including obesity and both asthma and diabetes. The REVIEWER COMMENTS. This study adds to the knowledge that association between type 2 diabetes and asthma is not genes and the environment combine to influence asthma surprising as a high proportion of youth were over- phenotype. In this case, ALOX12, a gene associated with weight or obese (90.6%) and the linkage between airway inflammation, appears to exhibit variation in asthma and increased BMI is well described in many methylation, not based on genotype alone, but possibly studies. It is interesting to note that children whose on environmental factors, including prenatal pollutant asthma was treated with leukotriene modifiers, alone or exposure. Therefore, the degree of methylation at certain in combination with inhaled corticosteroids or rescue CpG sites on this gene may be an early biomarker that inhalers, had the lowest prevalence of poor glycemic helps to predict wheezing phenotype. control; in fact, 72% had good glycemic control. The URL: www.pediatrics.org/cgi/doi/10.1542/peds.2012–2183OO authors speculate that this could be because leukotriene synthesisorreceptorblockersmayhelpreducethe Justin M. Skripak, MD systemic inflammation present in both obesity and di- Hoboken, NJ abetes as well the direct effect on ameliorating airway inflammation. Identification of IL6R and Chromosome 11q13.5 URL: www.pediatrics.org/cgi/doi/10.1542/peds.2012–2183NN as Risk Loci for Asthma Frank S. Virant, MD Ferreira MA, Matheson MC, Duffy DL, et al. Lancet. Seattle, WA 2011;378(9795):1006–1014 PURPOSE OF THE STUDY. To identify novel genetic variations DNA Hypomethylation at ALOX12 Is Associated imputing asthma risk. With Persistent Wheezing in Childhood Morales E, Bustamante M, Vilahur N, et al. Am J Respir Crit STUDY POPULATION. Pediatric and adult Australians of Eu- Care Med. 2012;185(9):937–943 ropean descent consisting of 2669 asthmatic subjects (28% diagnosed by clinical examination, 54% child- PURPOSE OF THE STUDY. To determine if epigenetic changes hood onset, 59% atopic) and 4528 controls (40% with play a role in asthma phenotypes. unknown asthma status) produced candidate asthma STUDY POPULATION. There were 2 groups studied, both in- genetic variations. Meta-analysis of 12 475 physician- volved children enrolled from pregnancy cohorts. The diagnosed asthmatic subjects and 19 967 controls provided first group (Menorca cohort) was 122 children with data a prioritization cohort. Four additional individual cohorts available through age 6 years. The second group (Sabadell totaling 3322 asthmatic subjects and 22 036 controls cohort) was 236 children with available DNA extracted provided replication. from whole cord blood. METHODS. Microarray-derived genotypes of Australian METHODS. Children were assigned wheezing phenotypes at asthmatic subjects and controls underwent a genome- age 4 to 6 years based on validated questionnaires (never, wide association study to produce asthma candidate loci. transient, late-onset, or persistent wheezing). Prenatal Meta-analysis using unique adult Australian and exposure data were collected through questionnaire previously published GABRIEL genotypes prioritized fi and by measuring for presence of a speci c pollutant, candidate novel genetic loci. The prioritized, novel dichlorodiphenyldichloroethylene, in cord blood. genetic loci endured replication analysis via 4 individual RESULTS. DNA hypomethylation was associated with in- cohorts and a combined meta-analysis. A genomic creased risk for persistent wheezing in both studies, phenotype prediction model for asthma was produced although only 1 of the 2 was statistically significant and subsequently tested. Secondary analysis considered (Menorca: odds ratio 1.13, 95% confidence interval asthma and other immune disease associations. 0.99–1.29, P 5 .077; Sabadell: odds ratio 1.16, 95% confidence interval 1.03–1.37, P 5 .017). Higher levels RESULTS. Two novel loci were significantly associated with of dichlorodiphenyldichloroethylene were associated asthma risk. The interleukin-6 receptor (IL6R) loci on with hypomethylation of ALOX12 in the Menorca study chromosome 1q21.3 associated more significantly (odds (P 5 .033), but not the Sabadell study (P 5 .377). Level ratio [OR] 5 1.09, P 5 .0033) than the indeterminate of methylation at ALOX12 was strongly influenced by loci (rs7130588) at chromosome 11q13.5 (OR 5 1.07, polymorphisms in the gene. P 5 .328) in the replication cohorts. However, when considering all available data, 1q21.3 and 11q13.5 both CONCLUSIONS. DNA hypomethylation at ALOX12 was as- demonstrated very significant asthma association (OR 5 2 2 sociated with a higher risk of persistent wheezing. This 1.09, P 5 2.3 3 10 8 and OR 5 1.09, P 5 1.8 3 10 8, may be an epigenetic biomarker that predicts increased respectively). Secondary analyses of 11q13.5 revealed likelihood of persistent wheezing in childhood. an association with atopy and no asthma risk association

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