PubMed Health⌕ Search

Biomedical subjects

Fernando D Martinez

Publications and source records attributed to Fernando D Martinez.

At least 19 recordsLinked to original sources
PubMed2026

Upper airway microbiome interacts with GSDMB and ORMDL3 asthma risk SNPs to influence early-life wheeze risk.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the chromosome 17q12-q21 region and, independently, early-life nasal microbiota dominated by Moraxella, Streptococcus, or Haemophilus (MSH) increase risk of chronic wheeze and asthma development. OBJECTIVE: We sought to determine whether 17q12-q21 risk SNPs and nasal microbiota interact to modulate childhood wheeze risk. METHODS: Nasal wash samples from 12-month-old infants in 2 birth cohorts, COAST (Childhood Origins of Asthma; n = 180) and URECA (Urban Environment and Childhood Asthma; n = 139), underwent 16S ribosomal RNA variable region 4 sequencing. Nasal microbiota dominated by MSH or Corynebacterium, Dolosigranulum, Staphylococcus, or Bacillus (CDSB) were assessed. Paired blood was genotyped for 9 17q12-q21 risk SNPs. Logistic regression tested interactions between 17q12-q21 SNPs and MSH or CDSB on wheeze risk in the first 3 years of life. A549 lung epithelial cells, CRISPR-edited to encode the rs7216389 risk genotype (rs7216389TT) were compared to the heterozygous (rs7216389CT) line using bulk RNA sequencing. RESULTS: SNPs, particularly those in the ORMDL3 (rs8076131; odds ratio [OR]: 1.72; 95% CI: 1.09-2.71; Pint = .031) and GSDMB (rs2305480; OR: 1.72; 95% CI: 1.09-2.71; Pint = 0.042; and rs7216389; OR: 1.73; 95% CI: 1.09-2.70; Pint = .047) genes, interact with MSH microbiota to increase early-life wheeze risk (false discovery rate Pint = .016 for all), while interactions with CDSB reduce risk. A549 airway epithelial cells homozygous for rs7216389TT exhibited decreased expression of genes involved in antimicrobial responses and neutrophil recruitment and evidence increased microbial adherence compared with the heterozygous cell line. CONCLUSION: Airway microbiota interact with SNPs at the 17q12-q21 locus in genes involved in sphingolipid metabolism and intracellular antimicrobial responses, to modulate wheeze risk.

Humans↗
PubMed2007

Gene-environment interactions in asthma: with apologies to William of Ockham.

Many environmental factors and a large number of genetic polymorphisms have been reported to be associated with asthma risk in different locales and at different ages. It seems that what we call asthma is a heterogeneous set of conditions for which the only common feature is recurrent airway obstruction that is at least partially responsive to usual asthma therapy. Recent studies in which environmental factors and genetic variants were studied concomitantly have suggested a potential unifying concept for the disease. It seems that asthma is a genetically mediated development dysregulation of diverse immune and airway responses to a variety of specific and nonspecific exposures. It thus seems improbable that most genetic variants associated with asthma influence the disease regardless of which environmental factors trigger it and at which lifetime phase they are present. More likely, the most important gene variants for asthma are polymorphisms that exert their influence on the network system controlling biological responses to asthma-related exposures.

Asthma↗
PubMed2006

Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial.

BACKGROUND: More evidence is needed on which to base recommendations for treatment of mild-moderate persistent asthma in school-aged children. OBJECTIVE: The Pediatric Asthma Controller Trial (PACT) compared the effectiveness of 3 regimens in achieving asthma control. METHODS: A total of 285 children (ages 6-14 years) with mild-moderate persistent asthma on the basis of symptoms, and with FEV(1) >or= 80% predicted and methacholine FEV(1) PC(20) or= 80% predicted, confirming current guideline recommendations.

Acetates↗
PubMed2006

Asthma treatment and asthma prevention: a tale of 2 parallel pathways.

