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Genetic Epidemiology of Diabetes M Washington University School of Medicine Digital Commons@Becker Open Access Publications 2005 Genetic epidemiology of diabetes M. Alan Permutt Washington University School of Medicine in St. Louis Jonathon Wasson Washington University School of Medicine in St. Louis Nancy Cox University of Chicago Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Permutt, M. Alan; Wasson, Jonathon; and Cox, Nancy, ,"Genetic epidemiology of diabetes." The ourJ nal of Clinical Investigation.,. 1431-1439. (2005). https://digitalcommons.wustl.edu/open_access_pubs/1460 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Downloaded on June 9, 2013. The Journal of Clinical Investigation. More information at www.jci.org/articles/view/24758 Review series Genetic epidemiology of diabetes M. Alan Permutt,1 Jonathon Wasson,1 and Nancy Cox2 1Department of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, USA. 2Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA. Conventional genetic analysis focuses on the genes that account for specific phenotypes, while traditional epide- miology is more concerned with the environmental causes and risk factors related to traits. Genetic epidemiology is an alliance of the 2 fields that focuses on both genetics, including allelic variants in different populations, and environment, in order to explain exactly how genes convey effects in different environmental contexts and to arrive at a more complete comprehension of the etiology of complex traits. In this review, we discuss the epidemiology of diabetes and the current understanding of the genetic bases of obesity and diabetes and provide suggestions for accelerated accumulation of clinically useful genetic information. Definition of the problem Prevalence Diabetes is a metabolic condition in which the body fails to pro- The prevalence of diabetes in the United States has risen 40%, from duce enough insulin. Type 1 diabetes (T1D) results from autoim- 4.9% in 1990 to 6.9% in 1999 (7). A breakdown of the prevalence of mune destruction of insulin-producing β cells, which leaves the diabetes by state from 1990 through 2001 and of obesity by state patient dependent on insulin injections for survival (1) T2D, for- from 1991 through 2003 is shown in Figure 1, A and B, respective- merly known as adult-onset diabetes, occurs when impaired insulin ly (8, 9). The disease affects various groups differently, occurring effectiveness (insulin resistance) is accompanied by the failure to 10 times more commonly in those older than 65 years compared produce sufficient β cell insulin. Patients can be placed on regimens with those younger than 45 years. Minority racial groups including to reduce weight or manage diet or treated with medication and, Hispanics, African Americans, and Native Americans are generally less often, insulin injections. This latter form of diabetes accounts affected at a rate 2–4 times that for white individuals. The recent for as much as 95% of cases. Gestational diabetes is another form of increased prevalence has also been noted in children and adoles- diabetes, defined as a state of glucose intolerance during pregnancy cents, where T2D may now occur more commonly than T1D (10). that usually subsides after delivery but has major implications for The estimated lifetime risk of developing diabetes for individuals subsequent risk of T2D, as pregnancy serves as an “environmental” born in the United States in 2000 is 33% for males and 39% for stressor that reveals a genetic predisposition. Other less common females (7). It is highest among Hispanic females, at 53%. Diabetes forms of diabetes include the rare, genetically determined disease is associated with large reductions in life expectancy, on the order maturity onset diabetes of the young (MODY), diabetes resulting of 11 years in males diagnosed at age 40. While an estimated 18.2 from surgery, and other illnesses that constitute only 1–5% of cases. million persons had diabetes in the United States in 2002 (11), dia- Based on plasma glucose measurements, 2 conditions have been betes worldwide has been estimated to affect 151 million persons, identified with increased risk of the disease (2): (a) impaired glucose and that number projected to increase to 324 million by 2025 (2). tolerance (IGT) is defined as hyperglycemia intermediate between normal and diabetic levels following a glucose load; (b) impaired The medical burden of diabetes fasting glucose (IFG), like IGT, is associated with increased cardio- The burden of diabetes is to a large extent the consequence of vascular disease (CVD) and future