusionsThe current data suggest that many of the previously established risk factors for MCI among non-Hispanic cohorts may not be predictive of MCI among Mexican Americans and point to the need for additional work aimed at understanding factors related to cognitive aging among this underserved segment of the population.

Cut points for Asthma Control Tests in Mexican children in Orange County, California

BackgroundThe Childhood Asthma Control Test (C-ACT) and the Asthma Control Test (ACT) are validated measures of asthma control in which a score of 19 is defined as uncontrolled according to published reports. However, different cut points may exist in different ethnic populations. ObjectiveTo determine the cut point for uncontrolled asthma in a Mexican descent population from Orange Country, California, compared with an age- and asthma severity–matched non-Hispanic cohort. MethodsThe C-ACT (in children 6–11 years old) and ACT (in children 12–17 years old) scores were collected from 151 children of Mexican descent and 48 non-Hispanic controls with mild-to-moderate asthma who lived in Orange County. Physicians were masked to C-ACT and ACT scores while assessing control based on National Asthma Education and Prevention program guidelines. The receiver operating characteristic method was used to examine the screening accuracy of the tests to detect uncontrolled asthma. The optimal cut points were selected by maximizing the total sensitivity and specificity. ResultsCronbach α values for the C-ACT (0.76) and the ACT (0.80) confirmed that both tests were reliable in our study population. The C-ACT and ACT scores were statistically higher in children of Mexican descent than non-Hispanic children (P = .008). A cut point of 22 was optimal to detect uncontrolled asthma in children of Mexican descent 6 to 11 years old (group 1: sensitivity, 0.74; specificity, 0.86; area under the curve [AUC], 0.83) and children 12 to 17 years old (group 3: sensitivity, 0.78; specificity, 0.68; AUC, 0.79). For non-Hispanic controls, a cut point of 20 were optimal to detect uncontrolled asthma in children 6 to 11 years old (group 2: sensitivity, 0.70; specificity, 0.91; AUC, 0.86) and children 12 to 17 years old (group 4: sensitivity, 0.83; specificity, 0.87; AUC, 0.91). ConclusionIn this cross-ethnic validation study, children of Mexican descent in Orange County seem to underreport asthma symptoms compared with a non-Hispanic population and may require higher C-ACT and ACT cut points to detect uncontrolled asthma.

Pharmacogenomics of Warfarin dose requirements in Hispanics

While Hispanics are the largest and most rapidly growing minority population in the United States, they are underrepresented in pharmacogenomic studies with warfarin. We sought to determine the combination of clinical and genetic influences of warfarin dose requirements in Hispanics. In addition, we tested the performance of published warfarin dosing algorithms derived from largely non-Hispanic cohorts in an inner-city U.S. Hispanic population. Genetic samples and clinical data were obtained from 50 Hispanics on a stable dose of warfarin. The contribution of cytochrome P450 2C9 ( CYP2C9) and vitamin K epoxide reductase complex-1 ( VKORC1) genotypes and clinical factors to warfarin dose requirements was determined. The correlation between the predicted dose using published algorithms and therapeutic dose was also assessed. Compared to the VKORC1-1639 GG genotype, warfarin dose requirements were 30% and 62% lower with the GA and AA genotypes, respectively ( p = 0.001). The combination of the VKORC1-1639G > A and CYP2C9 genotypes and clinical factors explained 56% of the inter-patient variability in warfarin dose. Warfarin dose predicted using algorithms derived from mostly non-Hispanic cohorts was significantly correlated with the therapeutic dose in our Hispanic cohort ( r 2 = 0.43 to 0.49; p < 0.001); the predicted dose was within 1.0 mg/day of the therapeutic dose for 40% to 50% of patients. Our data suggest that factors influencing warfarin dose requirements in Hispanic Caucasians are similar to those previously described in European Caucasians and that dosing algorithms derived from non-Hispanic Caucasian cohorts are applicable to Hispanics living in the U.S.

Active Comparator Trial of Teriparatide vs Alendronate for Treating Glucocorticoid-Induced Osteoporosis: Results From the Hispanic and Non-Hispanic Cohorts

Glucocorticoid use is a leading cause of secondary osteoporosis. This post hoc analysis compared teriparatide vs alendronate on bone mineral density (BMD) in Hispanic and non-Hispanic patients with glucocorticoid-induced osteoporosis. The 18-mo results from all patients (N = 428) in a double-blind trial of teriparatide (20 μg/d) and alendronate (10 mg/d) who had taken glucocorticoids for ≥3 mo were reported (Saag et al. N Engl J Med 2007). The present study analyzed results from the Hispanic (n = 61) and non-Hispanic (n = 367) cohorts. The BMD was measured by dual-energy X-ray absorptiometry (DXA). In the Hispanic cohort at 18 mo, there were significantly greater increases from baseline in the teriparatide vs alendronate group in lumbar spine BMD (9.8% ± 1.7% vs 4.2% ± 1.4%; p < 0.001; mean ± SE) and total hip BMD (5.9% ± 1.6% vs 1.3% ± 1.3%, p < 0.001), with no significant difference between groups at the femoral neck (4.3% ± 2.2% vs 2.0% ± 1.8%, p = 0.228). Within each treatment group, the BMD responses were not significantly different in the Hispanic vs non-Hispanic cohort. The number of patients reporting ≥1 adverse event was not significantly different between treatments in either cohort, with more patients reporting nausea in the teriparatide group. In summary, teriparatide was more efficacious than alendronate in increasing BMD in Hispanic and non-Hispanic patients with glucocorticoid-induced osteoporosis. Both treatments were generally well tolerated.