Three recent clinical trials used different study designs to test the hypothesis that early introduction of inhaled corticosteroids in infants and young children at high risk for the development of asthma could change the natural course of the disease. All 3 trials reached the same conclusion: treatment requirement, symptom frequency while off treatment, and lung function did not differ between children receiving active drug or placebo, with outcomes measured 2 to 4 years after randomization. These findings challenge the concept that the inflammatory processes that cause asthma symptoms and are responsive to inhaled corticosteroids are also responsible for the chronic changes in airway structure and function that are believed to predispose to the development of persistent asthma. This conclusion is supported by studies showing that bronchial hyperresponsiveness, independent of current asthma symptoms, is associated with subsequent deficits in airway function growth during childhood. Successful strategies for the prevention of asthma will require a better understanding of the genetic, environmental, and developmental factors that predispose toward inappropriate responses to airway injury. Abnormal airway remodeling and persistent dysregulation of airway tone might be the final common pathway for different disease mechanisms, and this might explain the heterogeneity of clinical phenotypic syndromes that go under the common label of "asthma."

Adrenal Cortex Hormones↗
PubMed2006

Long-term inhaled corticosteroids in preschool children at high risk for asthma.

BACKGROUND: It is unknown whether inhaled corticosteroids can modify the subsequent development of asthma in preschool children at high risk for asthma. METHODS: We randomly assigned 285 participants two or three years of age with a positive asthma predictive index to treatment with fluticasone propionate (at a dose of 88 mug twice daily) or masked placebo for two years, followed by a one-year period without study medication. The primary outcome was the proportion of episode-free days during the observation year. RESULTS: During the observation year, no significant differences were seen between the two groups in the proportion of episode-free days, the number of exacerbations, or lung function. During the treatment period, as compared with placebo use, use of the inhaled corticosteroid was associated with a greater proportion of episode-free days (P=0.006) and a lower rate of exacerbations (P<0.001) and of supplementary use of controller medication (P<0.001). In the inhaled-corticosteroid group, as compared with the placebo group, the mean increase in height was 1.1 cm less at 24 months (P<0.001), but by the end of the trial, the height increase was 0.7 cm less (P=0.008). During treatment, the inhaled corticosteroid reduced symptoms and exacerbations but slowed growth, albeit temporarily and not progressively. CONCLUSIONS: In preschool children at high risk for asthma, two years of inhaled-corticosteroid therapy did not change the development of asthma symptoms or lung function during a third, treatment-free year. These findings do not provide support for a subsequent disease-modifying effect of inhaled corticosteroids after the treatment is discontinued. (ClinicalTrials.gov number, NCT00272441.).

Administration, Inhalation↗
PubMed2006

Factors influencing gender differences in the diagnosis and treatment of asthma in childhood: the Tucson Children's Respiratory Study.

Studies identified gender differences in diagnosed asthma, but the extent to which they can be attributed to differences in symptom experience and frequency rather than factors influencing diagnosis has not been established. We investigated prevalence of, and consultation for, asthma symptoms, as well as diagnosis and treatment in 533 boys and 556 girls enrolled in the Tucson Children's Respiratory Study, a population-based birth-cohort study. Questionnaires regarding respiratory symptoms and diagnoses were obtained at ages 2, 3, 6, 8, 11, 13, 16, and 18 years. Boys were significantly more likely than girls to experience both wheeze and frequent wheeze most years in the first decade of life. However, girls with symptoms were less likely than boys to see a physician (74.1% vs. 83.4%, P < 0.001) and to be labeled as having asthma (43.3% vs. 53.8%, P < 0.009), even after adjusting for symptom frequency. A difference in symptom presentation also appeared to influence diagnosis: nocturnal cough without frequent wheeze was more prevalent among girls, and was associated with reduced diagnosis of asthma. Among subjects who consulted a physician for wheeze, boys were significantly more likely than girls to have taken medication (81.5% vs. 73.5%, P < 0.01). The lag time between age at first wheeze and first use of medication among those consulting a physician for wheeze or asthma was greater for girls, especially among subjects with frequent wheeze (2.8 vs. 1.6 years, P < 0.005). These findings indicate that gender differences in the diagnosis and treatment of asthma cannot be explained completely by differences in symptom prevalence and frequency.

Adolescent↗
PubMed2006

Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma.

