HLA Haplotypes in Familial Graves’Disease

Abstract

In order to further elucidate the genetics of Graves’disease, we studied two families with several affected members, as well as tested the degree to which HLA haplotypes were shared in affected sibpairs. Further, we sought to identify the disease related haplotypes by determining the haplotypes shared among affected parent‐child combinations. In one family, two affected sibs differed at four possible parental HLA haplotypes; no evidence of recombination was observed which could account for the result. In the other family, five siblings were affected. Four out of the five affected sibs shared the maternal haplotype HLA‐A11, Bw51, Cw5, Cw‐, DRw5, Bfs, GLO1, whereas three shared the paternal haplotype HLA‐Al, B8, Cw‐, DRw3, Bf and GLO1. Looking at haplotype sharing, two pairs of sibs were found to be HLA identical, whereas the fifth sib shared one haplotype with one of these pairs but not with the other. Out of 14 (eight of our own and six from the literature) affected sibpairs examined, nine were found to be HLA identical and four shared one haplotype, suggesting that the contribution of both paternal haplotypes may be necessary for the susceptibility to the disease. Fourteen parent‐child combinations were studied; in only three out of 13 in which the shared haplotype could be ascertained was the haplotype B8 positive; this distribution is similar to controls. However, of the remaining 10 combinations which did not share a B8 positive haplotype, five were B8 positive at one or the other of the nonshared haplotypes.

Peripheral immunophenotyping of AITD subjects reveals alterations in immune cells in pediatric vs adult-onset AITD

“…The high risk HLA-DR3 haplotype is more common in pediatric-onset AITD subjects Given that the underlying immunopathogenesis of AITD likely involves perturbations in multiple immune cells, such as T, B, and myeloid cells, as well as an imbalance in pro-inflammatory cytokine production, 1). These findings are consistent with previous reports that the HLA-DR3 haplotype is more common in young onset AITD patients compared to older onset AITD (Farid et al, 1980a;Jurecka-Lubieniecka et al, 2013). Interestingly, despite previous findings of gender disparity in adult AITD (i.e., increased female:male ratio), such disparity is less apparent in pediatric AITD.…”

Association of immunoglobulin A deficiency and elevated thyrotropin-receptor autoantibodies in two Nordic countries

“…Thus, our results and previous findings by others, demonstrate a marked difference in the association of IgAD with different autoimmune diseases associated with the 8.1 ancestral haplotype. The risk of developing GD is increased among individuals expressing HLA-B8 [28], even more so among those who carry HLA-DR3 [29,30]. Our results demonstrate similar findings with 54% of the Swedish IgAD cohort and 41% of the Icelandic IgAD cohort carrying the HLA-B8, DR3, DQ2 haplotype.…”

“…It has been shown that the risk of developing GD is increased among individuals expressing HLA-B8 [28], and even more so among those who carry HLA-DR3 [29,30]. Similarly, several studies have reported an increased frequency of the same alleles (or the HLA-B8, DR3 haplotype) within IgAD cohorts, particularly in individuals of white ethnicity [31,32].…”

HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system

“…A subgroup of rheumatoid arthritis patients bears the A*11:01 allele ( [Bhatia et al, 1988] and [Tsuchiya et al, 2001]), and the same has been found in the case of children with steroidresponsive nephrotic syndrome in Southeast Asia (Cheung et al, 2002). In addition, associations of A*11:01 with Grave's disease, parasitic skin diseases, and panbronchiolytis have been described ( [Farid et al, 1980], [Morsy et al, 1990] and [Park et al, 1999]). Similarly, A*31:01 has been reported to be associated with Vogt-Koyanagi-Harada syndrome in Korean ophthalmologic patients (Kim et al, 2000), elevated levels of the HLA-A33 antigen have been found in the blood of Japanese individuals affected by biliary atresia (Nakada et al, 1997), and the frequency of A*68:01 is increased in patients with dermatomyositis (O'Hanlon et al, 2005).…”