Primary Sjögren's Syndrome and Other Autoimmune Diseases in Families

Abstract

The relationships of human leukocyte antigen (HLA) and heavy chain immunoglobulin (Gm) haplotypes to disease and autoantibody expression were examined in six large kindreds, each having one or more members with primary Sjögren's syndrome. Various other autoimmune diseases and autoantibodies occurred among the 117 relatives in these families. The HLA and Gm haplotypes did not necessarily segregate persons into those with Sjögren's syndrome, other autoimmune disorders, or serologic abnormalities, but HLA alleles DR3 and DR2 occurred in significant excess in relatives with Sjögren's syndrome, irrespective of HLA haplotype. Segregation analysis suggested a Mendelian dominant genetic defect common to the many autoimmune diseases and serologic reactions that was not linked to HLA or Gm. A significant effect of female sex was also documented. These studies suggest that Sjögren's syndrome results from the interaction of several HLA-linked and non-HLA-linked genes.

Linkage studies of hla and primary sjögren's syndrome in multicase families

“…The Penrose method showed no evidence of association and linkage between primary S S and HLA-DR3 for any of the disease models, even when other published data were included (2,3). This suggests that the association of HLA-DR3 with primary SS within the families is dependent on the inclusion of non-siblings.…”

“…Associations with DRw52, DRw53, DQ, and complement alleles have also been described (3,(26)(27)(28)(29), and the association between HLA-DR3 and Ro seropositivity is stronger than that between HLA-DR3 and primary SS itself (26). The racial origin of the patients studied further affects the association with the HLA-DR phenotype (2)(3)(4)(5)8,(24)(25)(26). There is linkage disequilibrium between alleles of HLA loci, so it is often unclear whether it is the associated alleles or closely linked genes that are involved in disease susceptibility.…”

“…The Green and Woodrow method of sibship haplotype sharing analysis showed a trend toward sharing in models 1 and 2, but this was lost when milder primary SS (model 3) was included. The addition of 3 more sibships from published literature (2,3) to the analysis resulted in this trend reaching statistical significance for model 1 . The inclusion of affected individuals only may have enabled this trend to become evident by the Green and Woodrow method and not by LOD scores.…”

“…The present study showed no evidence of linkage between HLA and primary SS and thyroid disease taken as a discrete entity. This suggests that the common susceptibility factor to both primary SS and thyroid disease in the families is Several products of the HLA region have been observed to associate with primary SS, although no single phenotype associates with all racial groups and patterns of disease (2)(3)(4)(5)2429). It is possible that there are distinct forms of primary SS, with histologic, serologic, and clinical manifestations in common but with different genetic associations which reflect heterogeneity.…”

“…A study of multicase autoimmune phenomena showed no evidence of HLA linkage, and it was suggested that genetic susceptibility to autoimmunity in families followed a mendelian dominant trait, with variable penetrance depending on sex (9). However, the definition of autoimmune disease was broad, and the study included only a few subjects with primary SS (derived from a previous family study [2]). Our family study of primary SS is the largest to date and provides a population with which to investigate the possibility of linkage between primary SS and the HLA region.…”