New Gene Finding Creates Controversy

Data derived from the Science Watch/Hot Papers database and the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. In October 2000, a collaboration of American, Japanese, German, and Swedish researchers accomplished a major first: They positionally cloned the gene associated with a common polygenic disorder, namely, type 2 diabetes or non-insulin-dependent diabetes mellitus (NIDDM).1 Despite this Hot Paper's importance, researchers continue to dispute the significance of the gene across multiple ethnic populations. The intricacies of the positional cloning process and the investigators' seemingly unlikely culprit gene have generated skepticism from many. As senior author Graeme Bell explains, positional cloning is difficult because the targeted genome regions are not as precisely defined by recombination events as they are with monogenic disorders. Instead, the gene's location is defined statistically. "We worked in a region where we thought we had a 95% chance of finding it," says Bell, a Howard Hughes Medical Institute investigator and professor of molecular biology and biochemistry at the University of Chicago. "There was a 5% chance it might not have been there." Bell was able to narrow his search based on a previously identified region of chromosome 2, called NIDDM1, that had been shown to be a possible type 2 diabetes locus. Complicating matters were the large areas of the genome under investigation--in this case 15-20 centimorgans, or 15 million to 20 million base pairs. Bell notes that his group was somewhat lucky because they were working at the end of the chromosome, typically a region of more frequent recombination, and the search space shrank to 1.5 to 2 million base pairs. Through a genome-wide scan of a Mexican-American population from Starr County, Texas, Bell and his colleagues positionally cloned a gene called CAPN10, which encodes calpain-10, a member of a family of proteases identified previously. Although the researchers found the CAPN10 gene in the region of the previously identified NIDDM1, CAPN10 presented a fundamentally new avenue for exploring the biochemical pathways implicated in regulating blood-glucose levels. Skeptics still question the significance of CAPN10 as a susceptibility gene. Since the paper's publication, investigators have reported varying levels of association between CAPN10 and NIDDM. One recent paper reported no association in a large Finnish cohort;2 other papers have confirmed an association in African American3 and British4 populations. Bell argues that even studies reporting no association showed a hierarchy of risk. He also speculates that poorly chosen control populations may have generated misleading results, suggesting a lack of statistically significant association. An aged group of individuals with normal glucose tolerance may serve as a better control than the commonly used random population sample. "Maybe if the controls changed a little bit, some of the results might change," says Bell. He also attributes the disparate findings to the variety of nongenetic, disease- contributing factors that differ for every population. The same will likely be true, says Bell, of all genes associated with polygenic disorders. Photo: Courtesy of University of Chicago Graeme Bell Meanwhile, Bell and colleagues continue to investigate CAPN10 and its potential mechanisms of action. They have conducted genotype-phenotype studies in at-risk and normal individuals to compare glucose-stimulated insulin secretion and insulin's effect on glucose uptake by peripheral tissues in both groups. Subjects with the at-risk genotype appear to have differences in both insulin secretion and insulin action. Bell's group has also added calpain inhibitors to isolated pancreatic islet cells, as well as muscle and fat cells, to examine their effects on insulin secretion and action. They found calpain-sensitive pathways in the three cell types. Currently, Bell and colleagues are using transgenic mouse models in their attempts to clarify the role of calpain-10 in glucose regulation. They are creating lines with CAPN10 over-expression as well as total and tissue-specific knockouts of the CAPN10 gene. As other type 2-diabetes genes are discovered, Bell hopes investigators can piece together a limited number of biochemical pathways that include feasible drug targets. Eugene Russo (erusso@the-scientist.com) is a contributing editor. References 1. Y. Horikawa et al., "Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus," Nature Genetics, 26:163-75, October 2000. (Cited in 174 papers) 2. T.E. Fingerlin et al., "Variation in three single nucleotide polymorphisms in the calpain-10 gene not associated with type 2 diabetes in a large Finnish cohort," Diabetes, 51:1644-8, May 2002. 3. M.J. Garant et al., "SNP43 of CAPN10 and the risk of type 2 diabetes in African-Americans--The atherosclerosis risk in communities study," Diabetes, 51:231-7, January 2002. 4. J.C. Evans et al., "Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom," American Journal of Human Genetics, 69:544-52, September 2001.

New Gene Finding Creates Controversy

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