Genomic Differences between Spontaneous versus Indicated Extreme Preterm Birth.

OBJECTIVE: Extremely preterm infants are at high risk of neonatal mortality and morbidity. Extreme preterm birth (PTB) may result from spontaneous preterm labor or preterm premature rupture of membranes or may be indicated due to preeclampsia, eclampsia, hypertension, or other causes. Our objective was to identify single nucleotide polymorphisms (SNPs) and biological pathways associated with spontaneous versus indicated extreme PTB using the neonatal genome. STUDY DESIGN: We evaluated 523 spontaneous births and 134 indicated births weighing 401 to 1,000 g at birth from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network's Genomics dataset by genome-wide association study (GWAS) and pathway analysis. The TOLSURF cohort was used to replicate the results. RESULTS: In the NRN GWAS, no statistically significant results were found, although the Manhattan plot showed one almost significant peak (rs60854043 on chromosome 14 at p = 1.03E-07) along with many other modest peaks at p = 1-9E-06, for a total of 15 suggestive associations at this locus. In the NRN pathway analysis, multiple pathways were identified, with the most significant being "GO_mf:go_low_density_lipoprotein_particle_receptor_activity" at p = 1.14E-06. However, these results could not be replicated in the TOLSURF cohort. CONCLUSION: Genomic differences are seen between infants born by spontaneous versus indicated extreme PTB. Due to the limited sample size, there is a need for larger studies. KEY POINTS: · Genomic differences are seen between infants born by spontaneous versus indicated very PTB.. · Future studies with large sample sizes evaluating extreme PTB are necessary.. · Spontaneous PTB is more common than indicated extreme PTB..

The hydrocortisone-responsive urinary metabolome of premature infants.

BACKGROUND: Extremely premature infants are at risk for circulatory collapse or respiratory failure that are often treated with hydrocortisone (HC); however, there is no information on the metabolic consequences of this therapy. METHODS: Longitudinal urine samples from infants <28 weeks gestation in the Trial of Late Surfactant were analyzed by untargeted UHPLC:MS/MS. Fourteen infants who received a tapering course of HC beginning at 3 mg/kg/day for ≥9 days were compared to 14 matched control infants. A secondary cross-sectional analysis by logistic regression used urines from 314 infants. RESULTS: Of 1145 urinary metabolites detected, abundance of 219, representing all the major biochemical pathways, changed at p < 0.05 in the HC-treated group with 90% decreasing; 3 cortisol derivatives increased ~2-fold with HC therapy. Only 11% of regulated metabolites remained responsive at the lowest HC dose. Regulated metabolites included two steroids and thiamin that are associated with lung inflammation in infants. HC responsiveness was confirmed in 57% of metabolites by cross-sectional analysis. CONCLUSIONS: HC treatment of premature infants influenced in a dose-dependent manner abundance of 19% of identified urinary metabolites of diverse biochemical systems, primarily reducing concentrations. These findings indicate that exposure to HC reversibly impacts the nutritional status of premature infants. IMPACT: Hydrocortisone treatment of premature infants with respiratory failure or circulatory collapse alters levels of a subset of urinary metabolites representing all major biochemical pathways. This is the first description of the scope, magnitude, timing and reversibility of metabolomic changes in infants in response to hydrocortisone, and it confirms corticosteroid regulation of three biochemicals that are associated with lung inflammatory status. The findings indicate a dose-dependency of hydrocortisone for metabolomic and anti-inflammatory effects, that prolonged therapy may lower the supply of many nutrients, and that monitoring concentrations of cortisol and inflammation markers may be a useful clinical approach during corticosteroid therapy.

Easy-HLA: a validated web application suite to reveal the full details of HLA typing.

