Genetic Risk

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Clinical

Approximately 1/300 children in the United Sates develop type 1A diabetes throughout their life, with a reported incidence of approx 15/100,000. Finland has the highest incidence, approaching 50/100,000 (16), and Japan has one of the lowest (approx 1/100,000 in children). The incidence appears to be increasing worldwide and recent

Fig. 1. Hypothetical stages in the development of type 1A diabetes. IDDM, insulin-dependent diabetes mellitus. (Modified from ref. 2.)

data from Colorado suggest that the incidence has increased to 25/100,000 (17,18). The etiology of the increasing incidence is not defined, but it suggests environmental change (either decreasing protective factors or increasing "triggering" factors). First-degree relatives of patients with type 1A diabetes have a risk of approx 5%, including siblings, offspring, and parents. The risk of type 1A diabetes of an offspring of a mother with diabetes is less than for a father with type 1A diabetes (19), and siblings appear to have a risk for early childhood anti-islet autoimmunity and diabetes approximately twice that of offspring (20). Dizygotic twins have a risk similar to siblings, and monozygotic twins have a "lifetime" risk of approx 50% (21). As illustrated in Fig. 2, initially discordant monozygotic twins of patients with type 1A diabetes can progress to diabetes decades after the onset of diabetes in their proband twin. In addition, there appears to be genetic heterogeneity in eventual concordance, with twin mates whose twin developed diabetes after age 25 having a relatively low risk of progression to diabetes (21). Despite the high risk to relatives, it must be realized that between 85% and 90% of children developing type 1A diabetes do not have a relative with the disease.

In addition to a family history of diabetes predicting an increased risk, diabetes is also associated with other autoimmune diseases. Two of the most dramatic syndromes associated with diabetes begin in neonates or very young children, and mutations underlying autoimmunity have been defined. These syndromes are termed "autoimmune polyendocrine syndrome type I" (APS-1) (22) and "X-linked polyendocrinopa-thy, immune dysfunction, and diarrhea" (XPID) (23). Approximately 18% of patients with the autosomal mutations of the autoimmune regulator (AIRE) gene underlying the APS-I syndrome develop type 1A diabetes, in addition to their mucocutaneous candidiasis, Addison's disease, and/or hypoparathyroidism (24). The XPID syndrome presents with fatal overwhelming neonatal autoimmune disease, and it is suggested that such children might benefit from bone marrow transplantation (23).

Much more common associations with type 1A diabetes include celiac disease (25-27), thyroid autoimmunity, Addison's disease (often as part of APS-II) (28), myasthenia gravis, and pernicious anemia. For example, 1/20 children with type 1A

Fig. 2. Progression to diabetes of initially discordant monozygotic twins of patients with type 1A diabetes, subdivided by the age of diabetes onset of the proband twin. (From ref. 21.)

diabetes have celiac disease. Approximately 1/10 express antitransglutaminase autoantibodies, and half of these (thus, 1/20) have celiac disease on biopsy (27,29). Most of these children are asymptomatic. In addition, relatives of patients with type 1A diabetes also have an increased frequency of nondiagnosed celiac disease (27). Thyroid autoimmunity is usually screened for with determination of thyroid-stimulating hormone (TSH) levels. Addison's disease probably occurs in approx 1/200 individuals with type 1A diabetes compared to 1/20,000 in the general population. The presence of 21-hydroxylase autoantibodies suggests the need for prospective evaluation of adrenal function (28,30).

Laboratory-Defined Genetic Risk

At present, the best-defined genetic markers for common forms of type 1A diabetes are alleles of genes within the major histocompatibility complex (MHC) on the sixth chromosome (31-33). There are more than 100 genes within the complex, but the genes providing prognostic information are predominantly DRP, DQa, and DQP. Each allele of each of these genes is now defined at the nucleotide level and is given a specific number (e.g., DRB1*0301). The first two numbers usually refer to older serologic typing and the last two numbers specify a specific sequence. The genes of the complex are in close genetic proximity. Thus, they are linked when inherited (because crossing over between genes within a family is rare) and are in linkage dysequilibrium (alleles of different genes are nonrandomly associated with each other on the same chromosome in the population). Therefore, one can define alleles of a single gene, a group of alleles of different genes on the same chromosome (a haplotype), or, what is most important in determining

Table 1

Diabetes Risk by HLA DQ and DR Haplotypes

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