Monday, September 25, 2000
In the wave of interest spawned by the mapping of the human
genome, the public and Wall Street have focused on efforts to use single nucleotide
polymorphisms to identify target genes associated with disease or drug response.
However, it's not yet clear how often knowledge of an individual
SNP will have utility in the clinic or in drug development. Indeed, a paper
published recently by Genaissance Pharmaceuticals Inc. demonstrated in asthma,
at least, that the association of individual SNPs to form a complete haplotype
- the combination of SNPs that co-exist on a single chromosome - may be more
relevant in predicting drug response.
GNSC thus maintains that haplotype analysis is critical to
the medical utility of SNPs. But others question the importance of haplotypes.
And the debate is likely to go on for some time, as different companies are
taking different directions.
As is often the case, however, the answer is unlikely to turn
out to be black and white. Rather, SNPs alone may prove to be sufficient for
some diseases and for some of the individual variability in drug efficacy or
metabolism. In other cases haplotyping will be necessary to fully elucidate
the contribution of individual SNPs to a condition.
In any case, initial genotyping of SNPs is needed to provide
the data from which any haplotypes are derived. "The haplotype is the manner
in which individual SNPs are organized along a given stretch of DNA - that can
be one gene or multiple genes over a very long space," noted Dennis Grant, senior
director of pharmacogenetics at Orchid BioSciences Inc. (ORCH, Princeton, N.J.).
The albuterol example
GNSC's work in asthma showed a link between haplotypes of the
gene encoding the beta-2 adrenergic receptor and patient response to the asthma
drug albuterol, which targets the receptor. The report, published in the Proceedings
of the National Academy of Sciences, showed no link between individual SNPs
and drug response (see "Predicting Response", A5).