Reviews and feature article
Genetic risks and childhood-onset asthma

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Recent large-scale genome-wide association studies have successfully identified several genetic loci that influence asthma susceptibility. The loci thus far identified confer a high population attributable risk for childhood-onset disease and have provided a better understanding of the primary mechanisms underlying asthma and a clear focus for new therapies to treat the disease. The loci are of limited utility for diagnostic or predictive genetic testing. This review considers different aspects of genetic risk, including individual, population, and familial risks, and explores how these different measures interact and how the next generation of genetic studies might be best designed.

Section snippets

Genetic risk of asthma

There have been a number of GWASs for asthma,5, 6, 7, 8, 9, 10, 11, 12, 13 the largest of which contained 10,000 cases of asthma and 16,000 control subjects and was reported by the GABRIEL consortium.14 The GABRIEL subjects came from clinics and epidemiologic surveys in Europe and could be divided by age of onset, severity, and occupational exposure. The GWASs have identified 10 loci with genome-wide significance. Childhood-onset asthma consistently shows the strongest genetic effects,14 and

Genetic risks in populations

Population attributable risk, which is also known as the population attributable risk fraction (PARF), is widely used to estimate the burden of a risk factor in population surveys. Applied to genetic studies, the PARF estimates the fraction of cases that would not occur if no one in the population carried the risk allele.2

Use of the PARF as a measure of association in GWASs is attractive because typically such studies use a panel of tag SNPs to detect associations of diseases or traits with

Genetic risk in individuals

The GABRIEL GWAS represents the largest set of data currently analyzed for the ability of genetic variants to determine the risk of a subject having asthma.14 We assessed individual risk for the 7 SNPs associated with childhood asthma in a classification analysis based on a logistic regression model (Fig 1). Taking as a cut point the risk score exceeded by 25% of the nonasthmatic population (specificity, 75%), the sensitivity of classifying asthma was just 35% (false-negative rate, 65%).

Familial risk and heritability

A third component of genetic risk relates to families. The increase in risk in the siblings of affected subjects is known as the familial relative risk. A related measurement is that of heritability, which is defined as the variance in a complex trait caused by inherited factors. The heritability of childhood asthma has been estimated to be as high as 60%, but the variance in asthma prevalence accounted for by the loci in our large-scale GWAS was only 4%. This is consistent with other complex

Finding rare mutations

GWASs are generally directed at SNPs with minor allele frequencies of greater than 5% or 10%, although with the extension of imputation from the HapMap panel to more extensive reference panels derived from the 1000 Genomes project, it has recently become possible to test associations with SNPs with allele frequencies as rare as 1%. The power to detect genetic associations is not only higher when the underlying susceptibility alleles are common24 but also when the per-allele OR is higher.27 For

The epigenome

Epigenetic effects mediated through mechanisms other than sequence variation are another possible cause of familial clustering. The patterns of gene expression that determine cellular type and function become stably restricted during development, partly through methylation of CpG sequences and gene silencing.31 Islands of CpG sequences are positioned at the 5′ untranslated regions of many human genes.32 About one fifth of these islands are variably methylated, and in one third methylation

Other phenotypes at risk

In this review we have discussed the risk of asthma, as defined by a physician’s diagnosis in most genetic studies and by age of onset and country of origin in the GABRIEL GWAS.14 Other phenotypes might also be of interest, including severity; prognosis; different childhood wheezing phenotypes, such as transient and persistent symptoms39; atopy; and response to therapy.

The use of pharmacogenetics to tailor drug treatments to a person’s genetic profile has been strongly promoted, but the present

Conclusions

Recent genetic association studies for asthma have discovered genetic loci with high PARF but limited utility for diagnostic or predictive genetic testing. Next-generation sequencing strategies might identify rare variants that are of clinical utility, but this utility will be limited by the presence or absence of effectual courses of action arising from genetic information. It is salutary that the communication of personal risk to patients has had minimal effectiveness in promoting their

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    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

    Supported by the European Community Framework 6 Program and the Wellcome Trust.

    Terms in boldface and italics are defined in the glossary on page 267.

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