MOTIVATION: The HLA system plays a pivotal role in both clinical applications and immunology research. Typing HLA genes in patient and donor is indeed required in hematopoietic stem cell and solid-organ transplantation, and the histocompatibility complex region exhibits countless genetic associations with immune-related pathologies. Since the discovery of HLA antigens, the HLA system nomenclature and typing methods have constantly evolved, which leads to difficulties in using data generated with older methodologies. RESULTS: Here, we present Easy-HLA, a web-based software suite designed to facilitate analysis and gain knowledge from HLA typing, regardless of nomenclature or typing method. Easy-HLA implements a computational and statistical method of HLA haplotypes inference based on published reference populations containing over 600 000 haplotypes to upgrade missing or partial HLA information: 'HLA-Upgrade' tool infers high-resolution HLA typing and 'HLA-2-Haplo' imputes haplotype pairs and provides additional functional annotations (e.g. amino acids and KIR ligands). We validated both tools using two independent cohorts (total n = 2500). For HLA-Upgrade, we reached a prediction accuracy of 92% from low- to high-resolution of European genotypes. We observed a 96% call rate and 76% accuracy with HLA-2-Haplo European haplotype pairs prediction. In conclusion, Easy-HLA tools facilitate large-scale immunogenetic analysis and promotes the multi-faceted HLA expertise beyond allelic associations by providing new functional immunogenomics parameters. AVAILABILITY AND IMPLEMENTATION: Easy-HLA is a web application freely available (free account) at: https://hla.univ-nantes.fr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Blood metabolomics in infants enrolled in a dose escalation pilot trial of budesonide in surfactant.

BACKGROUND: The pathogenesis of BPD includes inflammation and oxidative stress in the immature lung. Corticosteroids improve respiratory status and outcome, but the optimal treatment regimen for benefit with low systemic effects is uncertain. METHODS: In a pilot dose escalation trial, we administered ≤5 daily doses of budesonide in surfactant to 24 intubated premature infants (Steroid And Surfactant in ELGANs (SASSIE)). Untargeted metabolomics was performed on dried blood spots using UPLC-MS/MS. Tracheal aspirate IL-8 concentration was determined as a measure of lung inflammation. RESULTS: Metabolomics data for 829 biochemicals were obtained on 121 blood samples over 96 h from 23 infants receiving 0.025, 0.05, or 0.1 mg budesonide/kg. Ninety metabolites were increased or decreased in a time- and dose-dependent manner at q ≤ 0.1 with overrepresentation in lipid and amino acid super pathways. Different dose response patterns occurred, with negative regulation associated with highest sensitivity to budesonide. Baseline levels of 22 regulated biochemicals correlated with lung inflammation (IL-8), with highest significance for sphingosine and thiamin. CONCLUSIONS: Numerous metabolic pathways are regulated in a dose-dependent manner by glucocorticoids, which apparently act via distinct mechanisms that impact dose sensitivity. The findings identify candidate blood biochemicals as biomarkers of lung inflammation and systemic responses to corticosteroids. IMPACT: Treatment of premature infants in respiratory failure with 0.1 mg/kg intra-tracheal budesonide in surfactant alters levels of ~11% of detected blood biochemicals in discrete time- and dose-dependent patterns. A subset of glucocorticoid-regulated biochemicals is associated with lung inflammatory status as assessed by lung fluid cytokine concentration. Lower doses of budesonide in surfactant than currently used may provide adequate anti-inflammatory responses in the lung with fewer systemic effects, improving the benefit:risk ratio.

Association of HLA-DRB1∗09:01 with tIgE levels among African-ancestry individuals with asthma.

BACKGROUND: Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (single nucleotide polymorphisms) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis. OBJECTIVE: To run the first HLA-centric association study with asthma and specific asthma-related phenotypes in a large cohort of African-ancestry individuals. METHODS: We collected high-density genomics data for the Consortium on Asthma among African-ancestry Populations in the Americas (N = 4993) participants. Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE (tIgE) levels in subjects with and without asthma. RESULTS: Among the 1607 individuals with asthma, 972 had available tIgE levels, with a mean tIgE level of 198.7 IU/mL. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1∗09:01 was associated with increased tIgE levels (P = 8.5 × 10-4; weighted effect size, 0.51 [0.15-0.87]). CONCLUSIONS: We identified for the first time an HLA allele associated with tIgE levels in African-ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations.

Intrapulmonary airway smooth muscle is hyperreactive with a distinct proteome in asthma.

Constriction of airways during asthmatic exacerbation is the result of airway smooth muscle (ASM) contraction. Although it is generally accepted that ASM is hypercontractile in asthma, this has not been unambiguously demonstrated. Whether airway hyperresponsiveness (AHR) is the result of increased ASM mass alone or also increased contractile force generation per unit of muscle directly determines the potential avenues for treatment.To assess whether ASM is hypercontractile we performed a series of mechanics measurements on isolated ASM from intrapulmonary airways and trachealis from human lungs. We analysed the ASM and whole airway proteomes to verify if proteomic shifts contribute to changes in ASM properties.We report an increase in isolated ASM contractile stress and stiffness specific to asthmatic human intrapulmonary bronchi, the site of increased airway resistance in asthma. Other contractile parameters were not altered. Principal component analysis (PCA) of unbiased mass spectrometry data showed clear clustering of asthmatic subjects with respect to ASM specific proteins. The whole airway proteome showed upregulation of structural proteins. We did not find any evidence for a difference in the regulation of myosin activity in the asthmatic ASM.In conclusion, we showed that ASM is indeed hyperreactive at the level of intrapulmonary airways in asthma. We identified several proteins that are upregulated in asthma that could contribute to hyperreactivity. Our data also suggest enhanced force transmission associated with enrichment of structural proteins in the whole airway. These findings may lead to novel directions for treatment development in asthma.

