Showing papers by "Esteban G. Burchard published in 2005"
TL;DR: The historical events that led to the formation of contemporary Latino populations are reviewed and results from recent genetic and clinical studies are used to illustrate the unique opportunity Latino groups offer for studying the interaction between racial, genetic, and environmental contributions to disease occurrence and drug response.
Abstract: Latinos are the largest minority population in the United States. Although usually classified as a single ethnic group by researchers, Latinos are heterogeneous from cultural, socioeconomic, and genetic perspectives. From a cultural and social perspective, Latinos represent a wide variety of national origins and ethnic and cultural groups, with a full spectrum of social class. From a genetic perspective, Latinos are descended from indigenous American, European, and African populations. We review the historical events that led to the formation of contemporary Latino populations and use results from recent genetic and clinical studies to illustrate the unique opportunity Latino groups offer for studying the interaction between racial, genetic, and environmental contributions to disease occurrence and drug response.
342 citations
TL;DR: ethnic-specific pharmacogenetic differences exist between Arg16Gly genotypes, asthma severity, and bronchodilator response in Puerto Ricans and Mexicans with asthma, and these findings underscore the need for additional research on racial/ethnic differences in asthma morbidity and drug responsiveness.
Abstract: Background: In the United States, Puerto Ricans and Mexicans have the highest and lowest asthma prevalence, morbidity, and mortality, respectively. Ethnic-specific differences in the response to drug treatment may contribute to differences in disease outcomes. Genetic variants at the β2-adrenergic receptor (β2AR) may modify asthma severity and albuterol responsiveness. We tested the association of β2AR genotypes with asthma severity and bronchodilator response to albuterol in Puerto Ricans and Mexicans with asthma. Methods: We used both family-based and cross-sectional tests of association with 8 β2AR single nucleotide polymorphisms in 684 Puerto Rican and Mexican families. Regression analyses were used to determine the interaction between genotype, asthma severity, and bronchodilator drug responsiveness. Results: Among Puerto Ricans with asthma, the arginine (Arg) 16 allele was associated with greater bronchodilator response using both family-based and cross-sectional tests (p = 0.00001–0.01). We found a...
234 citations
TL;DR: The results suggest that asthma severity may be influenced by genetic factors differentiating Europeans and Native Americans in Mexican Americans, although differing results for Puerto Ricans require further investigation.
Abstract: Genetic association studies in admixed populations may be biased if individual ancestry varies within the population and the phenotype of interest is associated with ancestry. However, recently admixed populations also offer potential benefits in association studies since markers informative for ancestry may be in linkage disequilibrium across large distances. In particular, the enhanced LD in admixed populations may be used to identify alleles that underlie a genetically determined difference in a phenotype between two ancestral populations. Asthma is known to have different prevalence and severity among ancestrally distinct populations. We investigated several asthma-related phenotypes in two ancestrally admixed populations: Mexican Americans and Puerto Ricans. We used ancestry informative markers to estimate the individual ancestry of 181 Mexican American asthmatics and 181 Puerto Rican asthmatics and tested whether individual ancestry is associated with any of these phenotypes independently of known environmental factors. We found an association between higher European ancestry and more severe asthma as measured by both forced expiratory volume at 1 second (r=-0.21, p=0.005) and by a clinical assessment of severity among Mexican Americans (OR: 1.55; 95% CI 1.25 to 1.93). We found no significant associations between ancestry and severity or drug responsiveness among Puerto Ricans. These results suggest that asthma severity may be influenced by genetic factors differentiating Europeans and Native Americans in Mexican Americans, although differing results for Puerto Ricans require further investigation.
186 citations
TL;DR: The genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease-related traits in African Americans.
Abstract: U.S. populations are genetically admixed, but surprisingly little empirical data exists documenting the impact of such heterogeneity on type I and type II error in genetic-association studies of unrelated individuals. By applying several complementary analytical techniques, we characterize genetic background heterogeneity among 810 self-identified African American subjects sampled as part of a multisite cohort study of cardiovascular disease in older adults. On the basis of the typing of 24 ancestry-informative biallelic single-nucleotide–polymorphism markers, there was evidence of substantial population substructure and admixture. We used an allele-sharing–based clustering algorithm to infer evidence for four genetically distinct subpopulations. Using multivariable regression models, we demonstrate the complex interplay of genetic and socioeconomic factors on quantitative phenotypes related to cardiovascular disease and aging. Blood glucose level correlated with individual African ancestry, whereas body mass index was associated more strongly with genetic similarity. Blood pressure, HDL cholesterol level, C-reactive protein level, and carotid wall thickness were not associated with genetic background. Blood pressure and HDL cholesterol level varied by geographic site, whereas C-reactive protein level differed by occupation. Both ancestry and genetic similarity predicted the number and quality of years lived during follow-up, but socioeconomic factors largely accounted for these associations. When the 24 genetic markers were tested individually, there were an excess number of marker-trait associations, most of which were attenuated by adjustment for genetic ancestry. We conclude that the genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease–related traits in African Americans. Complementary methods that identify discrete subgroups on the basis of genetic similarity may help to further characterize the complex biodemographic structure of human populations.
159 citations
TL;DR: A gene-by-environment interaction between CD14 genotypes and ETS, which affects pulmonary function and IgE levels among Latinos with asthma is suggested.
