RESUMO
OBJECTIVE: A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients. METHODS: Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene-gene interactions were tested by using multiple linear regression analyses. RESULTS: No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene-gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol. CONCLUSION: Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry.
Assuntos
Asma/tratamento farmacológico , Asma/genética , Broncodilatadores/uso terapêutico , Farmacogenética , Filogenia , Adolescente , Adulto , Negro ou Afro-Americano/genética , Indígena Americano ou Nativo do Alasca/genética , Estudos de Casos e Controles , Criança , Demografia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Interleucina-6/genética , Modelos Lineares , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Porto Rico/etnologia , Receptores de Interleucina-6/genéticaRESUMO
Mouse models have shown the importance of acidic mammalian chitinase activity in settings of chitin exposure and allergic inflammation. However, little is known regarding genetic regulation of AMCase enzymatic activity in human allergic diseases. Resequencing the AMCase gene exons we identified 8 non-synonymous single nucleotide polymorphisms including three novel variants (A290G, G296A, G339T) near the gene area coding for the enzyme active site, all in linkage disequilibrium. AMCase protein isoforms, encoded by two gene-wide haplotypes, and differentiated by these three single nucleotide polymorphisms, were recombinantly expressed and purified. Biochemical analysis revealed the isoform encoded by the variant haplotype displayed a distinct pH profile exhibiting greater retention of chitinase activity at acidic and basic pH values. Determination of absolute kinetic activity found the variant isoform encoded by the variant haplotype was 4-, 2.5-, and 10-fold more active than the wild type AMCase isoform at pH 2.2, 4.6, and 7.0, respectively. Modeling of the AMCase isoforms revealed positional changes in amino acids critical for both pH specificity and substrate binding. Genetic association analyses of AMCase haplotypes for asthma revealed significant protective associations between the variant haplotype in several asthma cohorts. The structural, kinetic, and genetic data regarding the AMCase isoforms are consistent with the Th2-priming effects of environmental chitin and a role for AMCase in negatively regulating this stimulus.
Assuntos
Quitinases/genética , Haplótipos , Polimorfismo de Nucleotídeo Único , Negro ou Afro-Americano/genética , Animais , Asma/etnologia , Asma/genética , Sítios de Ligação/genética , Catálise , Linhagem Celular , Quitinases/química , Quitinases/metabolismo , Dissacarídeos/química , Dissacarídeos/metabolismo , Frequência do Gene , Genótipo , Hispânico ou Latino/genética , Humanos , Concentração de Íons de Hidrogênio , Insetos , Isoenzimas/química , Isoenzimas/genética , Isoenzimas/metabolismo , Cinética , Desequilíbrio de Ligação , México , Estrutura Molecular , Estrutura Terciária de Proteína , Porto Rico , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Especificidade por SubstratoRESUMO
RATIONALE: Independent replication of genetic associations in complex diseases, particularly in whole-genome association studies, is critical to confirm the association. OBJECTIVES: A whole-genome association study identified ORMDL3 as a promising candidate gene for asthma in white populations. Here, we attempted to confirm the role of ORMDL3 genetic variants in asthma in three ethnically diverse populations: Mexican, Puerto Rican, and African American. METHODS: We used family-based analyses to test for association between seven candidate single-nucleotide polymorphisms (SNPs) in and around the ORMDL3 gene and asthma and related phenotypes in 701 Puerto Rican and Mexican parent-child trios. We also evaluated these seven SNPs and an additional ORMDL3 SNP in 264 African American subjects with asthma and 176 healthy control subjects. MEASUREMENTS AND MAIN RESULTS: We found significant associations between two SNPs within ORMDL3 (rs4378650 and rs12603332) and asthma in Mexicans and African Americans (P = 0.028 and 0.001 for rs4378650 and P = 0.021 and 0.001 for rs12603332, respectively), and a trend toward association in Puerto Ricans (P = 0.076 and 0.080 for SNPs rs4378650 and rs12603332, respectively). These associations became stronger among Mexican and Puerto Rican subjects with asthma with IgE levels greater than 100 IU/ml. We did not find any association between ORMDL3 SNPs and baseline lung function or response to the bronchodilator albuterol. CONCLUSIONS: Our results confirm that the ORMDL3 locus is a risk factor for asthma in ethnically diverse populations. However, inconsistent SNP-level results suggest that further studies will be needed to determine the mechanism by which ORMDL3 predisposes to asthma.
Assuntos
Asma/etnologia , Asma/genética , Negro ou Afro-Americano/genética , Proteínas de Membrana/genética , Americanos Mexicanos/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Feminino , Volume Expiratório Forçado , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Porto Rico/etnologia , Espirometria , Estados Unidos/epidemiologiaRESUMO
Socioeconomic and environmental differences do not fully explain differences in asthma prevalence, morbidity, and mortality among Puerto Ricans, African Americans, and Mexican Americans. Differences in response to albuterol may be a factor. We compared bronchodilator responsiveness between these three populations. All groups demonstrated below expected responsiveness. Puerto Ricans of all ages and African American children with moderate-to-severe asthma demonstrated the lowest responsiveness overall. Among subjects with moderate-to-severe asthma, children were even less likely than adults to show the expected bronchodilator response. We conclude that ethnic-specific differences in bronchodilator drug responsiveness exist between Mexicans, Puerto Ricans, and African Americans with asthma. This may be of importance in asthma management.
Assuntos
Albuterol/uso terapêutico , Asma/tratamento farmacológico , Asma/etnologia , Negro ou Afro-Americano , Broncodilatadores/uso terapêutico , Hispânico ou Latino , Americanos Mexicanos , Adolescente , Adulto , Asma/fisiopatologia , Criança , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Masculino , México , Cidade de Nova Iorque , Porto Rico , São Francisco , Estatísticas não Paramétricas , Capacidade Vital/efeitos dos fármacosRESUMO
BACKGROUND: High levels of IgE are associated with asthma. Whether higher levels of IgE are associated with more severe asthma is still unclear. OBJECTIVE: To determine whether IgE is associated with asthma severity among Latino and African American subjects with asthma. METHODS: We assessed lung function and asthma severity among African American, Mexican, and Puerto Rican patients with asthma with high IgE levels (> or =100 IU/mL; n = 492) and compared these values to those of patients with asthma with low IgE levels (<100 IU/mL; n = 247). We also examined IgE as a continuous variable among these groups. RESULTS: Patients with asthma with high IgE had a lower mean FEV(1) (87.6 +/- 17.1, percent of predicted) than patients with asthma with low IgE (91.5 +/- 17.0; P = .031). Regardless of race and ethnicity, baseline FEV(1), forced expiratory flow, and FEV(1)/forced vital capacity were lower among subjects with high IgE than among subjects with low IgE (P = .031, P < .0001, P = .0001, respectively). In addition, 54.7% of patients with asthma with high IgE had been previously hospitalized, compared with 44.1% of patients with asthma with low IgE (odds ratio, 1.33; 95% CI, 1.04-1.71). CONCLUSION: Higher IgE is associated with lower baseline lung function and more severe asthma among these populations. CLINICAL IMPLICATIONS: Among patients with asthma from 3 ethnically distinct groups, total IgE levels are inversely correlated with baseline lung function and asthma severity.