Rare Protein-Altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis.

Rationale: Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP).Objectives: Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP.Methods: Next-generation sequences from two CHP cohorts were analyzed to identify variants in TERT (telomerase reverse transcriptase), TERC (telomerase RNA component), DKC1 (dyskerin pseudouridine synthase 1), RTEL1 (regulator of telomere elongation helicase 1), PARN (poly[A]-specific RNase), and TINF2 (TERF1-interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR.Measurements and Main Results: Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age- and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 bp; 95% CI, -933 to -190; P = 0.003; replication: -612 bp; 95% CI, -870 to -354; P = 5.30 × 10-6). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28; P = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88; P = 0.011).Conclusions: A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival.

An admixture mapping meta-analysis implicates genetic variation at 18q21 with asthma susceptibility in Latinos.

BACKGROUND: Asthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies. OBJECTIVE: We sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility. METHODS: We leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups. RESULTS: We identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P < .001). In addition, lower expression of SMAD2 was associated with more frequent exacerbations among Puerto Ricans with asthma. CONCLUSION: Ancestry at 18q21 was significantly associated with asthma in Latinos and implicated multiple ancestry-informative noncoding variants upstream of SMAD2 with asthma susceptibility. Furthermore, decreased SMAD2 expression in blood was strongly associated with increased asthma risk and increased exacerbations.

A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma.

Short-acting ß2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the United States. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African-American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single-nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1830 Latinos (total = 2779). Finally, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p = 7.69 × 10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958 and rs7081864, p ≤ 5 × 10-8). Our results failed to replicate in three additional populations of 416 Latinos and 1615 African Americans. Our findings indicate that both population-specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.

Correction: Genetic variation in CRHR1 is associated with short-term respiratory response to corticosteroids in preterm infants at risk for bronchopulmonary dysplasia.

In the original version of this article, the Supplementary Information file contained incorrect reference numbers. 'Supplemental Table S1' has now been replaced with the corrected version, in which the correct reference numbers are cited. The authors would like to apologise for this error.

Genetic variation in CRHR1 is associated with short-term respiratory response to corticosteroids in preterm infants at risk for bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is an orphan disease and advances in prevention and treatment are lacking. The clinical efficacy of systemic corticosteroid therapy to reduce the severity of lung disease and BPD is highly variable. Our objective was to assess whether candidate SNPs in corticosteroid metabolism and response genes are associated with short-term phenotypic response to systemic corticosteroids in infants at high risk for BPD. METHODS: Pharmacogenetic analysis of data from a large randomized controlled trial (TOLSURF) in infants treated with dexamethasone or hydrocortisone using multivariate linear regression. The primary outcome was a change in respiratory severity score (RSS, mean airway pressure x FiO2) at day 7 of corticosteroid treatment. RESULTS: rs7225082 in the intron of CRHR1 is significantly associated with the magnitude of decrease in RSS 7 days after starting treatment with systemic corticosteroid (meta-analysis P = 2.8 × 10-4). Each T allele at rs7225082 is associated with a smaller absolute change in RSS at day 7, i.e., less response to systemic corticosteroids. CONCLUSIONS: Genetic variability is associated with corticosteroid responsiveness with regard to respiratory status in preterm infants. Identification of genetic markers of corticosteroid responsiveness may allow for therapeutic individualization, with the goal of optimizing the risk-to-benefit ratio for an individual child.

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10-7) and suggestive (P < 7.06 × 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and ß-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

Ancestry and genetic associations with bronchopulmonary dysplasia in preterm infants.

