Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2001-11-05
2004-08-31
Fredman, Jeffrey (Department: 1634)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091100, C435S091200, C536S023100
Reexamination Certificate
active
06783942
ABSTRACT:
FIELD OF THE INVENTION
The present invention is in the field of Type II diabetes, and in particular to genetic polymorphisms associated with Type II diabetes.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a syndrome which results in disregulation of glucose homeostasis with multiple etiologic factors that generally involve absolute or relative insulin deficiency or insulin resistance or both. All causes of diabetes ultimately lead to hyperglycemia, which is the hallmark of this disease syndrome. Several clinical subclasses are recognized, including: Type I (insulin-dependent or IDDM), Type II (non-insulin-dependent diabetes mellitus), maturity-onset diabetes of the young (MODY) and gestational diabetes.
An emerging model for obesity-induced Type II diabetes is based on forms of lipodystrophic diabetes and hypothesizes that diabetes can result from insufficient expansion of adipose in response to energy excess. In studies carried out by Kim et al. (Kim et al. (2000)
J. Biol. Chem.
275:8456-60), fatless mice were created using a P2 enhancer/promoter that targeted adipocyte-specific transgene expression of a dominant-negative protein termed A-ZIP/F1. This protein contains a domain that has been shown to inhibit the DNA binding and function of certain bZIP transcription factors. Despite the virtual absence of adipose tissue, the transgenic mice develop diabetes. It is presumed that if the adipose organ is unable to respond adequately to excess calories, then the excess is stored in the liver and muscle.
Overall, in the United States the prevalence of diabetes is about 2 to 4 percent, with IDDM comprising 7 to 10 percent of all cases. The prevalence of IDDM is probably more accurate than the estimates for Type II diabetes. This is due at least in part to the relative ease of ascertainment of IDDM, while many patients with Type II diabetes are asymptomatic and thus this form of the disease goes undiagnosed. Type II diabetes, the most common form of diabetes found in the United States, is characterized by a later age of onset, insulin resistance and impaired insulin secretion. Obesity and increased hepatic glucose output are also associated with Type II diabetes. Indeed, in the United States, 80 to 90 percent of Type II diabetes patients are obese. The precise role of obesity in the causes of Type II diabetes and the development of complications associated with diabetes remains equivocal.
Type II diabetes has been shown to have a strong familial transmission: 40% of monozygotic twin pairs with Type II diabetes also have one or several first degree relatives affected with the disease. Barnett et al. (1981)
Diabetologia
20:87-93. In the Pima Indians, the relative risk of becoming diabetic is increased twofold for a child born to one parent who is diabetic, and sixfold when both parents are affected (Knowler, W. C., et al. (1988)
Genetic Susceptibility to Environmental Factors. A Challenge for Public Intervention,
Almquist & Wiksele International: Stockholm. p. 67-74). Concordance of monozygotic twins for Type II diabetes has been observed to be over 90%, compared with approximately 50% for monozygotic twins affected with Type I diabetes (Barnett, A. H., et al. (1981)
Diabetologia
20(2):87-93). Non-diabetic twins of Type II diabetes patients were shown to have decreased insulin secretion and a decreased glucose tolerance after an oral glucose tolerance test (Barnett, A. H., et al. (1981)
Brit. Med. J.
282:1656-1658).
Central fat, particularly intra-abdominal adipose tissue (IAAT), is associated with increased risk for Type II diabetes (Vague, J. (1996)
Obesity Res.
4(2):201-3; Kissebah, A. H., et al. (1982)
J. of Clinical Endocrinology
&
Metabolism
54(2):254-60; Bjomtorp, P. (1992)
Obesity
579-586).
Diabetes is a complex syndrome affected not only by familial transmission but by environmental factors as well (Kahn, C. R. et al. (1996)
Ann. Rev. of Med.
