Genetic risk assessment can provide useful information about whether childhood asthma will remit or persist, but a clinically meaningful test based on identified gene variants is likely many years away, researchers found.
Analysis of data from a four-decade longitudinal study involving almost 1,000 people revealed that those with higher genetic risk scores were more than a third more likely to continue to suffer from asthma as adults than were those with lower scores, based on the 15-variant prediction model (RR 1.36, 95% CI 1.14-1.63).
Higher scores carried a greater risk of atopy (RR 1.07, 1.01-1.14), airway hyper-responsiveness (RR 1.16, 1.03-1.32), and incompletely reversible airflow obstruction (RR 1.28, 1.04-1.57), according to the study, published online in the journal Lancet Respiratory Medicine.
Genome-wide association studies have identified 17 single nucleotide polymorphisms, or SNPs, linked to asthma, and the study was designed to explore whether these known genetic variants could predict the onset, persistence, and severity of the disease, said researcher Daniel W. Belsky, PhD, of the Duke University Center for the Study of Aging and Human Development.
Belsky and colleagues from Duke and several other institutions constructed a genetic risk score based on 15 of the SNPs and then tested their predictive accuracy in 880 adults enrolled since birth in a longitudinal health and behavior study. All the participants were born between April 1972 and March 1973 in Dunedin, New Zealand.
When SNPs were selectively dropped from the scoring model one by one, no single SNP was found to account for a disproportionate share of the genetic-risk-score for asthma.
And family history of asthma was only weakly related to genotypic risk. Genotype-based and family-history-based measures were found to provide similar amounts of information about asthma risk, but having a high family history score did not predict a high genetic score.
"This lack of concordance between genotypic and family-based risk assessment is not unique to asthma," the researchers wrote. "We previously noted this finding in patients with obesity and smoking problems, and others have reported similar results for some patients with cancers."
They suggested that family history scores may capture not only genetic risk, but shared environmental risk and other interactions as well.
Among the other significant findings: Both males and females with higher genetic risk scores had a greater asthma risk over the 38 years of follow-up (HR 1.12, 95% CI 1.01-1.26), and they developed asthma earlier in life (HR 1.17, 95% CI 1.01-1.34) compared with those with lower scores. The 305 (35%) study participants who developed asthma over the course of the study were at higher risk for atopy at ages 13, 21, and 32 years of age if they scored high on the genetic risk assessment. High-scoring patients also had raised serum IgE concentrations (r
=0.13; P=0.02) at ages 11, 21, and 32. Lung function analysis showed persistent increases in airway hyper-responsiveness to methacholine or albuterol in the high scorers, which persisted across nine time periods between the ages of 9 and 38 years. High-scoring patients also had poorer lung function, as measured by post-albuterol ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) (r=0.13; P=0.03).Over 3 decades of follow-up, asthma patients with higher genetic risk assessment scores missed more days of school or work due to asthma symptoms than those with low scores (incident rate ratio 1.38, 95% CI 1.02-1.86) and were more likely to be admitted to hospitals for breathing problems (HR 1.38, 1.07-1.79).
Although the effect sizes seen for most of the tested outcomes were small, Belsky said it was "far from trivial" that high genetic risk scores were associated with a 36% increased risk for life-long, persistent asthma.
"The effect sizes we saw were well below the threshold for a diagnostically valid test, and we aren't proposing that people go out and get their children tested," he told MedPage Today.
"But the flip side is, the effect sizes we observed are entirely in line with other biomarkers assayed in the clinic."
He said it would be difficult to predict how long it will be before genetic risk assessment will be used by clinicians to predict who will develop asthma or how asthma patients will progress or respond to treatments.
"From where we are today it looks like this is at least 10 years down the road, but who knows? It could be 6 months," he said. "We are starting to break down some of the barriers to our understanding of how genome sequence relates to disease, but a critical piece of the puzzle that is still missing is how genes interact with the environment."
The study received grant support from the U.S. National Institute on Aging and the U.K. Medical Research Council. Additional funding was provided by the Jacobs Foundation.
