Novel loci affect asthma treatment response in children of African descent
By Eleanor McDermid, medwireNews Reporter
Researchers identify novel loci that may contribute to the success of asthma treatment in children of African descent, but find these differ between adolescents and younger children.
The study, published in The Lancet Child & Adolescent Health, is by Victor Ortega (Mayo Clinic, Scottsdale, Arizona, USA) and colleagues, who drew on data from 249 children (5–11 years) and 267 adolescents and adults (12–69 years) with asthma who participated in the Best African Response to Drug (BARD) trials.
In these randomised crossover trials, participants with uncontrolled asthma on fluticasone propionate 50 μg (for children) or 100 µg (for adolescents and adults) were stepped up to either a 2.0–2.5 times or 5.0 times higher dose, with or without the long-acting beta agonist salmeterol at 50 μg twice daily.
The trials showed no overall association between African ancestry (at least one grandparent) and treatment response, but did reveal a potential association between a higher proportion of African ancestry and increased risk of asthma exacerbations.
In this latest analysis, Ortega and team used established genetic ancestry data to look at how genetic variants throughout the genome derived from a common African ancestry might influence asthma treatment response.
In children, they identified two loci associated with a better response to a 5.0 times higher fluticasone dose combined with salmeterol than to the original low-dose fluticasone. One was located on chromosome 6 and mapped to two intronic variants within the SYCP2L gene and the other was on chromosome 12 and mapped to variants adjacent to RNFT2 and NOS1.
An additional locus on chromosome 6 – mapped to a variant between EDN1 and PHACTR1 – was associated with having a better response to a 5.0 times higher than a 2.0 times higher fluticasone dose.
These associations were not present in the adolescent and adult trial participants, however. Instead, the researchers identified a locus on chromosome 22 that was associated with a better response to a 5.0 times higher than a 2.0 times higher fluticasone dose. This mapped to two polymorphisms adjacent to TPST2.
Finally, using data from two independent African–American cohorts, the team was able to replicate the associations for a variant adjacent to TPST2 and nominally replicate that for a variant adjacent to RNFT2.
In a linked commentary, Elin Kersten and Gerard Koppelman, both from University Medical Center Groningen in the Netherlands, note the need for larger prospective studies to confirm the findings, as well as for functional genetic studies to determine which genes the variants regulate, and show how “these genes interact with asthma treatments”.
They stress: “Again, samples from patients of African descent are under-represented in databases that report the functional effects of genetic variation. Thus, future functional studies also need to prioritise inclusion of minority populations.”
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Lancet Child Adolesc Health 2021; 5: 862–872
Lancet Child Adolesc Health 2021; 5: 838–839