An international consortium led by researchers at Baylor College of Medicine have gotten closer to understanding why some people are more susceptible than others to frequent painful or chronic middle ear infections. As described in an article published in the June 29, 2015 issue of Nature Genetics, the culprit may be a rare genetic variant in a gene called A2ML1.

Regie Lyn Pastor Santos-Cortez, MD, PhD

Regie Lyn Pastor Santos-Cortez, MD, PhD, Baylor College of Medicine

Baylor College of Medicine announced that studies led by Regie Lyn Pastor Santos-Cortez, MD, PhD, assistant professor of molecular and human genetics at Baylor, uncovered the gene variant during an investigation of the genetic components of otitis media, or middle ear infections.

According to Baylor, in addition to being a genetics researcher, Santos-Cortez has practiced as an otolaryngologist in her native Philippines. As a post-graduate, Dr Santos-Cortez went on a medical missionary trip to an indigenous Filipino community in an area of her country where most of the people were related. While there, she created a family tree or pedigree that identified, among other things, who within the same community suffered from recurrent ear infections and who did not.

This pedigree served as a resource for Dr Santos-Cortez when she began investigating the role of genetics in middle ear infections. Dr Santos-Cortez found that everyone in the large pedigree she had created had a similar socioeconomic status, swam in the same sea water, were or had been mostly breastfed, ate the same food, and had the same exposure to cigarette smoke.

She determined that it was unlikely there was an environmental factor causing the middle ear infections in the indigenous population. Next-generation sequencing allowed her to determine the genetic sequence of several people in the population, which eventually enabled her to identify the gene involved in otitis media. Within the indigenous community, she found that 80% of those who carried the variant in the A2ML1 gene developed otitis media. She later found the same gene variant in three otitis-media-prone children in a population in Galveston, Texas.

Thus far, Dr Santos-Cortez and her colleagues have identified this rare genetic cause for susceptibility to middle ear infections in 37 Filipinos, one Hispanic-American and two European-Americans. It is likely that the variant has been present in the populations in the Philippines and Galveston at least 150 years and may even be the result of a “founder” effect, which suggests one person from outside the population, most likely from Spain, brought the gene variant into the two populations.

Additionally, rare A2ML1 variants were identified in six otitis-media-prone children who were Hispanic- or European-American, and none of these variants occurred in thousands of individuals without otitis media.

Dr Santos-Cortez suspects this is not the only gene involved in predisposing children to middle ear infections, but it could be an important one. The protein involved may play a role in the immune system that protects the ear. Perhaps the variant somehow derails the protection that the protein should be providing. Another gene called alpha 2-macroglobulin or A2M, which encodes a protein that is found at high levels in very infected ears, is formed in such a way that it can trap proteases, enzymes that can kill infectious microbes but can also damage the mucosa of the middle ear if left unchecked.

Because the protein sequences of A2M and A2ML1 are nearly identical, they may have similar or overlapping functions and one might compensate for the other when it is non-functional. An antibiotic called bacitracin is reportedly used in drop form to treat middle ear infections in Europe. However, because bacitracin dampens the effect of A2M, it may not be the best treatment for people who have genetic variants in A2ML1.

Further studies may uncover the mechanism by which A2ML1 variants cause susceptibility to otitis media, and may help determine alternate treatments.

“There are many other antibiotic drops on the market,” said Santos-Cortez.

Source: Baylor College of Medicine

Photo credits: Baylor College of Medicine; © Dayna More |