Genetic polymorphisms in arginase I and II and childhood asthma and atopy

doi:10.1016/j.jaci.2005.09.026

Journal of Allergy and Clinical Immunology

Volume 117, Issue 1, January 2006, Pages 119-126

https://doi.org/10.1016/j.jaci.2005.09.026 Get rights and content

Background

A recent microarray study implicated arginase I (ARG1) and arginase II (ARG2) in mouse allergic asthma models and human asthma.

Objectives

To examine the association between genetic variation in ARG1 and ARG2 and childhood asthma and atopy risk.

Methods

We enrolled 433 case-parent triads, consisting of patients with asthma 4 to 17 years old and their biologic parents, from the allergy clinic of a public hospital in Mexico City between 1998 and 2003. Atopy to 24 aeroallergens was determined by skin prick tests. We genotyped 4 single nucleotide polymorphisms (SNPs) of ARG1 and 4 SNPs of ARG2 with minor allele frequencies higher than 10% by using the TaqMan assay (Roche Molecular Systems, Pleasanton, Calif).

Results

ARG1 SNPs and haplotypes were not associated with asthma, but all 4 ARG1 SNPs were associated with the number of positive skin tests (P = .007-.018). Carrying 2 copies of minor alleles for either of 2 highly associated ARG2 SNPs was associated with a statistically significant increased relative risk (RR) of asthma (1.5, 95% CI = 1.1-2.1 for arg2s1; RR = 1.6, 95% CI = 1.1-2.3 for arg2s2). The association was slightly stronger among children with a smoking parent (arg2s1 RR = 2.1, 95% CI = 1.2 - 3.9 with a smoking parent; RR = 1.2, 95% CI = 0.8-1.9 without; interaction P = .025). Haplotype analyses reduced the sample size but supported the single SNP results. One ARG2 SNP was related to the number of positive skin tests (P = .027).

Conclusion

Variation in arginase genes may contribute to asthma and atopy in children.

Section snippets

Study design and subject enrollment

Using the case-parent triad design,6, 7 we recruited nuclear families consisting of a case and both parents. Cases were children age 4 to 17 years with asthma, diagnosed by a pediatric allergist at the allergy referral clinic of a large public pediatric hospital in central Mexico City (Hospital Infantil de Mexico Federico Gomez) between June 1998 and November 2003. Children and parents provided blood samples as sources of DNA. We enrolled 433 complete case-parent triads.

A pediatric allergist

Results

Cases had mean age of 9.1 years (SD, 2.5 years), and 58% were boys. Most had mild (69%) as opposed to moderate or severe asthma (31%). Nearly all cases (98.4%) had used medication for asthma in the past 12 months. Wheezing in the past 12 months was reported by 93%, and chronic dry cough was reported by 62.5%. For 71.8% of cases, asthma symptoms had interfered with daily activities or school attendance in the past 12 months. Exacerbation of asthma symptoms by exercise was reported by 72.1% of

Discussion

We found genetic variation in ARG2 to be associated with childhood asthma risk in our Mexican population. Carrying 2 copies of the minor allele of either of 2 highly associated SNPs in ARG2 (arg2s1 or arg2s2) conferred a modest but statistically significantly increased risk to asthma. The modest effect size, with a 40% increase in risk for minor allele homozygotes, is of the magnitude expected for individual SNPs in genes related to asthma,²⁰ a complex disease involving genetic and

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: Supported by Z01 ES49019 from the Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, and grant 26206-M from the National Council of Science and Technology (CONACYT), Mexico. Dr Romieu is supported by the National Center for Environmental Health at the Centers for Disease Control.

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Mechanisms of asthma and allergic inflammationGenetic polymorphisms in arginase I and II and childhood asthma and atopy

Background

Objectives

Methods

Results

Conclusion

Section snippets

Study design and subject enrollment

Results

Discussion

Trends Pharmacol Sci

Am J Hum Genet

Am J Hum Genet

Am J Hum Genet

Genomics

Am J Hum Genet

J Allergy Clin Immunol

Biochem Biophys Res Commun

Chest

Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis

J Clin Invest

Arginase: marker, effector, or candidate gene for asthma?

J Clin Invest

A review of asthma genetics: gene expression studies and recent candidates

J Appl Genet

Distinguishing the effects of maternal and offspring genes through studies of “case-parent triads.”

Am J Epidemiol

British guideline on the management of asthma

Thorax

Pocket Guide for Asthma Management and Prevention: Global Initiative for Asthma

Standardization of spirometry, 1994 update. American Thoracic Society

Am J Respir Crit Care Med

Spirometric function in children of Mexico City compared to Mexican-American children

Pediatr Pulmonol

Standardization of diagnostic work in allergy

Int Arch Allergy Appl Immunol

On measures of gametic disequilibrium

Genetics

Case-parent triad data: estimating single- and double-dose effects of fetal and maternal disease gene haplotypes

Ann Hum Genet

Method for using complete and incomplete trios to identify genes related to a quantitative trait

Genet Epidemiol

Mechanisms of asthma and allergic inflammation
Genetic polymorphisms in arginase I and II and childhood asthma and atopy