A genetic origin of the demon itch

One problem with writing a blog is that you write each post separately. It's hard to keep a grand plan in mind and so, even if you think you're focused enough (e.g. eczema research and what it's like to live day-to-day with the condition) you keep getting buffeted around by the news of the day. Such as that PLoS ONE report I wrote about on Thursday.

Hidden B tells me I ought to follow up on some of the promises I made earlier on-- such as to look more deeply at filaggrin and heritability-- and that this would make for a less disjointed read. What Hidden B wants, Hidden B gets.

Two journals in particular have begun to emerge for me as great sources of information about genetics, allergy, and eczema research. There's the Journal of Allergy and Clinical Immunology, of which Donald Leung is the editor. Leung is the scientist leading the Atopic Dermatitis Research Network, funded by $32M from the NIH. So it's no surprise that his journal publishes some good, relevant research. I've read a few papers from the journal and have been impressed by the quality of the work and the writing-- and, believe me, you can't say this about every journal.

Look up "filaggrin" in Wikipedia. The first reference for the entry is a paper from J Allergy Clin Immunol. It's a great introduction to filaggrin and how it may be at the root of a large number of family-related eczema cases. This paper (Weidinger et al.) references a number of papers from Nature Genetics; the most important ones are from 2006, when, it appears, two overlapping groups reported finding loss-of-function mutations in the filaggrin gene that are associated with eczema. Filaggrin looks guilty to me. (See fascinating blog entry in the Nature system.)

But, as anyone with eczema knows, it's a complex condition; the underlying science appears just as complex. Weidinger et al. analyzed 476 German families: from each family, the parents and one child with AD. I haven't digested the paper fully; but of the 476 kids, roughly one-quarter had one of the two known loss-of-function filaggrin mutations. So there are evidently other molecular causes of eczema. Maybe there are yet-unmapped filaggrin mutations. Maybe there are mutations of other genes that screw up the same processes as mutated filaggrin. There are probably many, many paths to the same end.

What is filaggrin? It's a protein product of the FLG gene on the q-arm of chromosome 1. The gene itself is complicated, which is why scientists took a long time to sequence it. I look forward to learning more!

FLG is expressed as profilaggrin, a larger protein, in skin cells in the lower levels of the epidermis. As the skin cells move toward the stratum corneum, they start expressing different proteins and making lipids and other molecules to form barrier impermeable to pathogens such as viruses and bacteria. When skin cells reach their final state, before they slough off as skin flakes, the profilaggrin is chopped up into small bits called peptides, and these filaggrin peptides bind filaments of keratin inside the cells. The filaments then get cross-linked by enzymes--something like the way fiberglass and resin combine to make one godawfully tough material.

If you have a mutation in your filaggrin gene (these mutations appear to be dominant, from what I can tell) then your skin has a crappy fiberglass coating instead of a smooth, impermeable one. It lets water out; it lets pathogens and allergens in.

This skin defect may be at the root of eczema. As a baby, if your skin is defective, it lets in viruses and allergens, which induce inflammation. And then because of the chronic inflammation, you then develop the allergies and sensitivities that later manifest as the confusing food-, aero-allergen, and stress-related flareups of classic eczema.

So why does eczema affect 20% of children, and then mostly disappear--though not for me, nor 2% of adults? What happens as kids grow up?

Fascinating stuff! You can't blame the scientists for being interested. I just wish the problem was purely academic.

If only Justin Bieber had eczema

If you want a blog to succeed, it's not enough just to write it--this has to be obvious to anyone who's tried. It's not enough to find a compelling topic and write thoughtful essays or even pop-eyed political rants. You have to connect to your audience and sell your blog.

I find self-promotion is about as fun as standing up in front of the class in sixth grade to give a presentation on newts. Fortunately, technology has made it slightly easier for people like me. There's Twitter, my main marketing tool until Google and Technorati finally register my existence. I tweet every post to this blog. And on Twitter, you get followers in a sort of pull-yourself-up-by-the-bootstraps method: you follow other people and hope they follow you back. To find people who might be interested in this stuff, I search for Twitterers whose posts include the word "eczema."

About 80% of these posts are from news outlets still regurgitating the cats-vs-dogs story of a couple weeks ago, or from sites claiming to have the miracle cure that will banish your eczema forever if only you dose yourself with primrose oil or cod livers or some homeopathic bullshit. There are people out there, though, who are bold enough to announce their current eczematous state to their 1,200 friends. (I should be so lucky to have 1,200 friends.) Most of these people are evidently aged 16-20, based on their tweetline: "Lord what my teacher talking about now"; "I am living in the library. Again :o/"; "Math homework can go away forever" and updates about the haircut of some guy named Justin Bieber.

And at least half of them are African-American. Possibly not the ones tweeting about Justin Bieber. This was a surprise to me. I'm Caucasian, of Swiss-German descent, and naturally, thinking it's all about me, I assumed that Swiss Germans had some monopoly on eczema. I've never seen an African-American with eczema. But then-- I rarely see anyone with eczema. Is this because we all cover up or stay home when we have flare-ups?

There's an interesting academic study recently out that describes eczema prevalence in children across the United States. (Haven't found good data on adults yet.) To quote the abstract: "Black race...significantly associated with a higher prevalence of eczema." Many other factors, too, of course. Even more interesting: prevalence was virtually identical for subjects of black or "multiple" race. Fascinating-- I had assumed that the history of eczema in my family was due to us coming from a region where people of similar heritage have been interbreeding for hundreds of years and keeping recessive genes in the population. I figured that what we needed to eradicate the disease was a few generations of vigorous outbreeding (OK, perhaps time to stop talking like a rancher). But, apparently, that wouldn't necessarily solve the problem.

Eczema, a family affair

Did I mention that eczema runs in my family? Those that I know for sure have it, or had it, are my father's father (deceased), whose scratching and ill temper were legendary; a cousin; my sister; me; and my daughter Voov.

My grandfather was a sea cook and a veteran of World War I. His life was hard and eczema didn't make it any easier. Then eczema skipped a generation, fortunately for my parents, and in the interim science and medicine made great improvements in emollients and steroids. We've had it much better than he did. But let's not have the impression the problem is solved. I believe some day we'll have complete control over the demon itch.

Our family probably shares a filaggrin mutation. Ten years from now, when you can get your genome sequenced for a hundred dollars, I bet that's what we're going to find. In future posts I'm going to explore what filaggrin does, or in our case doesn't do, for skin. And I'm going to ask the scientists studying filaggrin how they think their discoveries might lead to therapies or cures.

This blog is soon going to become, like eczema, a family affair. I've invited my sister to contribute posts. She's a resident or whatever you call someone who is undergoing the legalized hazing that the medical establishment enjoys inflicting after you graduate with an MD. She'll add medical legitimacy. She gets to pick her own moniker--hopefully not something to do with ferrets (she doesn't have kids at the moment, just pet ferrets). Until then, I'll call her Dr. Sis.

Dr. Sis lives in Newfoundland. So this blog is a California-Newfoundland axis. We can speak with authority on both endless summer and endless winter. The mind boggles to realize that the two regions share a continent and a language--though the latter is debatable, if you've ever met a real Newfie.