Bronchopulmonary dysplasia in premature infants is a common and often severe lung disease with long-term sequelae. A genetic component is suspected but not fully defined. We performed an ancestry and genome-wide association study to identify variants, genes, and pathways associated with survival without bronchopulmonary dysplasia in 387 high-risk infants treated with inhaled nitric oxide in the Trial of Late Surfactant study. Global African genetic ancestry was associated with increased survival without bronchopulmonary dysplasia among infants of maternal self-reported Hispanic white race/ethnicity [odds ratio (OR) = 4.5, P = 0.01]. Admixture mapping found suggestive outcome associations with local African ancestry at chromosome bands 18q21 and 10q22 among infants of maternal self-reported African-American race/ethnicity. For all infants, the top individual variant identified was within the intron of NBL1, which is expressed in midtrimester lung and is an antagonist of bone morphogenetic proteins ( rs372271081 , OR = 0.17, P = 7.4 × 10-7). The protective allele of this variant was significantly associated with lower nitric oxide metabolites in the urine of non-Hispanic white infants ( P = 0.006), supporting a role in the racial differential response to nitric oxide. Interrogating genes upregulated in bronchopulmonary dysplasia lungs indicated association with variants in CCL18, a cytokine associated with fibrosis and interstitial lung disease, and pathway analyses implicated variation in genes involved in immune/inflammatory processes in response to infection and mechanical ventilation. Our results suggest that genetic variation related to lung development, drug metabolism, and immune response contribute to individual and racial/ethnic differences in respiratory outcomes following inhaled nitric oxide treatment of high-risk premature infants.

The landscape of genomic imprinting across diverse adult human tissues.

Genomic imprinting is an important regulatory mechanism that silences one of the parental copies of a gene. To systematically characterize this phenomenon, we analyze tissue specificity of imprinting from allelic expression data in 1582 primary tissue samples from 178 individuals from the Genotype-Tissue Expression (GTEx) project. We characterize imprinting in 42 genes, including both novel and previously identified genes. Tissue specificity of imprinting is widespread, and gender-specific effects are revealed in a small number of genes in muscle with stronger imprinting in males. IGF2 shows maternal expression in the brain instead of the canonical paternal expression elsewhere. Imprinting appears to have only a subtle impact on tissue-specific expression levels, with genes lacking a systematic expression difference between tissues with imprinted and biallelic expression. In summary, our systematic characterization of imprinting in adult tissues highlights variation in imprinting between genes, individuals, and tissues.

Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients.

Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4, and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C0 /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1 ± 1.6 days for CYP3A extensive metabolizers (EM, P < 0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2 ± 0.5 days less (P = 0.01) and EM spent 2.1 ± 0.5 days less (P < 0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C0 /D (P < 0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, P = 0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, P = 0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes.

Genetic and socioeconomic study of mate choice in Latinos reveals novel assortment patterns.

Nonrandom mating in human populations has important implications for genetics and medicine as well as for economics and sociology. In this study, we performed an integrative analysis of a large cohort of Mexican and Puerto Rican couples using detailed socioeconomic attributes and genotypes. We found that in ethnically homogeneous Latino communities, partners are significantly more similar in their genomic ancestries than expected by chance. Consistent with this, we also found that partners are more closely related--equivalent to between third and fourth cousins in Mexicans and Puerto Ricans--than matched random male-female pairs. Our analysis showed that this genomic ancestry similarity cannot be explained by the standard socioeconomic measurables alone. Strikingly, the assortment of genomic ancestry in couples was consistently stronger than even the assortment of education. We found enriched correlation of partners' genotypes at genes known to be involved in facial development. We replicated our results across multiple geographic locations. We discuss the implications of assortment and assortment-specific loci on disease dynamics and disease mapping methods in Latinos.

Update on the State of the Science for Analytical Methods for Gene-Environment Interactions.

The analysis of gene-environment interaction (G×E) may hold the key for further understanding the etiology of many complex traits. The current availability of high-volume genetic data, the wide range in types of environmental data that can be measured, and the formation of consortiums of multiple studies provide new opportunities to identify G×E but also new analytical challenges. In this article, we summarize several statistical approaches that can be used to test for G×E in a genome-wide association study. These include traditional models of G×E in a case-control or quantitative trait study as well as alternative approaches that can provide substantially greater power. The latest methods for analyzing G×E with gene sets and with data in a consortium setting are summarized, as are issues that arise due to the complexity of environmental data. We provide some speculation on why detecting G×E in a genome-wide association study has thus far been difficult. We conclude with a description of software programs that can be used to implement most of the methods described in the paper.

A genome-wide association study of susceptibility to acute lymphoblastic leukemia in adolescents and young adults.

