By David N. Leff
Guilt by association is frowned upon as a basis for prosecuting a suspected criminal. But in prosecuting a search for the suspected perpetrator of an inherited disease, it's a method of choice.
Multiple sclerosis (MS) is a case in point.
Except for trauma (i.e., accidents and violent assault), MS is the leading cause of acquired neurologic disability in Caucasian adults. Tracking down its guilty gene or genes involves analyzing the DNA of affected individuals and seeking associations between suspect chromosomal variations and maverick genes of the immune system that encode antigens capable of triggering autoimmune diseases.
In MS, suspect antigens such as MBP (myelin basic protein) savage the nerve cells of the brain and spinal cord, stripping them of their protective myelin insulation. In consequence, MS victims suffer dysfunction of organ systems all over their bodies, from eyes to limbs to mentation.
Unlike many inherited syndromes, MS is far from rare. Worldwide it afflicts an estimated 3 million to 3.5 million men and women, a tenth of them — 350,000 — in the U.S. This latter number increases by 200 newly diagnosed cases per week, or 10,400 a year.
Nor does MS end with a mercifully prompt death. It shows up for positive diagnosis around the ages of 20 to 40, and gets slowly worse through an entire lifespan — but with frequent spontaneous remissions.
Whatever rogue molecule chews up the myelin coating on MS nerve cells is acting out the drama of autoimmunity: it mistakes the myelin for an alien substance, rather than part and parcel of the body's own self.
Lurking behind this molecular mayhem is an enormous array of genes on human chromosome 6 — the major histocompatiibility complex, or MHC. It's also known as HLA, for human leukocyte antigen. One stretch of this sequence, Class II HLA, specializes in warning the immune system that a non-self antigen, such as a microbe, has invaded the body. Among the cluster of genes that carry out this mission control operation is one called HLA-DR2.
"DR is an antigen expressed on MS nerve cells," said genetic epidemiologist Jonathan Haines, "where it helps with the autoimmunity. Exactly what's going on there, nobody knows, although its immune function makes sense.
"So if something foreign shows up in the body," he explained, "and it doesn't display the antigens that the immune system recognizes — doesn't have the HLA-DR2 or whatever — that tends to trigger an immune response. The basic idea is that somehow the body is not recognizing itself as self, so is starting to attack itself. In other words," he added, "we have met the enemy and it literally is us."
Closing In On MS Gene Loci
Haines — an associate professor of human genetics at Vanderbilt University, in Nashville, Tenn. — is lead author of a paper in the August issue of the journal Human Molecular Genetics (Oxford University Press) titled "Linkage of the MHC to familial multiple sclerosis suggests genetic heterogeneity." Molecular geneticists from the three academic centers in the U.S. constituting the Multiple Sclerosis Genetics Group collaborated on this guilt-by-association DNA analysis.
"Our major finding," Haines told BioWorld Today, "is that the linkage we see in the region of MHC seems to be due primarily, if not entirely, to a specific allele [chromosomal contribution of one parent] of a gene that resides, perhaps, on the HLA-DR2 extended haplotype.
"It may not be DR2 itself," Haines added, "but there is a lot of linkage disequilibrium going on in this region — which means that whole sections of the chromosome are being inherited together, through many, many, many generations. So there are a lot of genes on that particular segment, and we don't know yet which gene it is. But now," he went on, "we're pretty convinced that's where we should be looking —on that haplotype."
To get this far in their ongoing MS gene hunt, the co-authors assembled 255 MS-affected members of 94 families, and divided them into two equal cohorts.
"We wanted to find linkage to the HLA region, and then see if it was caused by the HLA-DR2 association," Haines explained. "That's why we split the families into two groups, one with HLA-DR2 and the other without. And all the linkage information in the HLA-DR2-positive families suggested that it is in fact the association with the HLA-DR2 antigen that's important.
"And that in turn suggests that whatever MS-predisposing gene exists, exists on the HLA-DR2 extended haplotype."
The results of their DNA analysis confirmed his suggestion that HLA would show linkage. "It did so quite strongly, at least in these families," Haines recounted. "In fact, more strongly than most people had seen in other studies. Some hadn't seen it at all. The results also verified the specific HLA-DR2 association that most people had seen."
Are Sporadic And Familial MS One And Same?
Like breast cancer, for example, MS comes in two pursuasions, familial and sporadic. That is, inherited, or apparently arising de novo.
"It's been recognized for a very long time," Haines pointed out, "that in some cases, MS tends to cluster in families."
"As we showed in a different paper earlier this year," he went on, "when we looked at a lot of the clinical parameters we found no difference between familial and sporadic MS; no reason to believe that the underlying etiology is any different."
In fact, Haines suggested that what passes for sporadic MS may merely reflect the inability so far to pin down its gene connection. "It's my bias," he observed, "— and I do have a bias here — that a lot of what we view as sporadic MS has a genetic component to it. It's just that the genetic risk factors involved are not showing up — for whatever reason — in the other members of the family."
He made the point, "We are making progress in dissecting the genetics of MS. We've defined what's going on with the HLA region. We know it's not the whole story. And I think there are multiple other genes involved, not all of them on chromosome 6 either. They're all over the place. We've got some evidence for chromosomes 9, 10, 11 and 12; one region on each.
"Some of these genes may be interacting with each other," he surmised. "You may have to locate whatever gene it is on chromosome 6 in the HLA region and whatever is on 9, for example, in order to determine an elevated genetic risk of MS.
"But there are still other genes to be found out there," Haines observed. "We need to search through perhaps 100 genes to find them. And that," he concluded, "is what we're spending most of our time on now." *