BACKGROUND: Outcome data are needed to base recommendations for controller asthma medication use in school-aged children. OBJECTIVE: We sought to determine intraindividual and interindividual response profiles and predictors of response to an inhaled corticosteroid (ICS) and a leukotriene receptor antagonist (LTRA). METHODS: An ICS, fluticasone propionate (100 mug twice daily), and an LTRA, montelukast (5-10 mg nightly, age dependent), were administered to children ages 6 to 17 years with mild-to-moderate persistent asthma using only as-needed bronchodilators in a multicenter, double-masked, 2-sequence, 16-week crossover trial. Clinical, pulmonary, and inflammatory responses to these controllers were evaluated. RESULTS: Improvements in most clinical asthma control measures occurred with both controllers. However, clinical outcomes (asthma control days [ACDs], the validated Asthma Control Questionnaire, and albuterol use), pulmonary responses (FEV(1)/forced vital capacity, peak expiratory flow variability, morning peak expiratory flow, and measures of impedance), and inflammatory biomarkers (exhaled nitric oxide [eNO]) improved significantly more with fluticasone than with montelukast treatment. eNO was both a predictor of ACDs (P = .011) and a response indicator (P = .003) in discriminating the difference in ACD response between fluticasone and montelukast. CONCLUSIONS: The more favorable clinical, pulmonary, and inflammatory responses to an ICS than to an LTRA provide pediatric-based group evidence to support ICSs as the preferred first-line therapy for mild-to-moderate persistent asthma in children. eNO, as a predictor of response, might help to identify individual children not receiving controller medication who achieve a greater improvement in ACDs with an ICS compared with an LTRA.

Acetates↗
PubMed2005

Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence.

RATIONALE: The effect of early life wheezing on respiratory function and continued symptoms through adolescence has not been fully described. Using data from a population-based birth cohort in Tucson, Arizona, we previously described four phenotypes based on the occurrence of wheezing lower respiratory illnesses before age 3 yr and active wheeze at age 6 yr: never wheezers (n = 425), transient early wheezers (n = 164), persistent wheezers (n = 113), and late-onset wheezers (n = 124). OBJECTIVE: We sought to determine the prognosis for these phenotypes, with reference to lung function and symptoms, through adolescence. METHODS: Current wheeze was assessed by questionnaire, lung function was measured by conventional spirometry, and atopy was determined by skin prick tests. RESULTS: The prevalence of atopy and wheeze by age 16 yr was similar for never and transient wheezers and for persistent and late-onset wheezers. Both transient early, and persistent wheezers had significantly lower FEF(25-75) (-259 ml/s, p < 0.001, and -260 ml/s, p = 0.001, respectively), FEV1 (-75 ml, p = 0.02, and -87 ml, p = 0.03, respectively), and FEV1:FVC ratio (-1.9%, p = 0.002, and -2.5%, p = 0.001, respectively) through age 16 yr compared with never wheezers. Late-onset wheezers had levels of lung function similar to those of never wheezers through age 16 yr. There was no significant change in lung function among subjects with any of the four phenotypes, relative to their peers, from age 6 to 16 yr. CONCLUSION: Patterns of wheezing prevalence and levels of lung function are established by age 6 yr and do not appear to change significantly by age 16 yr in children who start having asthma-like symptoms during the preschool years.

Adolescent↗
PubMed2005

Gene-environment interaction effects on the development of immune responses in the 1st year of life.

Asthma is a common disease that results from both genetic and environmental risk factors. Children attending day care in the 1st year of life have lower risks for developing asthma, although the mechanism for this "day care" effect is largely unknown. We investigated the interactions between day care exposure in the 1st 6 mo of life and genotypes for 72 polymorphisms at 45 candidate loci and their effects on cytokine response profiles and on the development of atopic phenotypes in the 1st year of life in the Childhood Onset of Asthma (COAST) cohort of children. Six interactions (at four polymorphisms in three loci) with "day care" that had an effect on early-life immune phenotypes were significant at P<.001. The estimated false-discovery rate was 33%, indicating that an estimated four P values correspond to true associations. Moreover, the "day care" effect at some loci was accounted for by the increased number of viral infections among COAST children attending day care, whereas interactions at other loci were independent of the number of viral infections, indicating the presence of additional risk factors associated with day care environment. This study identified significant gene-environment interactions influencing the early patterning of the immune system and the subsequent development of asthma and highlights the importance of considering environmental risk factors in genetic analyses.

Asthma↗
PubMed2005

Gene-environment interactions in asthma and allergies: a new paradigm to understand disease causation.

The example of complex interactions between environmental exposures and polymorphisms in the CD14 gene in predisposing for allergy-related conditions offers a good indication of the complexity of the mechanisms that determine susceptibility to these conditions. Contrary to what has been the rule for monogenic diseases, the association between genetic variations and polygenic conditions such as asthma and allergies may not always be unidirectional; that is, not always will the same alleles be associated with the conditions under study. Concepts of penetrance of genetic variations that ignore these nonlinear influences (which may affect gene-gene and gene-environment interactions) may hinder a better understanding of mechanisms of disease involved, and therefore may delay the development of preventive strategies for these common conditions. Discrepancies between well-designed genetic studies of asthma and allergies, therefore, may be suggesting something fundamental about how these diseases develop and how it will be possible to abolish them in the future.