Abstract: Background: A recent family-based genomewide screen revealed linkage between the 5q31 region and the diagnosis of asthma, but only in those exposed to environmental tobacco smoke (ETS). Among the candidate genes in this region is CD14. Methods: To determine whether polymorphisms in the CD14 gene are related to this gene-by-environment interaction in Latinos, we used both family-based and cross-sectional cohort analysis to test for interactions between CD14 genotypes/haplotypes, exposure to ETS, and asthma-related phenotypes in 659 Mexican and Puerto Rican families. Results: We identified 21 single nucleotide polymorphisms (SNPs) in the CD14 gene by sequencing 72 Puerto Ricans, Mexicans, and African Americans with asthma. Three SNPs, −810, −159, and +1437, were further genotyped in families with asthma. Among all subjects with asthma exposed to ETS, without regard to ethnicity, CD14 +1437 genotypes were associated with asthma severity. SNP +1437 GG or GC genotypes were significantly associated with lower b...
108 citations
TL;DR: It is demonstrated that approximately 100 ancestry informative markers (AIMs) are required to obtain estimates of ancestry that correlate with correlation coefficients more than 0.9 with the true individual ancestral proportions.
Abstract: Population stratification may confound the results of genetic association studies among unrelated individuals from admixed populations. Several methods have been proposed to estimate the ancestral information in admixed populations and used to adjust the population stratification in genetic association tests. We evaluate the performances of three different methods: maximum likelihood estimation, ADMIXMAP and Structure through various simulated data sets and real data from Latino subjects participating in a genetic study of asthma. All three methods provide similar information on the accuracy of ancestral estimates and control type I error rate at an approximately similar rate. The most important factor in determining accuracy of the ancestry estimate and in minimizing type I error rate is the number of markers used to estimate ancestry. We demonstrate that approximately 100 ancestry informative markers (AIMs) are required to obtain estimates of ancestry that correlate with correlation coefficients more than 0.9 with the true individual ancestral proportions. In addition, after accounting for the ancestry information in association tests, the excess of type I error rate is controlled at the 5% level when 100 markers are used to estimate ancestry. However, since the effect of admixture on the type I error rate worsens with sample size, the accuracy of ancestry estimates also needs to increase to make the appropriate correction. Using data from the Latino subjects, we also apply these methods to an association study between body mass index and 44 AIMs. These simulations are meant to provide some practical guidelines for investigators conducting association studies in admixed populations.
108 citations
TL;DR: Data indicate that the coding region of OAT1 has low genetic and functional diversity and suggest that coding region variants of Oat1 may not contribute substantially to interindividual differences in renal elimination of xenobiotics.
Abstract: ObjectivesThe organic anion transporter, OAT1 (SLC22A6), plays a role in the renal elimination of many drugs and environmental toxins. The goal of this study was to identify and functionally characterize OAT1 variants as a first step towards understanding whether genetic variation in OAT1 may contri
99 citations
TL;DR: A common polymorphism in ALK1 is associated with sporadic B AVM, suggesting that genetic variation in genes mutated in familial BAVM syndromes may play a role in sporadic BAVMs.
Abstract: Background and Purpose— Mutations in endoglin (ENG) and activin-like kinase (ALK1) cause hereditary hemorrhagic telangiectasias, disorders characterized by pulmonary and brain arteriovenous malformations (BAVMs). We investigated whether polymorphisms in these genes are also associated with sporadic BAVM. Methods— A total of 177 sporadic BAVM patients and 129 controls (all subjects white) were genotyped for 2 variants in ALK1 and 7 variants in ENG. Results— The ALK1 IVS3-35A>G polymorphism was associated with BAVM: (AnyA [AA+AG] genotype: odds ratio, 2.47; 95% CI, 1.38 to 4.44; P=0.002). Two ENG polymorphisms, ENG −1742A>G and ENG 207G>A, showed a trend toward association with BAVM that did not reach statistical significance. Conclusions— A common polymorphism in ALK1 is associated with sporadic BAVM, suggesting that genetic variation in genes mutated in familial BAVM syndromes may play a role in sporadic BAVMs.
79 citations
TL;DR: The genetic analysis and functional characterization of CNT3 variants suggest that this transporter does not tolerate nonsynonymous changes and is important for human fitness.
Abstract: The human concentrative nucleoside transporter, CNT3 (SLC28A3), plays an important role in mediating the cellular entry of a broad array of physiological nucleosides and synthetic anticancer nucleoside analog drugs. As a first step toward understanding the genetic basis for interindividual differences in the disposition and response to antileukemic nucleoside analogs, we examined the genetic and functional diversity of CNT3. In all, 56 variable sites in the exons and flanking intronic region of SLC28A3 were identified in a collection of 270 DNA samples from US populations (80 African-Americans, 80 European-Americans, 60 Asian-Americans, and 50 Mexican-Americans). Of the 16 coding region variants, 12 had not been previously reported. Also, 10 resulted in amino-acid changes and three of these had total allele frequencies of ≥1%. Nucleotide diversity (π) at nonsynonymous and synonymous sites was estimated to be 1.81 × 104 and 18.13 × 104, respectively, suggesting that SLC28A3 is under negative selection. All nonsynonymous variants, constructed by site-directed mutagenesis and expressed in Xenopus laevis oocytes, transported purine and pyrimidine model substrates, except for c. 1099G>A (p. Gly367Arg). This rare variant alters an evolutionarily conserved site in the putative substrate recognition domain of CNT3. The presence of three additional evolutionarily conserved glycine residues in the vicinity of p. Gly367Arg that are also conserved in human paralogs suggest that these glycine residues are critical in the function of the concentrative nucleoside transporter family. The genetic analysis and functional characterization of CNT3 variants suggest that this transporter does not tolerate nonsynonymous changes and is important for human fitness.
55 citations