Common diseases such as diabetes, heart disease and asthma are polygenic — disease susceptibility is influenced by several genes (referred to as polygenes), each thought to have a small effect. The identification of polygenes holds great promise for our understanding of disease aetiology and for the development of new therapies. However, efforts to apply positional cloning to the identification of polygenes have met with little success — until now. Graeme Bell and colleagues have used this approach to identify a gene that is strongly implicated in susceptibility to type 2 diabetes, the most common form of diabetes.

Bell's group had previously mapped a susceptibility locus for type 2 diabetes in Mexican Americans to a 12-cM region on chromosome 2. The latest work began by refining the locus to a 7-cM interval, which was then cloned into a contig and shown to encompass 1.7 Mb. This relatively high ratio of recombination rate to physical distance was one piece of good fortune and is thought to be caused by the region's proximity to the telomere. The region contained seven genes and 15 expressed sequence tags (ESTs).

The next phase of the work was to characterize new polymorphisms in the 1.7-Mb interval and to carry out association studies, with the aim of refining the location of the genetic determinant (or determinants) that is associated with disease susceptibility. A huge amount of work culminated in the identification of a single, intronic polymorphism (UCSNP-43) that was significantly associated with disease susceptibility. UCSNP-43 is in a gene ( CAPN10) that encodes a calpain-like protease. But does this polymorphism itself cause increased disease susceptibility or is it merely associated with a nearby causative variant?

To address this question, Horikawa et al. resequenced the 66-kb region that encompasses CAPN10 in 10 Mexican Americans and uncovered 179 polymorphisms, 63 of which were typed in 100 diabetic cases and 100 controls. Haplotype analysis led to the conclusion that significant elevated risk for diabetes is conferred by heterozygosity for two haplotypes — homozygosity for either haplotype had no association with altered disease susceptibility. This twist to the story suggests that there is a complex interplay of genetic variants in the vicinity of CAPN10 that leads to altered diabetes susceptibility in Mexican Americans. However, the identity of the causative variants is still not known, and might even lie outside CAPN10.

Like Baroness Orczy's Scarlet Pimpernel, the polygene is proving to be an elusive and tantalizing quarry. The study by Horikawa et al. is the most successful report to date, and it provides a novel line of inquiry that could be pursued by diabetologists — how might a calpain-like protease be involved in diabetes? But the work also demonstrates just how difficult it is to make the jump from evidence for a disease-susceptibility locus to the gene, and ultimately to the molecular defect, that underlies that susceptibility.