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Tobacco-related disease in native California twins

Institution: University of Southern California
Investigator(s): Thomas Mack, M.D., M.P.H.
Award Cycle: 1997 (Cycle 6) Grant #: 6RT-0354 Award: $889,746
Subject Area: Epidemiology
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
The study of interactions between inherited susceptibility to disease and lifestyle exposures, including smoking, is greatly facilitated by the availability of a large registry of twins who can be asked if they are willing to participate in such studies. Having begun to form such a registry in the first years of TRDRP, we propose to complete the registry, thereby forming a roster of 65,000 individuals who have indicated their willingness to participate. Many studies of tobacco related disease as well as of other medical topics will thereby be facilitated. We also propose to identify all twin pairs in which one has smoked and in which one has died or as been affected by cancer, looking to determine the degree to which the smoker tends to be the person more often affected when inheritance and early environment are held constant.

Final Report
The initial objectives of this proposal were to identify identical twin cases of bladder, renal, and pancreas cancer who smoked but who had co-twins who did not smoke, and compare the genetic characteristics of the twins with those of unrelated controls, specifically spouses. The scientific goal was to test the hypothesis that variations in a specific gene (responsible for the enzyme N-acetyl-tranferase) might be important determinants of bladder, renal and/or pancreas cancer. This enzyme competes with the enzyme responsible for turning the products of smoking into potent carcinogens, and if it works rapidly, little toxic material is created to bathe the tissues of these organs. If, on the other hand, it works slowly, as it does under some genetic conditions, carcinogens are more readily formed. Since the genetic methods in 1993 were not well developed, we initially proposed to test the functionality of the genes by collecting urine after a test dose of caffeine, known to be changed by the enzyme in the same way as the tobacco products. The twin cases had occurred in the years 1975-90. After the grant was approved, the Governor cut the research funds, and only after nearly 2 years did a limited proportion became available, although additional funds did appear in the succeeding year. We cut costs by eliminating renal cancer, giving bladder cancer priority, collecting DNA itself instead of the functional assay, and arranging for scientists at the National Institute of Environmental Health Sciences to do the genetic lab work. Unfortunately, by the time we got to the twins, many had moved or died, and others had less interest in cooperating.

In addition, by the time the material was collected, the scientific interest at the NIEHS had cooled, since other studies had successfully tested the hypothesis, and the bladder cancer material remains stored there untested. In the last year of the grant and the succeeding period we tried to collect similar material from the families of twins with pancreas cancer, in some cases diagnosed more than 20 years before. We succeeded in about a third of the available pairs, but got material from very few of the unrelated controls. Anyway, after the laboratory analysis was completed on the 26 specimens available, no evidence was found to suggest a role for these enzymes in pancreas cancer, but such a possibility could not be ruled out.
Publications

Grave's disease, genetics and environment: revised estimates of the concordance rates in monozygotic and dizygotic twin populations
Periodical: Endocrinology Index Medicus:
Authors: ART
Yr: 1999 Vol: Nbr: Abs: Pg: