The Value of FLG Null Mutations in Predicting Treatment Response in Atopic Dermatitis: An Observational Study in Finnish Patients

Abstract

The contribution of filaggrin null mutations to predicting atopic dermatitis (AD) treatment response is not clear, nor have such mutations been studied in the Finnish population. This study tested the association of the 4 most prevalent European FLG null mutations, the 2 Finnish enriched FLG null mutations, the FLG 12-repeat allele, and 50 additional epidermal barrier gene variants, with risk of AD, disease severity, clinical features, risk of other atopic diseases, age of onset, and treatment response in 501 patients with AD and 1,710 controls. AD, early-onset AD, palmar hyperlinearity, and asthma showed significant associations with the combined FLG null genotype. Disease severity and treatment response were independent of patient FLG status. Carrier frequencies of R501X, 2282del4, and S3247X were notably lower in Finns compared with reported frequencies in other populations. This data confirms FLG mutations as risk factors for AD in Finns, but also questions their feasibility as biomarkers in predicting treatment response.

Clinical Characteristics and Genetic Variations in Early-Onset Atopic Dermatitis Patients

“…It is suggested that the onset age of AD is not deci- sively determined by AD-related genetic variations. FLG mutations are associated with earlier AD onset in previous studies 15,17,18 . Patients with major genetic risks develop symptoms earlier, but in patients whose genetic susceptibility is not prominent, the disease probably initiates later and prolonged environmental exposure is needed to fully develop AD 24 .…”

“…Genetic variations play a significant role in AD occurrence 14 . Some studies have attempted to identify genetic variations that can predict early AD development and have reported that FLG mutations are associated with an earlier onset 2,[15][16][17][18][19] . Dežman et al 20 suggested that polymorphism rs2303067 in SPINK5 is associated with early-onset AD, whereas Heo et al 21 reported that COL6A6 poly-morphisms are novel candidate variants in early-onset AD.…”

Filaggrin Polymorphisms and the Uptake of Chemicals through the Skin—A Human Experimental Study

“…Indeed, it would be interesting to investigate whether a high CNV in the wt allele could to some degree compensate for the partial loss of functional FLG in heterozygotes carrying a wt allele and a FLG null allele. Low CNV is frequent in the European population (CNV10 allele frequency around 30%) Liljedahl et al 2019;Luukkonen et al 2017;Wahlberg et al 2019) and the contribution of CNV to dermal barrier function should be studied further.…”

Epidermal Barrier Dysfunction in Atopic Dermatitis

“…89,[92][93][94] Variants of claudin-1 gene (CLDN1) have been associated with AD risk in an African-American cohort, 26,89 early onset AD in an Ethiopian cohort, 95 and AD with specific IgE to environmental molds, 96 but not in a Finish cohort. 51 There is also evidence that levels of claudin-4, claudin-23 and ZO-1, may be decreased in some AD patients. 89,94 As for filaggrin and lipid lamellae, TJs influence and are influenced by the immune response, although contradictory results have been reported.…”