Familial clustering of autoimmune diseases in patients with type 1 diabetes mellitus
Introduction
Autoimmune diseases (AIDs) are chronic conditions initiated by a loss of immunological tolerance to self-antigens. The chronic nature of many of these diseases results in a significant impact in terms of medical care utilization, direct and indirect economic costs, and quality of life. The estimated incidence of AIDs is about 90 per 100,000 person-years and their prevalence is about 3% of the population [1]. Almost all AIDs disproportionately affect middle-aged women, being one of the leading causes of death among this group of patients. The older the patient, the lower the male:female ratio becomes [1].
Although the etiology of AIDs is unknown, several factors are involved in the development of these diseases, including genetic and environmental factors [2], [3]. Population studies have established that each population holds a mutational pool, in which most mutations individually (i.e. polymorphisms) will have mild effects; if not undetectable, but in combination with other alleles would favor or avoid autoimmune phenomena. Such interplay within genetic variants will generate a change in the measurable risk of developing an autoimmune phenotype. This characteristic is the main reason why AIDs are not inherited in a classical simple Mendelian way, but instead have a complex or yet unknown mode of inheritance [3]. Genetic contribution to AIDs is supported by the high rates of concordance, ranging from 15% to 60%, and by high recurrent risk ratios (λR) [4].
There is evidence indicating that some AIDs will concentrate within families. This includes not only cases of a single type of AID (several members having the same trait) appearing among siblings, twins and relatives of patients [5], [6], [7], [8], but also several different ones (several family members with diverse AIDs) appearing [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], thus indicating that autoimmune phenotypes could represent pleiotropic outcomes of non-specific disease genes that underlie similar immunogenetic mechanisms. This common origin hypothesis for different AIDs is also supported by results of genome-wide scans showing that several loci may overlap in different AIDs [20], [21], and by microarray expression profile studies disclosing a similar pattern of gene expression in different AIDs [22], [23]. Finally, the multiple autoimmune syndrome, characterized by the presence of three or more AIDs in a single individual [24], is a clear example of how diverse phenotypes may be related to a single genotype.
Type 1 diabetes mellitus (T1D) is an organ-specific AID resulting from the damage of insulin-producing pancreatic β cells. This disease constitutes the earliest-onset AID, with a male:female ratio of 1:1 [25]. Similar to other AIDs, T1D is an immune-mediated disease that develops in genetically susceptible individuals, in whom one or more additional AIDs may coexist, autoimmune thyroid diseases (AITD) (i.e. Graves' disease or Hashimoto's thyroiditis) and celiac disease (CD) being the most prevalent [26], [27], [28]. First-degree relatives (FDR) are more predisposed to develop T1D and to have a higher proportion of autoantibodies compared to the general population [25]. Considering the interaction between AIDs that is summarized above and the fact that there is growing evidence supporting a common genetic origin for these diseases, the familial aggregation of autoimmunity within first degree relatives (FDR) of T1D patients was examined.
Section snippets
Demographics of T1D patients and healthy individuals
Cases were children with T1D all of whom fulfilled the diagnostic classification criteria proposed by the American Diabetes Association (ADA) [29] and who belonged to our T1D cohort [30]. Their information on demographics and cumulative clinical manifestations over the course of disease were obtained by both chart review and discussion with the patient and was collected in a standard data collection form. A total of 98 patients with T1D were evaluated. Controls were 113 healthy children without
Diverse autoimmune diseases in pedigrees of T1D patient and controls
In this study 98 T1D patients were examined. In the families cases, 25 (25.5%) presented at least one FDR having an AID compared with 9 (8%) in control families (OR: 3.96, 95% CI: 1.75–9; p = 0.0006) (Table 1). There were not differences within gender, with a female: male ratio of 1:1.
Specific AIDs in FDR of T1D patients and healthy individuals are shown in Table 2. There were a total of 26 (8.3%) AIDs among the 312 FDR in cases compared with 9 (2.4%) AIDs among 362 FDR in controls (OR: 3.56, 95%
Discussion
These results indicate familial clustering of AIDs in patients with T1D in our population, and are consistent with previous results showing familial autoimmunity in other AIDs such as rheumatoid arthritis (RA) [9], systemic lupus erythematosus (SLE) [10], [11], primary Sjögren's syndrome [12], [13], polymyositis [14], juvenile RA [15], multiple sclerosis [16], vitiligo [17], and pemphigus [18].
Tait et al. [19] examined the presence of AIDs in British family members of patients with T1D.
Acknowledgments
We thank all the patients and participants of this study. Some of the results of this study were obtained by using the program package S.A.G.E., which is supported by a U.S. Public Health Service Resource Grant (RR03655) from the National Center for Research Resources. We also thank the two anonymous reviewers of this paper for their important comments.
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