Asthma↗
PubMed2005

Association of defensin beta-1 gene polymorphisms with asthma.

BACKGROUND: Defensins are antimicrobial peptides that may take part in airway inflammation and hyperresponsiveness. OBJECTIVE: We characterized the genetic diversity in the defensin beta-1 (DEFB1) locus and tested for an association between common genetic variants and asthma diagnosis. METHODS: To identify single nucleotide polymorphisms (SNPs), we resequenced this gene in 23 self-defined European Americans and 24 African Americans. To test whether DEFB1 genetic variants are associated with asthma, we genotyped 4 haplotype-tag SNPs in 517 asthmatic and 519 control samples from the Nurses' Health Study (NHS) and performed a case-control association analysis. To replicate these findings, we evaluated the DEFB1 polymorphisms in a second cohort from the Childhood Asthma Management Program. RESULTS: Within the NHS, single SNP testing suggested an association between asthma diagnosis and a 5' genomic SNP (g.-1816 T>C; P = .025) and intronic SNP (IVS+692 G>A; P = .054). A significant association between haplotype (Adenine, Cytosine, Thymine, Adenine [ACTA]) and asthma ( P = .024) was also identified. Associations between asthma diagnosis and both DEFB1 polymorphisms were observed in Childhood Asthma Management Program, a second cohort: g.-1816 T>C and IVS+692 G>A demonstrated significant transmission distortion ( P = .05 and .007, respectively). Transmission distortion was not observed in male subjects. The rare alleles (-1816C and +692A) were undertransmitted to offspring with asthma, suggesting a protective effect, contrary to the findings in the NHS cohort. Similar effects were evident at the haplotype level: ACTA was undertransmitted ( P = .04) and was more prominent in female subjects ( P = .007). CONCLUSION: Variation in DEFB1 contributes to asthma diagnosis, with apparent gender-specific effects.

Asthma↗
PubMed2005

Characterization of within-subject responses to fluticasone and montelukast in childhood asthma.

BACKGROUND: Responses to inhaled corticosteroids (ICSs) and leukotriene receptor antagonists (LTRAs) vary among asthmatic patients. OBJECTIVE: We sought to determine whether responses to ICSs and LTRAs are concordant for individuals or whether asthmatic patients who do not respond to one medication respond to the other. METHODS: Children 6 to 17 years of age with mild-to-moderate persistent asthma were randomized to one of 2 crossover sequences, including 8 weeks of an ICS, fluticasone propionate (100 microg twice daily), and 8 weeks of an LTRA, montelukast (5-10 mg nightly depending on age), in a multicenter, double-masked, 18-week trial. Response was assessed on the basis of improvement in FEV 1 and assessed for relationships to baseline asthma phenotype-associated biomarkers. RESULTS: Defining response as improvement in FEV 1 of 7.5% or greater, 17% of 126 participants responded to both medications, 23% responded to fluticasone alone, 5% responded to montelukast alone, and 55% responded to neither medication. Compared with those who responded to neither medication, favorable response to fluticasone alone was associated with higher levels of exhaled nitric oxide, total eosinophil counts, levels of serum IgE, and levels of serum eosinophil cationic protein and lower levels of methacholine PC(20) and pulmonary function; favorable response to montelukast alone was associated with younger age and shorter disease duration. Greater differential response to fluticasone over montelukast was associated with higher bronchodilator use, bronchodilator response, exhaled nitric oxide levels, and eosinophil cationic protein levels and lower methacholine PC(20) and pulmonary function values. CONCLUSIONS: Response to fluticasone and montelukast vary considerably. Children with low pulmonary function or high levels of markers associated with allergic inflammation should receive ICS therapy. Other children could receive either ICSs or LTRAs.

Acetates↗
PubMed2005

Opposite effects of CD 14/-260 on serum IgE levels in children raised in different environments.

