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).