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is characterized by distinct presenting features and inferior prognosis compared with pediatric ALL. We performed a genome-wide association study (GWAS) to comprehensively identify inherited genetic variants associated with susceptibility to AYA ALL. In the discovery GWAS, we compared genotype frequency at 635 297 single nucleotide polymorphisms (SNPs) in 308 AYA ALL cases and 6,661 non-ALL controls by using a logistic regression model with genetic ancestry as a covariate. SNPs that reached P ≤ 5 × 10(-8) in GWAS were tested in an independent cohort of 162 AYA ALL cases and 5,755 non-ALL controls. We identified a single genome-wide significant susceptibility locus in GATA3: rs3824662, odds ratio (OR), 1.77 (P = 2.8 × 10(-10)) and rs3781093, OR, 1.73 (P = 3.2 × 10(-9)). These findings were validated in the replication cohort. The risk allele at rs3824662 was most frequent in Philadelphia chromosome (Ph)-like ALL but also conferred susceptibility to non-Ph-like ALL in AYAs. In 1,827 non-selected ALL cases, the risk allele frequency at this SNP was positively correlated with age at diagnosis (P = 6.29 × 10(-11)). Our results from this first GWAS of AYA ALL susceptibility point to unique biology underlying leukemogenesis and potentially distinct disease etiology by age group.

Genetic variants and risk of asthma in an American Indian population.

BACKGROUND: Asthma is recognized as a complex, multifactorial disease with a genetic component that is well recognized. Certain genetic variants are associated with asthma in a number of populations. OBJECTIVE: To determine whether the same variants increase the risk of asthma among American Indian children. METHODS: The electronic medical records of an Indian Health Service facility identified all children between 6 and 17 years of age with case-defining criteria for asthma (n = 108). Control children (n = 216), matched for age, were also identified. Real-time polymerase chain reaction assays were used to genotype 10 single-nucleotide polymorphisms (SNPs) at 6 genetic loci. Genotypic distributions among cases and controls were evaluated by χ2 and logistic regression methods. RESULTS: A variant at 5q22.1 revealed a statistically significant imbalance in the distribution of genotypes between case-control pairs (rs10056340, P < .001). In logistic regression analyses, the same variant at 5q22.1 and a variant at 17q21 were associated with asthma at P < .05 (rs10056340 and rs9303277). Inclusions of age, body mass index, and atopy in multivariate models revealed significant associations between rs10056340 (odds ratio, 2.020; 95% confidence interval, 1.283-3.180; P = .002) and all 5 17q21 SNPs and asthma in this population. In analyses restricted to atopic individuals, the association of rs10056340 was essentially unchanged, whereas among nonatopic individuals the trend was in the same direction but nonsignificant. The reverse was true for the 17q21 SNPs. CONCLUSION: These findings demonstrate that many variants commonly associated with asthma in other populations also accompany this condition among American Indian children. American Indian children also appear to have an increased risk of asthma associated with obesity.

Air Pollution and Lung Function in Minority Youth with Asthma in the GALA II (Genes-Environments and Admixture in Latino Americans) and SAGE II (Study of African Americans, Asthma, Genes, and Environments) Studies.

RATIONALE: Adverse effects of exposures to ambient air pollution on lung function are well documented, but evidence in racial/ethnic minority children is lacking. OBJECTIVES: To assess the relationship between air pollution and lung function in minority children with asthma and possible modification by global genetic ancestry. METHODS: The study population consisted of 1,449 Latino and 519 African American children with asthma from five different geographical regions in the mainland United States and Puerto Rico. We examined five pollutants (particulate matter ≤10 µm and ≤2.5 µm in diameter, ozone, nitrogen dioxide, and sulfur dioxide), derived from participant residential history and ambient air monitoring data, and assessed over several time windows. We fit generalized additive models for associations between pollutant exposures and lung function parameters and tested for interaction terms between exposures and genetic ancestry. MEASUREMENTS AND MAIN RESULTS: A 5 µg/m(3) increase in average lifetime particulate matter less than or equal to 2.5 µm in diameter exposure was associated with a 7.7% decrease in FEV1 (95% confidence interval = -11.8 to -3.5%) in the overall study population. Global genetic ancestry did not appear to significantly modify these associations, but percent African ancestry was a significant predictor of lung function. CONCLUSIONS: Early-life particulate exposures were associated with reduced lung function in Latino and African American children with asthma. This is the first study to report an association between exposure to particulates and reduced lung function in minority children in which racial/ethnic status was measured by ancestry-informative markers.