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Type 1 diabetes mellitus (T1DM) is an autoimmune disease arising through a complex interaction of both genetic and environmental factors. Similar to the majority of autoimmune diseases, T1DM is characterized by both humoral and cellular immuno-logical abnormalities, which precede the clinical onset of the disease process (1,2). In T1DM, the presence of multiple antibodies to islet autoantigens can serve as a surrogate marker of disease in primary intervention strategies among first-degree relatives (3-5). As a general rule, in the bulk of chronic autoimmune disorders, antibody laboratory testing in addition to genetic typing can facilitate decision-making for disease management based on the identification of disease activity (6).

Familial clustering is indicated by the observation that the overall risk for developing T1DM in North American Caucasian siblings, parents, and offspring of individuals with T1DM ranges from 1% to 15% (7-13), as compared to less than 1% for individuals without T1DM relatives and 1.2/1000 of the general population (14) (see Table 1). It is noteworthy that an increased risk of T1DM seems to be present also in first-degree relatives of individuals with non-insulin-dependent diabetes mellitus (15-20). How-

From: Contemporary Endocrinology: Type 1 Diabetes: Etiology and Treatment Edited by: M. A. Sperling © Humana Press Inc., Totowa, NJ

Table 1

Empiric Risk of Type 1 Diabetes

Table 1

Empiric Risk of Type 1 Diabetes

Empiric risk

First-degree relatives of T1DM probands*

5-7%a

Individuals without relatives with T1DM*

<l%

Children of affected father**

~6%

Children of affected mother**

~2%

Note: Estimates are for North American Caucasian (*) and Scandinavian (**) populations. T1DM, type 1 diabetes mellitus. a 1-15% range depending on the populations. Source: ref. 12.

Note: Estimates are for North American Caucasian (*) and Scandinavian (**) populations. T1DM, type 1 diabetes mellitus. a 1-15% range depending on the populations. Source: ref. 12.

ever, over 80% of cases of T1DM occur in individuals with no apparent family history of the disease. In the remaining 20%, this disease aggregates in families.

Specific human leukocyte antigen (HLA) haplotypes account for susceptibility to both T1DM and to a subtype of type 2 diabetes (21-24). The latter finding is supported by the occurrence of P-cell humoral autoimmunity in 10-33% of Caucasian adult-onset diabetic patients not treated with insulin (15-18,25). Therefore, a subset of patients with type 2 diabetes manifests similar genetic susceptibility and immunologic abnormalities to those characteristic of classical T1DM. Because of the peculiar characteristics of this subgroup of type 2 diabetes, the term "latent autoimmune diabetes in adults" (LADA) has been coined.

Studies conducted in the United States and Scandinavia have shown that offspring of parents with T1DM have a higher risk to progress to T1DM if the father, rather than the mother, is affected by the disease (13,26-30). In fact, the risk is increased to about 1/40 in offspring of fathers with T1DM and to 1/66 in offspring of type 1 diabetic mothers (31). A number of explanations have been proposed for this finding, including genomic imprinting of genes involved in the susceptibility to T1DM, leading to an increase in spontaneous abortion by T1DM mothers of fetuses that might develop T1DM (7,12), maternal environmental factors that allow the fetus to remain tolerant to islet autoantigens (7), or a preferential paternal transmission of HLA diabetogenic alleles (32).

Not only genetic but also environmental factors may contribute to determine the risk of progression to the clinical stage of the disease. A discordance rate of greater than 50% between monozygotic twins indicates a potential involvement of environmental factors on disease development (33,34). This aspect of the disease is supported by the observed tendency to develop T1DM after exposure to viral agents. Viral antigens may, in fact, play a role in the generation of P-cell autoimmunity (35-40). These observations are supported by the increasing seasonal incidence of T1DM in many Western countries (41,42) and that enteroviruses may be involved in the autoimmune pathogenesis of T1DM (36,43,44).

WHAT ARE THE GENES?

Although it has been suggested that multiple genes play a role in disease susceptibility, there is strong evidence that at least two chromosomal regions are closely associated with and linked to T1DM: the HLA region on chromosome 6p21 (IDDM1), and the

Table 2

Summary of Human IDDM Susceptibility Loci

Table 2

Summary of Human IDDM Susceptibility Loci

Chromosome

Locus

Linkage status (according to ref. 45)

6p21

IDDM1; HLA-DQB

Confirmed

11p15.5

IDDM2; INS 5' VNTR

Confirmed

15q26

IDDM3; IGF1R

Suggestive (p < 0.001, MLS > 2.2)d

11q13

IDDM4; FGF3

Confirmed (p < 2.2 x 10-5, MLS > 3.6)

6q25

IDDM5; ESR1

Confirmed (p < 2.2 x 10-5, MLS > 3.6)

18q21

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