Mechanisms of asthma and allergic inflammation
A common mitochondrial haplogroup is associated with elevated total serum IgE levels

https://doi.org/10.1016/j.jaci.2007.05.029Get rights and content

Background

Maternal history of asthma or atopy is among the most consistently reported risk factors for asthma and atopy in children, yet the molecular basis for this observation remains unclear. Mitochondria are inherited exclusively through the maternal line, raising the possibility that sequence variation in the mitochondrial genome contributes to the pathogenesis of asthma and atopy.

Objective

We set out to determine whether common European mitochondrial haplogroups are associated with asthma-related atopic phenotypes.

Methods

We studied 654 self-reported white children age 5 to 12 years with mild to moderate asthma participating in the Childhood Asthma Management Program. Eight haplogroup-tagging polymorphisms were genotyped with TaqMan probe hybridization assays, and mitochondrial haplogroup tests of association with asthma-related and atopy-related phenotypes were performed with haplo.stats.

Results

We found significant evidence of mitochondrial haplogroup association with total serum IgE levels (global significance, P = .04), with carriers of European haplogroup U (frequency 11%) having higher total serum IgE levels (median level, 684 IU/L) compared with noncarriers (389 IU/L; P = .001). Haplogroup U carriers also had trends of greater skin prick test reactivity (P = .03) and higher frequency of atopic dermatitis (P = .07), although global haplogroup tests for these later 2 phenotypes were not significant at an α level of 0.05.

Conclusion

These data are the first to suggest that common mitochondrial haplogroups influence the atopic diathesis.

Clinical implications

These findings may provide a molecular explanation for the prominent influence of maternal history of atopy on the development of atopy in offspring.

Section snippets

Human subjects

The Institutional Review Boards of the Brigham and Women's Hospital and of the other Childhood Asthma Management Program (CAMP) study centers approved this study. Informed assent and consent were obtained from the study participants and their parents to collect DNA for genetic studies.

Population

The CAMP Study is a multicenter North American clinical trial designed to investigate the long-term effects of inhaled anti-inflammatory medications in 1041 children with mild-to-moderate asthma.25, 26 Enrollment

Mitochondrial single nucleotide polymorphism genotyping

Torroni et al21 previously defined the common mitochondrial haplogroups among Western Europeans, describing 9 common haplogroups with frequencies >.01. For this initial survey of mitochondrial genetic variation in relation to atopic phenotypes, we selected 8 single nucleotide polymorphisms (SNPs) with minor allele frequencies of at least 0.05 that in combination efficiently tag these common European mitochondrial haplogroups.23 Genotype completion rates were at least 95% at all 8 loci (Table I

Discussion

Despite substantial epidemiologic evidence supporting maternal inheritance of asthma and atopy, this is the first report exploring the relationship between these phenotypes and mitochondrial genomic sequence variation. Our preliminary evidence shows an association between common European mitochondrial haplogroups and atopic phenotypes in a cohort of children with mild to moderate asthma. The common mitochondrial haplogroup U, present in 11% of the cohort, was associated with significantly

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    The CAMP Genetics Ancillary Study was supported by the National Heart, Lung, and Blood Institute (NHLBI), NO1-HR-16049. Additional support for this research came from grants P50 HL67664 and T32 HL07427 from the National Institutes of Health and the NHLBI. B.A.R. is a recipient of a Mentored Clinical Scientist Development Award from the National Institutes of Health/NHLBI (K08 HL074193).

    Disclosure of potential conflict of interest: C. A. Camargo, Jr, has consultant arrangements with Altana, Pfizer, AstraZeneca, Critical Therapeutics, Dey, Genentech, Novartis, GlaxoSmithKline, MedImmune, Merck, NuPharmx, Praxair, Respironics, Schering-Plough, and Sepracor and has received research support from AstraZeneca, Aventis Pasteur, Dey, GlaxoSmithKline, Janssen, MedImmune, Merck, Oridion, and Novartis. E. K. Silverman has consultant arrangements with GlaxoSmithKline; has received research support from GlaxoSmithKline; and has served on the speakers' bureau for GlaxoSmithKline, Wyeth, and Bayer. The rest of the authors have declared that they have no conflict of interest.

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