Familial aggregation of autoimmune diseases and phenotypes

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A common means of establishing the extent of the genetic contribution to a disease or phenotype is to examine the degree of familial aggregation. For Mendelian disorders, the pattern of familial aggregation often suggests a genetic model (dominant or recessive). However, for the common autoimmune diseases, the extent of familial aggregation is quite modest, large extended families are rare in the population, and the genetic model is unknown. A commonly accepted method of quantifying familial aggregation is to compare the prevalence of disease in relatives of affected individuals (e.g., siblings), with the prevalence in the general population. In the case of siblings, this value is designated the relative risk to siblings (^s) and is generally in the range of 10-20 for many autoimmune diseases [12]. In the case of rheumatoid arthritis, the Xs is probably somewhat lower, in the range of 5-10 [13]. Although shared environmental factors among siblings can also explain a Xs that is greater than 1, it is likely that a substantial proportion of the increased risk to siblings is due to the fact that siblings share genetic variation in common with the affected individuals in these families. In addition, for phenotypes that are dependent on complex combinations of relatively uncommon genotypes, there may be very low degrees of familial aggregation, even in the presence of a large genetic component to the phenotype [14].

In addition to this evidence for familial aggregation of particular disease pheno-types, it is also apparent that in some cases different autoimmune disorders also tend to aggregate together in families with one another. This issue is difficult to study since it requires the study of sizable populations of affected subjects with careful characterization of disease phenotypes in their relatives. The best evidence for familial aggregation across diseases involves type 1 diabetes, rheumatoid arthritis and autoimmune thyroid disease [15-17]. SLE probably also falls into this group [18, 19], as well as other less common autoimmune disorders [20]. Multiple sclerosis may also have some tendency toward familial aggregation with these disorders although the data on this is less clear [21-23].

With the exception of MS, an excess of autoantibodies in unaffected relatives is also well described for many of these diseases. For example, approximately 20% of the first degree relatives of patients with SLE have evidence of humoral autoimmu-nity to one or more nuclear antigens [24-26]. There is also evidence of increased thyroid autoimmunity and anti-thyroid antibodies in unaffected family members of SLE patients [27], as well as an increase in anti-thyroglobulin autoantibodies in the SLE patients themselves [28]. Antibodies to citrullinated peptides (anti-CCP) are now widely accepted as being quite specific for rheumatoid arthritis: anti-CCP Abs are present in up to 80% of RA patients but less than 1% in the general population [29, 30]. There is no published data concerning the rate of these antibodies in relatives of RA patients. However autoimmune thyroid disease is present in 15-20% of patients with RA [31] and the rate of thyroid autoantibodies in their unaffected first degree relatives is approximately double the rate expected in a control population

Thus, the available data indicates that there is a significant tendency for some autoimmune phenotypes to aggregate with another in families, and this suggests that common genes may underlie these different disorders.

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