Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study.

OBJECTIVE The Old Order Amish (OOA) are a genetically well-defined closed Caucasian founder population. The Amish Family Diabetes Study was initiated to identify susceptibility genes for type 2 diabetes. This article describes the genetic epidemiology of type 2 diabetes and related traits in this unique population. RESEARCH DESIGN AND METHODS The study cohort comprised Amish probands with diabetes who were diagnosed between 35 and 65 years of age and their extended adult family members. We recruited 953 adults who represented 45 multigenerational families. Phenotypic characterization included anthropometry, blood pressure, diabetes status, lipid profile, and leptin levels. RESULTS The mean age of study participants was 46 years, and the mean BMI was 26.9 kg/m2. Subjects with type 2 diabetes were older, more obese, and had higher insulin levels. The prevalence of diabetes in the OOA was approximately half that of the Caucasian individuals who participated in the Third National Health and Nutrition Examination Survey (95% CI 0.23-0.84). The prevalence of diabetes in the siblings of the diabetic probands was 26.5% compared with a prevalence of 7.0% in spouses (lambdaS = 3.28, 95% CI 1.58-6.80). The heritability of diabetes-related quantitative traits was substantial (13-70% for obesity-related traits, 10-42% for glucose levels, and 11-24% for insulin levels during the oral glucose tolerance test; P = 0.01 to <0.0001). CONCLUSIONS Type 2 diabetes in the Amish has similar phenotypic features to that of the overall Caucasian population, although the prevalence in the Amish community is lower than that of the Caucasian population. There is significant familial clustering of type 2 diabetes and related traits. This unique family collection will be an excellent resource for investigating the genetic underpinnings of type 2 diabetes.

[1]  F. Collins,et al.  Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[2]  L. Cardon,et al.  Familiality of physical and metabolic characteristics that predict the development of non-insulin-dependent diabetes mellitus in Pima Indians. , 1997, American journal of human genetics.

[3]  J. Petersen,et al.  Detection of GAD65 Antibodies in Diabetes and Other Autoimmune Diseases Using a Simple Radioligand Assay , 1994, Diabetes.

[4]  M. Leppert,et al.  A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians. , 1999, Diabetes.

[5]  C. Bouchard,et al.  Relationship between changes in physical activity and plasma insulin during a 2.5-year follow-up study. , 1997, Metabolism: clinical and experimental.

[6]  D. Rimoin,et al.  Inheritance of diabetes mellitus. , 1971, The New England journal of medicine.

[7]  H. A. Kahn,et al.  Statistical Methods in Epidemiology , 1989 .

[8]  R. Hegele,et al.  Genetic variation on chromosome 1 associated with variation in body fat distribution in men. , 1995, Circulation.

[9]  M. Harris.  Epidemiological Correlates of NIDDM in Hispanics, Whites, and Blacks in the u.s. Population , 1991, Diabetes Care.

[10]  H. Cross.  Population studies and the Old Order Amish , 1976, Nature.

[11]  M. Khoury,et al.  Inbreeding and prereproductive mortality in the Old Order Amish. I. Genealogic epidemiology of inbreeding. , 1987, American journal of epidemiology.

[12]  D. Rimoin.  Inheritance in diabetes mellitus. , 1976, The Medical clinics of North America.

[13]  T Varilo,et al.  Molecular genetics of the Finnish disease heritage. , 1999, Human molecular genetics.

[14]  F. Collins,et al.  Familiality of Quantitative Metabolic Traits in Finnish Families with Non-Insulin-Dependent Diabetes mellitus , 1999, Human Heredity.

[15]  L. Almasy,et al.  Diabetes and hypertension in Mexican American families: relation to cardiovascular risk. , 1999, American journal of epidemiology.

[16]  C. R. Kahn,et al.  Genetics of non-insulin-dependent (type-II) diabetes mellitus. , 1996, Annual review of medicine.

[17]  K. Flegal,et al.  Varying body mass index cutoff points to describe overweight prevalence among U.S. adults: NHANES III (1988 to 1994). , 1997, Obesity research.

[18]  R. Agarwala,et al.  Software for constructing and verifying pedigrees within large genealogies and an application to the Old Order Amish of Lancaster County. , 1998, Genome research.

[19]  D. Carmelli,et al.  Genetic and behavioral influences on body fat distribution. , 1990, International Journal of Obesity.

[20]  M. R. Young,et al.  Comparison of sequential and fixed-structure sampling of pedigrees in complex segregation analysis of a quantitative trait. , 1988, American journal of human genetics.

[21]  S. Rich.  Mapping Genes in Diabetes: Genetic Epidemiological Perspective , 1990, Diabetes.

[22]  Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping. , 1999, The Journal of clinical endocrinology and metabolism.

[23]  J. Rotter,et al.  Molecular genetics of insulin-dependent diabetes mellitus. , 1986, Molecular biology & medicine.

[24]  S. Hunt,et al.  Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins. , 1989, American journal of epidemiology.

[25]  C. R. Kahn,et al.  Insulin Action, Diabetogenes, and the Cause of Type II Diabetes , 1994, Diabetes.

[26]  V. Somers,et al.  Heritability of plasma leptin levels: a twin study. , 1999, Journal of hypertension.

[27]  M. Knuiman,et al.  Familial correlations, cohabitation effects, and heritability for cardiovascular risk factors. , 1996, Annals of epidemiology.

[28]  R. DeFronzo.  The Triumvirate: β-Cell, Muscle, Liver: A Collusion Responsible for NIDDM , 1988, Diabetes.

[29]  L. Almasy,et al.  Multipoint quantitative-trait linkage analysis in general pedigrees. , 1998, American journal of human genetics.

[30]  J. Blangero,et al.  Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study. , 1996, Circulation.

[31]  L. Groop.  The molecular genetics of non‐insulin‐dependent diabetes mellitus , 1997, Journal of internal medicine.

[32]  K. Flegal,et al.  Prevalence of Diabetes, Impaired Fasting Glucose, and Impaired Glucose Tolerance in U.S. Adults: The Third National Health and Nutrition Examination Survey, 1988–1994 , 1998, Diabetes Care.

[33]  R. Eckel,et al.  Relationship Between Habitual Physical Activity and Insulin Area Among Individuals With Impaired Glucose Tolerance: The San Luis Valley Diabetes Study , 1995, Diabetes Care.

[34]  A A Schäffer,et al.  Towards a complete North American Anabaptist genealogy: A systematic approach to merging partially overlapping genealogy resources. , 1999, American journal of medical genetics.

[35]  N. Schork,et al.  A genome-wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Vas.  New Perspectives in Clinical Microbiology , 1979 .

[37]  D. Morton,et al.  Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish. , 1996, American journal of human genetics.

[38]  P. Poulsen,et al.  Heritability of Type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance – a population-based twin study , 1999, Diabetologia.

[39]  M. Rewers,et al.  Global Estimates for Prevalence of Diabetes Mellitus and Impaired Glucose Tolerance in Adults , 1993, Diabetes Care.

[40]  P. Bennett,et al.  Diabetes mellitus in the Pima Indians: incidence, risk factors and pathogenesis. , 1990, Diabetes/metabolism reviews.

[41]  L. Groop,et al.  Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. , 1999, Diabetes.

[42]  W. Reitsma,et al.  [WHO Expert Committee on diabetes mellitus]. , 1981, Nederlands tijdschrift voor geneeskunde.

[43]  H. Ostrer,et al.  Mutations in the connexin 26 gene (GJB2) among Ashkenazi Jews with nonsyndromic recessive deafness. , 1998, The New England journal of medicine.