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1.  Identification of FGF7 as a novel susceptibility locus for chronic obstructive pulmonary disease 
Thorax  2011;66(12):1085-1090.
Traditional genome-wide association studies (GWAS) of large cohort of subjects with chronic obstructive pulmonary disease (COPD) have successfully identified novel candidate genes, but several other plausible loci do not meet strict criteria for genome-wide significance after correction for multiple testing.
We hypothesize that by applying unbiased weights derived from unique populations we can identify additional COPD susceptibility loci.
We performed a homozygosity haplotype analysis on a group of subjects with and without COPD to identify regions of conserved homozygosity (RCHH). Weights were constructed based on the frequency of these RCHH in case vs. controls, and used to adjust the P values from a large collaborative GWAS of COPD.
We identified 2,318 regions of conserved homozygosity, of which 576 were significantly (P < .05) overrepresented in cases. After applying the weights constructed from these regions to a collaborative GWAS of COPD, we identified two single nucleotide polymorphisms in a novel gene (FGF7) that gained genome-wide significance by the false discovery rate method. In a follow-up analysis, both SNPs (rs12591300 and rs4480740) were significantly associated with COPD in an independent population (combined P values of 7.9E-07 and 2.8E-06 respectively). In another independent population, increased lung tissue FGF7 expression was associated with worse measures of lung function.
Weights constructed from a homozygosity haplotype analysis of an isolated population successfully identify novel genetic associations from a GWAS on a separate population. This method can be used to identify promising candidate genes that fail to meet strict correction for multiple testing.
PMCID: PMC3348619  PMID: 21921092
2.  Risk Factors for Allergic Rhinitis in Costa Rican Children with Asthma 
Allergy  2009;65(2):256-263.
Risk factors for allergic rhinitis (AR) in asthmatics are likely distinct from those for AR or asthma alone. We sought to identify clinical and environmental risk factors for AR in children with asthma.
We performed a cross-sectional study of 616 Costa Rican children aged 6–14 years with asthma. Candidate risk factors were drawn from questionnaire data, spirometry, methacholine challenge testing, skin testing, and serology. Two outcome measures, skin test reaction (STR)-positive AR and physician-diagnosed AR, were examined by logistic regression.
STR-positive AR had high prevalence (80%) in Costa Rican children with asthma, and its independent risk factors were nasal symptoms after exposure to dust or mold, parental history of AR, older age at asthma onset, oral steroid use in the past year, eosinophilia, and positive IgEs to dust mite and cockroach. Physician-diagnosed AR had lower prevalence (27%), and its independent risk factors were nasal symptoms after pollen exposure, STR to tree pollens, a parental history of AR, inhaled steroid and short-acting β2 agonist use in the past year, household mold/mildew, and fewer older siblings. A physician’s diagnosis was only 29.5% sensitive for STR-positive AR.
Risk factors for AR in children with asthma depend on the definition of AR. Indoor allergens drive risk for STR-positive AR. Outdoor allergens and home environmental conditions are risk factors for physician-diagnosed AR. We propose that children with asthma in Costa Rica and other Latin American nations undergo limited skin testing or specific IgE measurements to reduce the current under-diagnosis of AR.
PMCID: PMC2807901  PMID: 19796208
allergic rhinitis; asthma; physician diagnosis; risk factor; skin test
3.  Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma 
Allergic rhinitis (AR) affects up to 80% of children with asthma and increases asthma severity. Thymic stromal lymphopoietin (TSLP) is a key mediator of allergic inflammation. The role of the TSLP gene (TSLP) in the pathogenesis of AR has not been studied.
To test for associations between variants in TSLP, TSLP-related genes, and AR in children with asthma.
We genotyped 15 single nucleotide polymorphisms (SNPs) in TSLP, OX40L, IL7R, and RXRα in three independent cohorts: 592 asthmatic Costa Rican children and their parents, 422 nuclear families of North American children with asthma, and 239 Swedish children with asthma. We tested for associations between these SNPs and AR. As we previously reported sex-specific effects for TSLP, we performed overall and sex-stratified analyses. We additionally performed secondary analyses for gene-by-gene interactions.
Across the three cohorts, the T allele of TSLP SNP rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone. The SNP was associated with reduced odds for AR (odds ratios ranging from 0.56 to 0.63, with corresponding Fisher's combined P value of 1.2 × 10-4). Our findings were significant after accounting for multiple comparisons. SNPs in OX40L, IL7R, and RXRα were not consistently associated with AR in children with asthma. There were nominally significant interactions between gene pairs.
