Researchers home in on interstitial cystitis genes

San Antonio-With new technology that performs large-scale genotyping, researchers are homing in on the genes responsible for interstitial cystitis. It won't be long before they know what those genes are, and a specific drug target or even gene therapy for IC could soon follow.

Researchers in the United States as well as Dr. Dimitrakov and his European colleagues have already found higher rates of IC in monozygotic twins than in dizygotic twins of patients and clustering of IC in families, suggesting IC has a genetic basis.

"An autosomal dominant pattern for IC is a rare find," Dr. Dimitrakov told Urology Times. "It actually gives you a better chance of finding the gene."

Sequencing first candidate

He and his colleagues have been seeking the genes in these families using the Affymetrix GeneChip Human Mapping 10K Array, which quickly maps large portions of the genome and identifies the locations of single nucleotide polymorphisms (SNPs)-one-nucleotide differences in DNA base pairs at same locations from different subjects. Linkage analysis then identifies the location of the SNPs held in common among family members with the disease versus those who don't have it and calculates the probability that the commonalities are beyond chance. Those locations identify the chromosomes where the candidate gene or genes lie.

So far, Dr. Dimitrakov and the team have analyzed DNA from four large families with inherited IC. Two of those families share a common linkage peak on chromosome 1. That commonality is highly significant. With linkage analysis, probabilities are expressed as a logarithm of the odds, and scores from multiple families can be added. A score of 3.3 is the accepted threshold, which corresponds to p=.05. In these two families, the combined LOD score is well beyond that at 4.85, which corresponds to p=.001, according to Dr. Dimitrakov.

The affected members of both families share the same genetic signature across five SNPs in the overlapping portion of the peak, which spans 13 genes on chromosome 1. That's where the team is looking for candidate genes. In fact, they are now sequencing the first candidate.

Two other families show evidence of linkage at two other locations elsewhere in the genome, although without LOD scores exceeding 3.3. The three linkage peaks the researchers have found imply that at least three genes are involved in IC, which fits with the current thinking that IC is a heterogeneous disease, noted Dr. Dimitrakov.

"The three genes, however, may actually be involved in a single pathway," he said.

That finding would parallel that of genetic research on familial Alzheimer's disease in an isolated population, where researchers thought they were looking for a single gene and instead found three that were involved in a single chemical pathway.

These three locations in the human genome linked to IC are not near where the frizzled 8 protein is thought to be coded. Antiproliferative factor (APF), the peptide unique to IC patients' urine and implicated in the IC disease process, is part of that protein. But that doesn't mean that either this or APF research is on the wrong track. In fact, Dr. Dimitrakov noted, these three potential genes may even be responsible for transmitting a signal from APF inside a cell, turning it into an IC cell.