diabetes. Because complications macrovascular and microvascular complications of the disease, of diabetes may develop years before overt disease, many consider which result in large increases in morbidity and mortality. For the disease part of a cluster of CVD risk factors that include hyper- example, the prevalence of ischemic heart disease is 2–14 times tension, hyperinsulinemia, dyslipidemia, visceral obesity, hyperco- the rate in age-matched nondiabetics (12). Diabetic retinopathy agulability, and microalbuminuria. This collection of risk factors is is the chief cause of blindness in the US. In 2000, diabetic renal also known as the metabolic syndrome (3, 4). disease accounted for 40% of new cases of end-stage renal disease, While insulin therapy can reverse many of the metabolic distur- and diabetics are the largest group receiving dialysis (more than bances, and numerous improvements in management have been 50% of all cases) and renal transplants (approximately 25%). Lower introduced (5), the disease has reached epidemic proportions. extremity disease resulting from a combination of peripheral vas- According to the WHO (6), it is likely to be one of the most sub- cular disease and neuropathy causes an increase in lower extremity stantial threats to human health in the 21st century. amputations. While improved glycemic control has been shown to reduce the incidence of microvascular complications, episodes of severe symptomatic hypoglycemia were 3 times higher in those Nonstandard abbreviations used: ASP, affected sibling pair; CVD, cardiovascular receiving intensive insulin management therapy (13). Along with disease; DZ, dizygotic; IGT, impaired glucose tolerance; IRAS, Insulin Resistance Ath- experiencing physical and cognitive disabilities, adults with dia- erosclerosis Study; MODY, maturity onset diabetes of the young; MZ, monozygotic; betes have an age-adjusted mortality rate estimated to be twice SNP, single nucleotide polymorphism; T1D, type 1 diabetes; T2D, type 2 diabetes; VNTR, variable number of tandem repeats. that of nondiabetics (12). Risk factors for CVD, including systolic Conflict of interest: The authors have declared that no conflict of interest exists. hypertension, elevated cholesterol levels, and cigarette smoking, Citation for this article: J. Clin. Invest. 115:1431–1439 (2005). independently predict CVD mortality, and any 1 risk factor affects doi:10.1172/JCI24758. outcomes more in persons with diabetes (14). The Journal of Clinical Investigation http://www.jci.org Volume 115 Number 6 June 2005 1431 Downloaded on June 9, 2013. The Journal of Clinical Investigation. More information at www.jci.org/articles/view/24758 review series Figure 1 (A) Diabetes trends among adults in the US. *Includes gestational diabetes. Adapted from ref. 8. (B) Obesity trends among US adults. **BMI ≥ 30 (about 30 pounds overweight for a 5-ft 4-in. individual). Adapted from ref. 9. Although increase in diabetes prevalence occurs mostly in mid- The molecular and physiological relationships between obesity dle-aged and older adults, there is strong evidence of an increase and diabetes are not fully understood, and this subject is an area of in the prevalence of T2D in children (10). For example, in Japan intense investigation (see ref. 22 for review). The “thrifty genotype” the incidence in school children (6–15 years old) has doubled over hypothesis was proposed to account for a genetic advantage of a 20-year period, such that T2D is now more common than T1D accelerated fat deposition during times of restricted availability of (15). In the US, up to 45% of the newly diagnosed diabetics in the calories, which leaves individuals faced with harmful consequenc- pediatric age group have T2D (10). This rise in diabetes rates in es given the abundant food supply and reduced levels of physical children reflects, at least in part, the growing prevalence of obesity activity in developed countries today (24). Noting an association in this age group (16). between low birth weight and increased incidence of diabetes in Direct medical expenditures and lost productivity due to diabe- later life, Hales and Barker have hypothesized that intrauterine mal- tes were estimated to cost the US $132 billion in 2002 (17). The nutrition result in reduced birth weight and to subsequent changes per capita expenditures were twice those for individuals without leading to disease in adults (25, 26). This phenomenon, also known the disease. While the prevalence of diagnosed diabetes is less than as the “thrifty phenotype” hypothesis, proposes that fetal malnutri- 5% of the population,
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