TSLP SNP rs1837253 is associated with reduced odds for AR in boys with asthma. Our findings support a role for TSLP in the pathogenesis of AR in children with asthma.
PMCID: PMC3032752  PMID: 21244681
4.  MMP12, Lung Function, and COPD in High-Risk Populations 
The New England journal of medicine  2009;361(27):2599-2608.
Genetic variants influencing lung function in children and adults may ultimately lead to the development of chronic obstructive pulmonary disease (COPD), particularly in high-risk groups.
We tested for an association between single-nucleotide polymorphisms (SNPs) in the gene encoding matrix metalloproteinase 12 (MMP12) and a measure of lung function (prebronchodilator forced expiratory volume in 1 second [FEV1]) in more than 8300 subjects in seven cohorts that included children and adults. Within the Normative Aging Study (NAS), a cohort of initially healthy adult men, we tested for an association between SNPs that were associated with FEV1 and the time to the onset of COPD. We then examined the relationship between MMP12 SNPs and COPD in two cohorts of adults with COPD or at risk for COPD.
The minor allele (G) of a functional variant in the promoter region of MMP12 (rs2276109 [−82A→G]) was positively associated with FEV1 in a combined analysis of children with asthma and adult former and current smokers in all cohorts (P=2×10−6). This allele was also associated with a reduced risk of the onset of COPD in the NAS cohort (hazard ratio, 0.65; 95% confidence interval [CI], 0.46 to 0.92; P = 0.02) and with a reduced risk of COPD in a cohort of smokers (odds ratio, 0.63; 95% CI, 0.45 to 0.88; P = 0.005) and among participants in a family-based study of early-onset COPD (P = 0.006).
The minor allele of a SNP in MMP12 (rs2276109) is associated with a positive effect on lung function in children with asthma and in adults who smoke. This allele is also associated with a reduced risk of COPD in adult smokers.
PMCID: PMC2904064  PMID: 20018959
5.  Serum Vitamin D Levels and Markers of Severity of Childhood Asthma in Costa Rica 
Rationale: Maternal vitamin D intake during pregnancy has been inversely associated with asthma symptoms in early childhood. However, no study has examined the relationship between measured vitamin D levels and markers of asthma severity in childhood.
Objectives: To determine the relationship between measured vitamin D levels and both markers of asthma severity and allergy in childhood.
Methods: We examined the relation between 25-hydroxyvitamin D levels (the major circulating form of vitamin D) and markers of allergy and asthma severity in a cross-sectional study of 616 Costa Rican children between the ages of 6 and 14 years. Linear, logistic, and negative binomial regressions were used for the univariate and multivariate analyses.
Measurements and Main Results: Of the 616 children with asthma, 175 (28%) had insufficient levels of vitamin D (<30 ng/ml). In multivariate linear regression models, vitamin D levels were significantly and inversely associated with total IgE and eosinophil count. In multivariate logistic regression models, a log10 unit increase in vitamin D levels was associated with reduced odds of any hospitalization in the previous year (odds ratio [OR], 0.05; 95% confidence interval [CI], 0.004–0.71; P = 0.03), any use of antiinflammatory medications in the previous year (OR, 0.18; 95% CI, 0.05–0.67; P = 0.01), and increased airway responsiveness (a ≤8.58-μmol provocative dose of methacholine producing a 20% fall in baseline FEV1 [OR, 0.15; 95% CI, 0.024–0.97; P = 0.05]).
Conclusions: Our results suggest that vitamin D insufficiency is relatively frequent in an equatorial population of children with asthma. In these children, lower vitamin D levels are associated with increased markers of allergy and asthma severity.
PMCID: PMC2675563  PMID: 19179486
6.  Polymorphisms in IL12A and cockroach allergy in children with asthma 
IL12A has been implicated in T-cell development and may thus influence the development of atopy and allergic diseases.
We tested for association between four linkage disequilibrium (LD)-tagging SNPs (rs2243123, rs2243151, rs668998, and rs17826053) in IL12A and asthma and allergy-related (serum total and allergen-specific IgE, and skin test reactivity [STR] to two common allergens) phenotypes in two samples: 417 Costa Rican children with asthma and their parents, and 470 families of 503 white children in the Childhood Asthma Management Program (CAMP). The analysis was conducted using the family-based association test (FBAT) statistic implemented in the PBAT program.
