By David N. Leff

Try this multiple-choice quiz: The best guesstimate as to the number of people in the world who suffer from leprosy (Hansen's disease) is (a) 1 million; (b) 500,000; (c) 55,000; (d) 11.5 million.

The World Health Organization's answer is (d).

"Leprosy is still a substantial public health problem," observed Oxford University immunologist and geneticist Adrian Hill. "And even though we're doing very well in terms of treating existing patients, and the treatment has improved greatly over the last 10 years, what hasn't changed is the incidence of the disease.

"In other words," he pointed out, "we're seeing as many new cases today as we were five years ago. So we're not getting any reduction in the emerging patient population. Leprosy," Hill explained, "caused by Mycobacterium leprae, is like its close bacterial relative, Mycobacterium tuberculosis, in the sense that the great majority of people who get infected by the leprosy bug don't develop the disease. They become either latent carriers of the bacteria or they simply cure it - using their immune system."

"The small percentage of people who become infected," Hill continued, "end up getting the disease. And that's always been one of the puzzles: What's different between those few and the majority who shrugs it off and is fine? Part of the answer," he answered, "is genetics."

Hill is senior author of a paper in the April issue of Nature Genetics, titled: "A major susceptibility locus for leprosy in India maps to chromosome 10p13."

"What we are reporting here," he told BioWorld Today, "is that we've managed to find the location of the major gene affecting susceptibility to leprosy in this Indian population. And that gives us a clear idea as to where it is on the human genome. But it doesn't tell us what it is. That will require some further work. But now it really does open the door to being able to find this gene, identify it and understand how it works.

"Susceptibility," Hill defined as, "just meaning that people with this particular gene variant are more likely to develop leprosy than people without it."

It Takes A Parent Or Two

"What we did," he recounted, "was work with our collaborators at Madurai Kamaraj University in the heart of South India, where there's a great deal of leprosy. Our objective was to find families with the disease. So we went working with the teams who screened people in villages to find those with leprosy. That meant checking the household, checking that there isn't anybody who's come into contact with them and developed leprosy as well. And picking out those families where there were at least two members infected with leprosy.

"Then," he went on, "we asked them to participate in the study by giving a blood sample that would allow us to look at their genes, and do a genetic analysis of the family. We ended up with 224 families, a very large number, which included in total 245 pairs of siblings. A pair means both individuals are affected by leprosy.

"We recruited any sibling pair, whether they were children or adults," Hill said. "And what we were very successful in doing was finding their parents, because to do the analysis with the greatest statistical power it's helpful to have not only the affected pair of siblings but their parents, so we can track the inheritance of those genes from parent to child.

"Leprosy often appears in childhood," Hill explained, "and unless it's treated once it's appeared, it's unusual for it to disappear. There are two types of leprosy, one more severe that the other."

The commoner, less severe type is called tuberculoid leprosy, which generally manifests itself by a pale color change in the skin and the loss of sensation. The bacillus grows in the skin and in the nerves. So loss of sensation is one of the big problems in leprosy. People can end up having no sensation in a limb near the fire, and burning themselves.

"Then there's the more severe type, lepromatous leprosy, where there's a much higher number of bacteria in the skin than in the milder type," Hill said. "That tends to generate a lot of deformities, a lot of nerve damage, and is the traditional horrifying image that people have of a leper. Even though we can treat them now and kill the bacteria, that doesn't improve the deformities or damages that have been done.

"It was quite a substantial effort," Hill recalled, "the biggest study of disease genetics of this type. We then analyzed that DNA by looking for genetic markers through the genome, from all 23 chromosomes, and asked if there was any significant genetic linkage of particular markers of disease. The answer was that on a particular segment of chromosome 10 we saw very striking, very strong, very statistically impressive signals. We've been able to narrow down that region to a manageable size, and now we're working on that genomic neighborhood to see if we can localize the relevant susceptibility gene."

Gene: From Neighborhood To Neighbor

"We would estimate," Hill pointed out, "that there are at least 50 genes in that region. And we have to tease out which one it is. What's been very helpful," he added, "is that over the last year emerging information on the sequence of our chromosome was revealed by the genome projects just a month or so ago.

And even more valuable, he said, were single nucleotide polymorphisms to fine-map that region. "These SNPs couldn't have arrived at a better time for people in our situation," Hill remarked. "We're spending a lot of time and effort trying to figure our exactly which gene on chromosome 10 it is."

Once this gene is nailed down, Hill foresees several lines of clinical application.

"The immediate application," he suggested, "would be to understand how that gene works. Our best guess is that this will somehow affect the immune response - particularly its cellular arm - to the leprosy bacillus. The big hope here is that what we learn will be relevant not just to leprosy but also to TB, and possibly other intracellular pathogens, maybe viruses. And that may have immediate applications for vaccine design. More generally," he concluded, "it may give us clues to pathways that are involved in antimycobacterial immunity, which would lead eventually to new drug targets." n

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