BACKGROUND: Most complex diseases are the result of interactions between polymorphisms in the genome and environmental exposures. OBJECTIVE: We sought to investigate the previously reported association between a polymorphism in the promoter region of CD 14 (CD 14/-260 C-->T) and serum IgE levels in relation to the environment to which children are exposed. METHODS: In 624 children living in 2 rural communities in Europe, we compared total and specific serum IgE levels between the genotypes of CD 14/-260 in relation to exposure to animals and in relation to house dust endotoxin. RESULTS: We found that the C allele of CD 14/-260 was associated with higher levels of both total and specific serum IgE to aeroallergens in children with regular contact with pets, whereas an association in the opposite direction was found in children with regular contact with stable animals. This modifying effect of animal exposure was not explained by levels of house dust endotoxin. However, in children with high levels of house dust endotoxin, the C allele was associated with less specific IgE, independently from animal exposure. CONCLUSION: Because CD 14 is a pattern recognition receptor for microbial molecules, the results suggest that the type and concentrations of such molecules present in the environment strongly determine the direction of the association between CD 14/-260 and serum markers of atopy.

Animals↗
PubMed2005

Association of atopy and eczema with polymorphisms in T-cell immunoglobulin domain and mucin domain-IL-2-inducible T-cell kinase gene cluster in chromosome 5 q 33.

BACKGROUND: The T-cell immunoglobulin domain and mucin domain (TIM) gene family and the gene for IL-2-inducible T-cell kinase (ITK), located in chromosome 5 q 33 and potentially involved in the T-cell proliferation and differentiation, are good candidate genes for allergic diseases. OBJECTIVE: We assessed the role of polymorphisms in the TIM family genes and ITK in atopy, eczema, and asthma. METHODS: Twenty-one polymorphisms in the TIM-ITK gene cluster were genotyped in 564 children enrolled in the Tucson Children's Respiratory Study. Skin prick tests to common allergens were performed at age 6.1 years (n=508), age 10.8 years (n=539), and age 16.6 years (n=424). Asthma and eczema were assessed by questionnaire at these 3 points. Averaged relative risks were estimated. RESULTS: One 15-bp insertion/deletion in exon 4 of TIM 1 was significantly related to atopy and eczema (relative risk associated with carrying at least 1 rare allele=1.24 [1.07--1.45], P=.005; and 1.43 [1.01--2.01], P=.004, respectively). The 3 tested single nucleotide polymorphisms (SNPs) in TIM 3 were significantly related to atopy and eczema. One of them, at position +4259 calculated from the translation start site, predicts a putative change in the amino acid sequence of the protein, and was the most strongly related to atopy (relative risk=1.28 [1.12--1.47]; P=.0003). SNPs in the 5' genomic region in ITK, which show moderate linkage disequilibrium with those in TIM 3, had an independent effect on atopy. None of the polymorphisms studied was related to asthma. CONCLUSION: Our findings support a potential role for SNPs in TIM 1, TIM 3, and ITK, independent of each other, in allergic diseases.

Adolescent↗
PubMed2005

The relation of rhinitis to recurrent cough and wheezing: a longitudinal study.

BACKGROUND: Recurrent cough can be a clinical manifestation of rhinitis. However, it remains unclear if the association between rhinitis and recurrent cough among children is independent of asthma. OBJECTIVE: The aim of the present study was to determine, in a large longitudinal cohort, whether rhinitis is significantly associated with recurrent cough alone, wheezing alone, or the combination of both symptoms during childhood. METHODS: We investigated determinants of recurrent cough, with or without wheezing, using longitudinal data from the Tucson Children's Respiratory Study. Among the 1246 subjects originally enrolled, 1024 children completed at least one questionnaire between the ages of 6 and 18 years and were included in the present study. In any survey, wheezing was defined as at least one wheezing episode during the past year and recurrent cough as two or more coughing episodes lasting at least 1 week without a cold during the past year. Generalized estimating equations were used to determine significant risk factors. RESULTS: After adjusting for sex, skin test reactivity and parental asthma, both rhinitis (OR = 2.47 CI = 1.84, 3.30) and sinusitis (OR = 1.54 CI = 1.11, 2.14) were associated with an increased risk of recurrent cough plus wheezing. The OR associated with rhinitis were significantly reduced for subjects reporting only recurrent cough or only wheezing (OR = 1.43, CI = 1.03, 1.99; and OR = 1.30, CI = 1.07, 1.58, respectively). Recurrent cough and wheezing, when examined independently, showed different patterns of risk factors. CONCLUSION: We found rhinitis to be an independent risk factor for both recurrent cough and wheezing during childhood. Different pathways may be involved in the association of rhinitis with recurrent cough and wheezing.

Adolescent↗