Epidemiology, Heritability, and Genetic Linkage of C-Reactive Protein in African Americans (from the Jackson Heart Study)

C-reactive protein (CRP) has been studied largely in white non-Hispanic cohorts. There is limited information on CRP's range of values, heritability, and relation to cardiovascular disease risk factors in African Americans. The aim of this study was to evaluate the distribution, clinical correlates, heritability, and genetic linkage of log-transformed CRP in participants in the middle-aged to elderly African American cohort in the community-based Jackson Heart Study. The distribution and correlates of CRP were analyzed for the entire study cohort who underwent the first examination (2001 to 2004). Heritability was estimated for the family cohort nested within the larger Jackson Heart Study (246 families, n = 1,317). The relation between CRP and cardiovascular disease risk factors was tested with multivariable stepwise regression analyses. Heritability was estimated using a variance-components method. Linkage analysis was performed using the multipoint variance-components approach. The study sample consisted of 4,919 participants (mean age 55 +/- 13 years, 63% women); the median CRP concentration was 2.7 mg/L. In stepwise models, traditional risk factors explained 23.8% of CRP's variability, with body mass index (partial R(2) = 13.6%) explaining 57.1% of the variability of CRP due to traditional risk factors. The heritability of CRP (adjusted for age, gender, and body mass index) was 0.45. The strongest linkage evidence for CRP was observed on chromosome 11 (11p13 to 11p11.2), with a logarithm of odds score of 2.72. In conclusion, in this large population-based cohort of African Americans, circulating CRP concentration was heritable and associated with several traditional cardiovascular risk factors, particularly body mass index.

OBESITY, DIABETES, AND INSULIN RESISTANCE: RELATION TO ELEVATED C-REACTIVE PROTEIN LEVELS IN AFRICAN AMERICANS.

Purpose Elevated C-reactive protein (CRP) has been strongly related to obesity, diabetes (DM), and insulin resistance (IR) in predominantly white non-Hispanic cohorts. There is limited information on systemic inflammation in African Americans. Methods The study cohort consisted of 5,202 participants (55 ± 13 years, 64% female) who presented for Jackson Heart Study Exam 1 (2001-2004). The contribution of traditional risk factors to the variability of CRP was tested using a stepwise regression model. We evaluated the relation of obesity, DM and IR to CRP among participants using analysis of variance. Results In the stepwise regression, the amount of variability in CRP explained by clinical covariates was 23%. BMI explained 57% of the variability of CRP due to traditional risk factors. The mean CRP for participants was 1.4 mg/L for those nonobese without IR, 3.2 mg/L for those obese without IR, 2.2 mg/L for those nonobese with IR, 4.0 mg/L for those obese with IR, 1.9 mg/L for those nonobese with DM, and 4.1 mg/L for those obese with DM. CRP was significantly higher for obese participants compared with nonobese participants regardless of IR or DM status (p Conclusions In this large population-based cohort of African Americans, we found that among traditional risk factors, BMI contributed the greatest to the variability of CRP. DM and IR were also significantly related to CRP.

Blood pressure control and cardiovascular outcomes in high-risk Hispanic patients—Findings From the International Verapamil SR/Trandolapril Study (INVEST)

People of Hispanic origin are the fastest growing ethnic minority in the United States and often have hypertension and other comorbidities which increase the risk associated with coronary artery disease (CAD). An analysis of the 8045 Hispanic patients enrolled in INVEST was conducted, and comparisons were made to the 14,531 non-Hispanic patients. INVEST was a prospective, randomized, open, blinded end point study in CAD patients with hypertension. After 61,835 patient-years of follow-up, treatment with either a verapamil sustained release (SR) or atenolol antihypertensive strategy resulted in greater blood pressure control in Hispanic patients, and Hispanic patients were at significantly lower risk of experiencing a nonfatal myocardial infarction, nonfatal stroke, or death (hazard ratio [HR] 0.87, 95% CI 0.78-0.97). Hispanic ethnicity was associated with an increase (HR 1.19, 95% CI 1.04-1.36), and randomization to the verapamil SR strategy was associated with a decrease (HR 0.85, 95% CI 0.76-0.95), in the risk of new-onset diabetes. Use of trandolapril in the verapamil SR strategy was associated with reduced risk of new-onset diabetes, whereas increasing doses of atenolol and hydrochlorothiazide in the atenolol strategy were associated with increased risk of new-onset diabetes. The Hispanic cohort of INVEST had better blood pressure control and lower risk of adverse cardiovascular outcomes compared with the non-Hispanic cohort. A verapamil SR strategy is an alternative to an atenolol strategy for the treatment of Hispanic patients with hypertension and CAD and can reduce the risk of new-onset diabetes.