47:509-31; Aitman, T. J. and Todd, A. J. (1995)
Baillieres Clin. Endocrinology
&
Metabolism
9(3):631-56). There is a high prevalence of the disease in world populations. Expression is strongly age-dependent and the etiology is heterogeneous. The combined effect of these factors makes mapping the genes responsible for Type II diabetes particularly challenging. For example, a major pitfall for using linkage analysis with a complex trait such as diabetes is the difficulty in establishing transmission models. The high prevalence of the disease in world populations, reduced penetrance, and the presence of phenocopies each contributes to reducing the power of linkage studies. Sib pair studies and the transmission disequilibrium test, non-parametric methods which do not require a model for mode of inheritance, are hampered by heterogeneity and the large number of phenocopies expected for such a complex common disease. A number of published findings suggest linkage of diabetes to chromosome 20q (Ji et al. (1997)
Diabetes
46:876-81; Bowden, D. W., et al. (1997)
Diabetes
46:882-86; Velho et al. (1997)
Diabetes and Metabolism
23:34-37; and Zouali et al. (1997)
Human Molec. Genet.
6:1401-1408), but definition of a locus linked to susceptibility to Type II diabetes has thus far been unsuccessful.
Segregation analyses of Type II diabetes or related phenotypes have provided support for a major gene (Hanson, R. L., et al. (1995)
Amer. J. of Human Genetics
57:(1):160-70; Serjeantson, S. W. and Zimmet, P. (1991)
Baillieres Clin. Endocrinology
&
Metabolism
5(3):477-93; Elston, R. C., et al. (1974)
Amer. J. of Human Genetics
26(1):13-34), though in some analysis models incorporating a major gene effect did not provide a significantly better fit than those with multifactorial inheritance, and more complex models were required to explain the data (Cook, J. T., et al. (1994)
Diabetologia
37(12):1231-40; McCarthy, M. I. et al. (1994)
Diabetologia
37(12):1221-30). Segregation analysis of Type II diabetes is complicated by the fact that disease expression is strongly age dependent and, in certain populations, by the increase in recent years of the incidence of the disease. Since obesity is commonly associated with Type II diabetes, it can also influence the familial relationships.
Mutations in hepatocyte nuclear factor-4&agr; gene, which is located on chromosome 20, have been associated with maturity onset diabetes of the young (MODY), a form of Type II diabetes. Yamagata et al. (1996) Nature 384:458-460. However, genetic studies appear to have ruled out a role for the so-called MODY1 gene as a major late-onset Type II diabetes susceptibility gene. Velho and Froguel (1998)
Eur. J. Endocrinol.
138:233-239. Ji et al. ((1997)
Diabetes
46:876-881) tested whether a gene or genes in the MODY1 region of chromosome 20 contributes to the development of Type II diabetes. They reported a possible linkage between Type II diabetes and markers D20S119, D20S178, and D20S197. Bowden et al. ((1997)
Diabetes
46:882-886) also examined the potential contribution of MODY genes to Type II diabetes susceptibility in African American and Caucasian Type II diabetes-affected sibling pairs with a history of adult-onset diabetic nephropathy. While a linkage was seen among Caucasian sib pairs between MODY1-linked marker D20S197 and Type II diabetes, no evidence for linkage of MODY1 marker to Type II diabetes in Africa-American sib pairs was observed.
Linkage disequilibrium (LD) analysis is a powerful tool for mapping disease genes and may be particularly useful for investigating complex traits. LD mapping is based on the following expectations: for any two members of a population, it is expected that recombination events occurring over several generations will have shuffled their genomes, so that they share little in common with their ancestors. However, if these individuals are affected with a disease inherited from a common ancestor, the gene responsible for the disease and the markers that immediately surround it will likely be inherited without change, i.e., will be identical by descent (IBD), from that ancestor. The size of the region
Borden Paula A.
Bozicevic Field & Francis LLP
Fredman Jeffrey
Goldberg Jeanine
UAB Research Foundation
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