Age, HLA, and Sex Define a Marked Risk of Organ-Specific Autoimmunity in First-Degree Relatives of Patients With Type 1 Diabetes

Abstract

Autoimmune diseases can be diagnosed early through the detection of autoantibodies. The aim of this study was to determine the risk of organ-specific autoimmunity in individuals with a family history of type 1 diabetes. RESEARCH DESIGN AND METHODS The study cohort included 2,441 first-degree relatives of patients with type 1 diabetes who were prospectively followed from birth to a maximum of 29.4 years (median 13.2 years). All were tested regularly for the development of autoantibodies associated with type 1 diabetes (islet), celiac disease (transglutaminase), or thyroid autoimmunity (thyroid peroxidase). The outcome was defined as an autoantibody-positive status on two consecutive samples. RESULTS In total, 394 relatives developed one (n = 353) or more (n = 41) of the three diseaseassociated autoantibodies during follow-up. The risk by age 20 years was 8.0% (95% CI 6.8-9.2%) for islet autoantibodies, 6.3% (5.1-7.5%) for transglutaminase autoantibodies, 10.7% (8.9-12.5%) for thyroid peroxidase autoantibodies, and 21.5% (19.5-23.5%) for any of these autoantibodies. Each of the three disease-associated autoantibodies was defined by distinct HLA, sex, genetic, and age profiles. The risk of developing any of these autoantibodies was 56.5% (40.8-72.2%) in relatives with HLA DR3/DR3 and 44.4% (36.6-52.2%) in relatives with HLA DR3/DR4-DQ8. CONCLUSIONS Relatives of patients with type 1 diabetes have a very high risk of organ-specific autoimmunity. Appropriate counseling and genetic and autoantibody testing for multiple autoimmune diseases may be warranted for relatives of patients with type 1 diabetes. Prospective studies that follow children from birth have established that autoimmunity can start very early in life and years before clinical symptoms appear (1-3). In type 1 diabetes, autoimmunity often appears between 6 months and 3 years of age (1-3), and the large majority of children who develop autoantibodies against multiple pancreatic islet antigens at this age progress to clinical disease (4). New disease paradigms have emerged from such studies, leading to extensive screening (5), the

Increased risk of endocrine autoimmunity in first-degree relatives of patients with autoimmune Addison’s disease

“…Serum aTPO and aTg are relatively common in subjects suffering from other endocrine conditions, such as T1D and AD, and in systemic autoimmunity (2,3,39,40). A prospective study in close relatives of patients with T1D revealed that by 20 years of age the overall risk of developing aTPO exceeds 10% (40). In our analysis, aTPO were the only autoantibodies, which displayed gender difference, with more than twice increased preponderance in females.…”

“…Their frequencies in iodine-sufficient populations range between 5 and 18% and tend to rise in elderly women (17). Serum aTPO and aTg are relatively common in subjects suffering from other endocrine conditions, such as T1D and AD, and in systemic autoimmunity (2,3,39,40). A prospective study in close relatives of patients with T1D revealed that by 20 years of age the overall risk of developing aTPO exceeds 10% (40).…”

Celiac Disease and the Autoimmune Web of Endocrinopathies

“…2. First-degree relatives had an increased risk of developing both the disorders compared to the general population [5,13].…”

Preventing type 1 diabetes in childhood

“…These studies have revealed that over 90% of children with T1D have autoantibodies to at least one islet-specific autoantibody at diagnosis and that these can appear years before clinical diagnosis of T1D. The first autoantibody to appear is against insulin, with a peak incidence around age 12 months [14,15]. Up to 90% of children with a single type of islet-specific autoantibody do not progress to T1D, but seroconversion to the presence of two or more autoantibodies (which occurs at a median age of 2.1 yrs) comes with an 84% risk of clinical T1D by the age of 18 [16].…”