Autoimmune diseases and 8.1 ancestral haplotype: An update

Abstract

The aim of the present review is to provide an update of the current research into the pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype. This is a common Caucasoid haplotype carried by most people who type for HLA-B8, DR3. Numerous genetic studies reported that individuals with certain HLA alleles have a higher risk of specific autoimmune disorders than those without these alleles. However, much remains to be learned about the heritability of autoimmune conditions. Recently, progress and advances in the field of genome-wide-association studies have revolutionized the capacity to perform large, economically feasible, and statistically robust analyses of HLA within 8.1 ancestral haplotype, and understand its contribute to autoimmune events. In this paper, the characteristic features of this haplotype that might give rise to diverse autoimmune phenotypes are reviewed, focusing on the contribution of the HLA-DRB1 gene, the most polymorphic sequence within the HLA II region.

HLA association in MOG-IgG– and AQP4-IgG–related disorders of the CNS in the Dutch population

“…Of interest, this ancestral European haplotype including HLA-DRB1*03 has also been linked to several other autoimmune diseases, such as SLE, Sjögren syndrome, myasthenia gravis, Graves disease, and celiac disease. 32,33 This is in accordance with the clinical observation in AQP4-IgG-seropositive patients that around 25% of these patients have coexisting autoimmune disorders as listed above. [34][35][36][37][38] In our AQP4-IgG-seropositive patients 19% also had an accompanying autoimmune disease.…”

“…Nonetheless, HLA-A*01 and HLA-B*08 are also known to form an ancestral European haplotype together with (among others) HLA-DRB1*03 due to linkage. 33 Whether there is an independent contribution of HLA-A*01 and HLA-B*08 in AQP4-IgG-mediated NMOSD or whether these HLA Class I associations are only a result of linkage with DRB1*03 remains to be established.…”

The complexity and diversity of major histocompatibility complex challenge disease association studies

“…However, recently also neurobiological processes of synaptogenesis have been shown to be dependent on HLA and non‐HLA molecules of the MHC . Till date, over 160 different diseases associated with MHC have been identified by candidate gene analyses, gene expression, and proteomic analyses, with genome‐wide association studies (GWAS), Immunochip, and phenome‐wide association studies (PheWAS) (Table ) . Importantly, in HLA‐associated diseases, population‐based variation in the frequencies of risk/protective alleles and haplotypes is significant and should be included in phenotype characterization of disease subgroups and interventional trials …”

“…[50][51][52] Till date, over 160 different diseases associated with MHC have been identified by candidate gene analyses, gene expression, and proteomic analyses, with genome-wide association studies (GWAS), Immunochip, and phenome-wide association studies (PheWAS) ( Table 4). 29,[52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] Importantly, in HLA-associated diseases, population-based variation in the frequencies of risk/protective alleles and haplotypes is significant and should be included in phenotype characterization of disease subgroups and interventional trials. 69 We have challenged the drawbacks of the HLA-DRB1 imputation in combining GWA SNP results with the allele copy numbers of HLA-DRB1*01 determined by genomic quantitative polymerase chain reaction (PCR) as a priori candidate gene associated with the complex disease of coronary artery disease.…”

In-depth genetic analysis of 6p21.3 reveals insights into associations between HLA types and complex traits and disease

“…Our data are a valuable resource for both the genetics and disease-focus communities, providing insights into the genetic architecture of the MHC region that have not previously been described. To demonstrate the utility of our resource, we examined the common Caucasian 8.1 ancestral haplotype (8.1AH), which spans the entire MHC region and is associated with many autoimmune disorders and other diseases (Gambino et al, 2018), but is protective against bacterial colonization in Cystic Fibrosis (CF) patients (Laki et al, 2006). We show that 8.1AH is associated with decreased expression of RNF5, which in turn stabilizes the cystic fibrosis transmembrane conductance regulator (CFTR) protein, thereby rescuing its function.…”