Starr County, Texas, is among the poorest and remotest of the 254counties in the Lone Star State. Bordering on the Rio Grande river,some 200 miles dead south of San Antonio, rural Starr is home toabout 28,000 inhabitants, 97 percent of them Mexican-Americans.
Starr is ranked first in the state for death and disease due to diabetes.So for two decades it's been the site of long-term genetic andepidemiologic studies of adult-onset diabetes mellitus by researchersat the University of Texas, in Houston.
This Type 2 form of the disease usually strikes its victims in their 40sor 50s. Unlike the juvenile-onset Type 1, which descends on childrenand adolescents (See BioWorld Today, April 15, 1996, p. 1), Type 2patients secrete insulin. However, the hormone fails to do its job ofcontrolling levels of glucose in blood.
The two types, though both marked by insulin deficiency, are reallyseparate diseases. The juvenile form is called insulin-dependentdiabetes mellitus (IDDM), because autoimmune attacks destroy theirvictims' ability to make insulin.
Type 2, the non-insulin-dependent diabetes mellitus (NIDDM) adultdisease, affects an estimated 15 million people in the U.S. alone,where it is the seventh leading cause of death.
"This is the garden-variety form of diabetes," said moleculargeneticist Graeme Bell. "Probably 10 percent of typical Caucasianpopulations have Type 2, but among Mexican-Americans, 25 percentmay be afflicted."
In Native Americans, particularly the Pima Amerindians, Bell added,the proportion of diabetics reaches a staggering 60 to 70 percent.This tribe, once lean and sinewy farmers and hunters, consists todayof grossly obese and sedentary men and women, beset by diabetes.And the hapless Mexican-Americans of Starr Country have a 31percent admixture of Amerindian blood in their veins, anddiabetogenic genes in their genomes.
Many academic, governmental and commercial laboratories arestriving to locate those genes, not least among them Bell, who is aHoward Hughes Medical Institute researcher at the University ofChicago, and a former senior scientist at Chiron Corp., of Emeryville,Calif.
He is project leader of an international academic effort to track downthe first Type 2-causing gene, named _ in anticipation of itsdiscovery _ NIDDM1. The seven-center consortium has justannounced cornering their candidate gene in a five-million-base-pairgenomic stretch on the long arm of human chromosome 2.
Bell is senior author of their report in Nature Genetics for June 1996,published today. Its title: "A genome-wide search for human non-insulin-dependent [Type 2] diabetes genes reveals a majorsusceptibility locus on chromosome 2."
He and his 32 co-authors in Texas, Pennsylvania, Washington, Japanand Germany now are closing in on their presumed gene target."Judging from the progress in the human genome project," Bell toldBioWorld Today, "I wouldn't be at all surprised if it took us only aslittle time as two years."
Their genetic linkage analysis method, he said, "is incrediblysophisticated." But then, unraveling the genetics of NIDDM diabetesis incredibly complex, especially in their initial population ofMexican-Americans.
"This form of diabetes is familial, but it does not have a simpleMendelian form of inheritance," Bell explained. Because it's late-onset, the parents are usually not available for study, and if it's adiabetes-prone family, one or more of them will have alreadysuccumbed to their disease. The kids of the diabetic siblings weanalyze are not old enough to manifest the symptoms of disease, sowe're restricted to carrying out our genetic study in a singlegeneration."
Hence, they collected 330 pairs of adult Mexican-American siblingsin Starr County, all NIDDM patients, and scrutinized all of the DNAin all 23 of their chromosomes (omitting the male Y chromosome) forsequence similarities hinting at a nearby diabetogenic gene.
"Three years ago, when we started this project," Bell recalled, "therereally weren't good genetic maps of the human genome. Now youcan order standard markers from the appropriate companies, oursbeing Research Genetics Inc., of Huntsville, Ala."
They obtained 490 off-the-shelf microsatellite markers, separatedalong the genome by intervals of 10 million to 15 million base pairs.Using PCR, the co-authors systematically typed these simple tandemrepeats, beginning with chromosome 1, and ending with X. It took 30months.
Pay dirt came on a marker along chromosome 2. "When we looked atthe distribution of this marker among the sibling pairs, we could seethat the affected ones showed more sharing of two alleles than onewould expect by chance alone," Bell said.
From Tex-Mex To Non-Hispanic Siblings
While narrowing the gap to discovering the NDDM1 gene in timeand in base pairs, the consortium also is expanding its populationstudies from Mexican-Americans to non-Hispanic white and Japanesesiblings. "We think there will be other major genes in thosepopulations that we don't see in Starr County," Bell said.
"In addition to a group at the National Institutes of Health," heobserved, "at least three small biotech companies" also arecontenders in the race to identify the first Type 2 gene: "MillenniumPharmaceuticals Inc., of Cambridge, Mass., Mercator Genetics Inc.,of Menlo Park, Calif., and Sequana Therapeutics Inc., of La Jolla,Calif. have similar programs," he said.
Unlike the somewhat parallel quest to commercialize the BRCAgenes for familial breast cancer for prognostic testing, the primaryrole foreseen for the Type 2 diabetes gene will be to aid in"development of therapeutic drugs," Bell said, "based on how itsprotein functions, how it regulates blood glucose levels. Then maybeone can develop an antagonist or agonist, based on that geneproduct."
But like BRCA1 and 2, "The list of major susceptibility genes forType 2 diabetes is not going to end with NIDDM1. There's going tobe a 2, a 3, a 4 and a 5. So it's really the first step in understandingthe genetics of this very common disorder." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.