BARCELONA, Spain—The ability to quickly assess up to 1 million genes in an individual patient opens new vistas for clinical application, but too few of these biomarker and genotype possibilities have been validated for clinical use, Peter K. Gregersen, MD, told the opening plenary of the 2007 EULAR meeting.¹ Dr. Gregersen is director of the Robert S. Boas Center for Genomics and Human Genetics at the Feinstein Institute for Medical Research, in Manhasset, NY, and professor of medicine and pathology at New York University School of Medicine, in New York City.

"With a biomarker, you are a beggar. With a cohort, you are a king," Dr. Gregersen said. "We do not have the population organized to test these biomarkers or genes yet. We should do no clinical trials without genetics."

Predicting that the next 12 months will be "a watershed in genetics," Dr. Gregersen pointed to two important factors. "First, there are no perfect human specimens. All of us carry a number of DNA glitches, and the genome is continually adjusting to a changing environment," he said. "Second, virtually all diseases except trauma have a genetic component."

Scanning the genetic barcode

In rheumatology, the two fundamental questions are why B-cells produce autoantibodies and why T cells destroy tissue. Dr. Gregersen said that 50 to 100 common genetic variants, including those in HLA, PTPN22, CTLA4, IL23 and IL12, STAT4, TRAF1, and PTPN2, are being studied for their association with changes in risk of autoimmune disease.

The International HapMap, a haplotype mapping project, has shown that haplotype variations tend to occur in groups, forming a genetic "barcode" of blocks of DNA. Dr. Gregersen said that it is now technologically possible to tag single nucleotide polymorphisms (SNPs) and use, for instance, the Illumina BeadScanR whole genome DNA array and very high throughput technology to search for patterns of SNP halotypes associated with a specific disease.

"This technology has really exploded," Dr. Gregersen said. "Three years ago I would have been proud to say that we did 1 million genotypes in a year. Today I have three people working on this who routinely do 300 million genotypes per week. The cost for doing 1 million genotypes on a single individual is in the $500 to $1000 range, and you can go on the Web today and have it done for yourself."

At this pace, an analysis of 100 million genotypes will be enough to capture all the relevant genotypes for an individual. "We are about to be inundated with data, and the challenge will be interpreting it," Dr. Gregersen pointed out.

Different genetic influences at different stages of disease

Different genetic influences effect different stages of disease (susceptibility, preclinical, or clinical). "The question is whether genetics is not only a discovery tool but also ‘actionable'—something that will change the behavior of doctors, patients, or both," he said. Moving to action will require interpreting genetic data in the context of the disease life cycle, integrating genetic information with other clinical information, and meeting the increased demands on physician and patient for interpreting new information about risk. Ultimately, he foresees practical clinical use of genotype information in assessing disease susceptibility (the presence of shared epitope alleles) and environmental factors (smoking), in identifying both patients at risk for specific rheumatoid diseases and patients most likely to benefit from new therapies.

But ethics review boards have thrown up roadblocks

Dr. Gregersen urged clinicians to contribute cases to haplotype databases. During the discussion period, however, a rheumatologist from Canada said that his colleagues would like to assist with this effort but have been stymied by institutional ethics review committees, which are currently demanding written consent for each individual genetic test. "That means [one for each of the] 100 million genotype assays you mentioned. Obviously, this is impossible."

Dr. Gregersen said that this problem is being addressed through an ongoing US survey to determine whether those who have contributed their genotype information to such a research project have ever suffered any adverse consequences. "I want to emphasize that participating in a genetic study is not the same as genetic testing, where the information is given back to the patient and becomes part of that patient's records," he said. "If, as I suspect, we find that there have not been adverse consequences for subjects who participated in genetic research, I expect this will enable review boards to classify most of these projects as ‘minimal risk' and approve them."

Reference

1. Gregersen PK. What can genetics offer the clinical rheumatologist in the future? Presented at: EULAR 2007; June 13-16, 2007; Barcelona, Spain. (no abstract)