Among Costa Rican children with asthma, homozygosity for the minor allele of each of two SNPs in IL12A (rs2243123 and rs2243151) was associated with increased risks of STR to American cockroach (P ≤ 0.03 for both SNPs), STR to German cockroach (P ≤ 0.01 for both SNPs), and having a positive IgE to German cockroach (P < 0.05 for both SNPs). Among children in CAMP, homozygosity for the minor allele of SNP rs2243151 in IL12A was inversely associated with STR to German cockroach (P = 0.03) and homozygosity for the minor allele of SNP rs17826053 in IL12A was associated with increased risks of STR to American cockroach (P = 0.01) and STR to German cockroach (P = 0.007). There was no significant association between any SNP in IL12A and asthma, STR to dust mite, or total IgE in Costa Rica or CAMP.
Our findings suggest that variants in IL12A influence cockroach allergy among children with asthma.
PMCID: PMC2525650  PMID: 18671862
7.  Genome-wide association study reveals class I MHC–restricted T cell–associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations 
It has recently been shown that vitamin D deficiency can increase asthma development and severity and that variations in vitamin D receptor genes are associated with asthma susceptibility.
We sought to find genetic factors that might interact with vitamin D levels to affect the risk of asthma exacerbation. Methods: We conducted a genome-wide study of gene–vitamin D interaction on asthma exacerbations using population-based and family-based approaches on 403 subjects and trios from the Childhood Asthma Management Program. Twenty-three polymorphisms with significant interactions were studied in a replication analysis in 584 children from a Costa Rican cohort. Results: We identified 3 common variants in the class I MHC–restricted T cell–associated molecule gene (CRTAM) that were associated with an increased rate of asthma exacerbations based on the presence of a low circulating vitamin D level. These results were replicated in a second independent population (unadjusted combined interaction, P =.00028–.00097; combined odds ratio, 3.28–5.38). One variant, rs2272094, is a nonsynonymous coding polymorphism of CRTAM. Functional studies on cell lines confirmed the interaction of vitamin D and rs2272094 on CRTAM expression. CRTAM is highly expressed in activated human CD8+ and natural killer T cells, both of which have been implicated in asthmatic patients.
The findings highlight an important gene-environment interaction that elucidates the role of vitamin D and CD8+ and natural killer T cells in asthma exacerbation in a genome-wide gene-environment interaction study that has been replicated in an independent population. The results suggest the potential importance of maintaining adequate vitamin D levels in subsets of high-risk asthmatic patients.
PMCID: PMC3360942  PMID: 22051697
Gene-environment interaction; genome-wide association study; vitamin D; asthma exacerbation
8.  Asthma-susceptibility variants identified using probands in case-control and family-based analyses 
BMC Medical Genetics  2010;11:122.
Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs.
We used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study designs: (1) probands were combined with publicly available population controls in a case-control design, and (2) probands and their parents were used in a family-based design. We followed a two-stage replication process utilizing three independent populations to validate our primary findings.
We found that single nucleotide polymorphisms with similar case-control and family-based association results were more likely to replicate in the independent populations, than those with the smallest p-values in either the case-control or family-based design alone. The single nucleotide polymorphism that showed the strongest evidence for association to asthma was rs17572584, which replicated in 2/3 independent populations with an overall p-value among replication populations of 3.5E-05. This variant is near a gene that encodes an enzyme that has been implicated to act coordinately with modulators of Th2 cell differentiation and is expressed in human lung.
Our results suggest that using probands from family-based studies in case-control designs, and combining results of both family-based and case-control approaches, may be a way to augment our ability to find SNPs associated with asthma and other complex diseases.
PMCID: PMC2927535  PMID: 20698975
9.  The Association of a SNP Upstream of INSIG2 with Body Mass Index is Reproduced in Several but Not All Cohorts 
PLoS Genetics  2007;3(4):e61.
A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.
Author Summary
Obesity is an epidemic in the United States of America and developing world, portending an epidemic of related diseases such as diabetes and heart disease. While diet and lifestyle contribute to obesity, half of the population variation in body mass index, a common measure of obesity, is determined by inherited factors. Many studies have reported that common sequence variants in genes are associated with an increased risk for obesity, yet most of these are not reproducible in other study cohorts, suggesting that some are false. Recently, Herbert et al. reported a slightly increased risk of obesity for people carrying two copies of the minor allele at a common variant near INSIG2. We present our attempts to further evaluate this potential association with obesity in additional populations. We find evidence of increased risk of obesity for people carrying two copies of the minor allele in five out of nine cohorts tested, using both family- and population-based testing. We indicate possible reasons for the varied results, with the hope of encouraging a combined analysis across study cohorts to more precisely define the effect of this INSIG2 gene variant.
PMCID: PMC1857727  PMID: 17465681

Results 1-9 (9)