Medical Genetics - V. M. Zaporozhan 2005

Multifactorial Diseases
Genetics of Certain Common Multifactorial Diseases
Diabetes Mellitus

Insulin-dependent diabetes mellitus (IDDM), or type 1 diabetes of juvenile onset, is an autoimmune disease characterized by the destruction of insulin-producing pancreatic beta Cells. The genetic component of IDDM remains insufficiently understood. Linkage analysis has identified one of the candidate genes, NQ01 (16q22.1), which is responsible for the synthesis of NAD(P)H—an enzyme that catalyzes quinone detoxification and protects cells from oxidative stress. A P183S polymorphism has been discovered (substitution of Serine for Proline at position 183). Homozygotes for this mutation show a complete loss of protein activity, whereas heterozygotes exhibit a twofold reduction in activity. This low enzymatic activity may trigger the apoptosis of pancreatic beta cells. The frequency of homozygotes (P183S/P183S) in the European population is 3.3%.

A close genetic linkage between IDDM and HLA genes has been established. More than 90% of patients carry the DR3 and DR4 alleles in their genome, which is taken into account when calculating genetic risk in families with a hereditary predisposition (Table 7.7).

Non-insulin-dependent diabetes mellitus (NIDDM), or type 2 diabetes, typically manifests in adulthood and is associated with cellular resistance to the glucose-lowering effects of insulin across various Organs and Tissues. Glucose METABOLISM and the maintenance of normal glucose tolerance are determined by insulin secretion from beta cells—The rate of which depends on Blood glucose levels—and by peripheral insulin action. Tissue sensitivity to insulin is modulated by age, excess body weight, blood pressure, coronary artery disease, dyslipidemia, smoking, and physical fitness.

The genetic mechanisms underlying insulin resistance in type 2 diabetes are heterogeneous. Potential causes include various Mutations in the Insulin Receptor Gene (over 30 mutations identified), as well as in genes encoding Glycogen synthase, protein phosphokinase, Transcription factors, and others (Table 7.8). Investigations into candidate genes have helped identify maturity-onset diabetes of the young (MODY), a monogenically inherited form of diabetes that accounts for 2–3% of all diabetes cases.

Table 7.7. Genetic risk in diabetes (R. F. Mueller, I. D. Young, 2001)