Some call eczema the itch that rashes. In the nearly 1 in 5 children who have eczema or atopic dermatitis (the other name), this skin condition can range from annoying to life-changing. Scientists have long recognized that eczema goes deeper than just redness and dry flaky skin. In various research the concept of leaky skin keeps rearing its head. In epidemiologic studies, eczema and its family of allergic diseases like asthma and allergic rhinitis cluster in family trees. The exact expression of allergic response may vary from eczema in one sibling to asthma in another, but when taken as a group, these diseases clearly follow family trees. Combining these concepts together prompted researchers to search for those genetic markers to both understand the disease better and find better therapies against it.
A recently published study from the National Institute of Health by Mariana L. Stevens and others built on prior studies linking a KIF3A gene (Kinesin Family Member 3A) with allergic disease by uncovering the likely mechanism by which the resulting protein contributed to the development of asthma and eczema. The kinesin protein was known to be a component of cilia, a cell appendage that can be used for cell movement or movement of mucous on the surface of tissues. Other studies revealed that some of the single nucleotide changes in the gene’s DNA led to gene sites where increased methylation could occur (call CpG sites). Increased methylation would turn the gene off and decrease the amount of protein produced.
Mariana L. Stevens group found that mice with these gene changes showed an increased loss of water across the skin, suggesting some type of skin barrier disruption. They then searched for the mechanism by which the KIF3A genetic change could cause such disruption. Their research indicated “dysregulation of adherens and tight junction markers, E-cadherin and claudin-1, respectively” as likely underlying the problem. Basically, it appears that lower amounts of KIF3A production leads to dysfunction of tight junctions between cells which leads to leaky skin losing water. The water loss creates drier skin which is more susceptible to allergen triggers.
While they did not fully explore the next connection, they did mention that the KIF3A gene is located near the IL4 (interleukin 4) and IL 13 (interleukin 13) genes. These two immune messengers (cytokines) participate in activating the Th2 response of the immune system. This Th2 arm is responsible for allergic responses while the Th1 arm activated by different cytokines deals more with microbial responses of the immune system. Further research will be needed to determine if the IL4 and IL13 genes are turned up by these same changes which turn down the KIF3A.
In functional medicine, we already incorporate an in-depth family history looking for allergic tendencies when caring for patients with eczema or asthma or other allergic conditions. We appreciate research like this which highlights the growing prevalence of allergic disease and offers mechanistic explanations. By better understanding the mechanisms, we can better target the root causes like leaky tissues. In this situation, addressing leaky gut with gut healing therapies, addressing inflammation that worsens the Th2 response, and improving skin barrier function, we can achieve deeper and more long-lasting success. In other words, we can target root causes as we strive for patients to have healthier, more abundant lives.
Mariana L. Stevens, Zhonghua Zhang, Elisabet Johansson, Samriddha Ray, Amrita Jagpal, Brandy P. Ruff, Arjun Kothari, Hua He, Lisa J. Martin, Hong Ji, Kathryn Wikenheiser-Brokamp, Matthew T. Weirauch, Dorothy M. Supp, Jocelyn M. Biagini Myers, Gurjit K. Khurana Hershey. Disease-associated KIF3A variants alter gene methylation and expression impacting skin barrier and atopic dermatitis risk. Nature Communications, 2020; 11 (1) DOI: 10.1038/s41467-020-17895-x
Thanks to Science Daily:
NIH/National Institute of Allergy and Infectious Diseases. “Scientists demonstrate how genetic variations cause eczema: Finding could lead to genetic tests that identify infants at risk for the disease.” ScienceDaily. ScienceDaily, 14 August 2020. <www.sciencedaily.com/releases/2020/08
Other articles mentioned:
1 in 5 children have Eczema
Weidinger, S. & Novak, N. Atopic dermatitis. Lancet 387, 1109–1122 (2016).
CpG site methylation and gene expression:
Zhi, D. et al. SNPs located at CpG sites modulate genome-epigenome interaction. Epigenetics 8, 802–806 (2013).
Shoemaker, R., Deng, J., Wang, W. & Zhang, K. Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome. Genome Res. 20, 883–889 (2010).
Eczema and other genetics:
Lepre, T. et al. Association of KIF3A, but not OVOL1 and ACTL9, with atopic eczema in Italian patients. Br. J. Dermatol. 168, 1106–1108 (2013).
Hirota, T. et al. Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nat. Genet. 44, 1222–1226 (2012).
Kim, M. et al. Corrigendum: KIF3A binds to beta-arrestin for suppressing Wnt/beta-catenin signalling independently of primary cilia in lung cancer. Sci. Rep. 7, 46773 (2017).
Kovacic, M. B. et al. Identification of KIF3A as a novel candidate gene for childhood asthma using RNA expression and population allelic frequencies differences. PLoS ONE 6, e23714 (2011).
Michel, S. et al. Unifying candidate gene and GWAS approaches in asthma. PLoS ONE 5, e13894 (2010).
Johansson, E. et al. KIF3A genetic variation is associated with pediatric asthma in the presence of eczema independent of allergic rhinitis. J. Allergy Clin. Immunol. 140, 595–598 (2017).
Marenholz, I. et al. Meta-analysis identifies seven susceptibility loci involved in the atopic march. Nat. Commun. 6, 8804 (2015).
Sanctuary Functional Medicine, under the direction of Dr Eric Potter, IFMCP MD, provides functional medicine services to Nashville, Middle Tennessee and beyond. We frequently treat patients from Kentucky, Alabama, Mississippi, Georgia, Ohio, Indiana, and more... offering the hope of healthier more abundant lives to those with chronic illness.