Review article: the genetics of the human leucocyte antigen region in inflammatory bowel disease

Abstract

Summary Background The human leucocyte antigen (HLA) complex, located at chromosome 6p21.3 is a highly polymorphic region containing the classical class I and II HLA genes. The region is highly associated with inflammatory bowel disease (IBD), largely through genome‐wide association studies (GWAS). Aims To review the role of HLA in immune function, summarise data on risk/protective HLA genotypes for IBD, discuss the role of HLA in IBD pathogenesis, treatment and examine limitations that might be addressed by future research. Methods An organised search strategy was used to collate articles describing HLA genes in IBD, including Crohn's disease and ulcerative colitis. Results All classical HLA genes with variation (including HLA‐A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1) harbour IBD‐associated genotypes. The most implicated gene is HLA‐DRB1, with HLA‐DRB1*03:01 the most associated risk allele in both Crohn's disease and ulcerative colitis. Elucidating precise disease associations is challenging due to high linkage disequilibrium between HLA genotypes. The mechanisms by which risk alleles cause disease are multifactorial, with the best evidence indicating structural and electrostatic alteration impacting antigen binding and downstream signalling. Adverse medication events have been associated with HLA genotypes including with thiopurines (pancreatitis) and anti‐TNF agents (antibody formation). Conclusions The HLA complex is associated with multiple risk/protective alleles for IBD. Future research utilising long‐read technology, ascertainment of zygosity and integration in disease modelling will improve the functional understanding and clinical translation of genetic findings.

HLA -A, -C, -B, -DRB1, -DQB1 and -DPB1 allele and haplotype frequencies in 4514 healthy Norwegians

“…S2 and S3 Paper I). The AH8.1 haplotype is positively associated with a wide variety of AID, including myasthenia gravis, systemic lupus erythematosus and coeliac disease [224], but also negatively associated to rheumatoid arthritis [94,225] and inflammatory bowel disease [226]. Therefore, negative association to the general "autoimmunity risk haplotype" AH8.1 could potentially indicate a protection against ME/CFS based on immune regulating functions of HLA.…”

Levels of Anti-Citrullinated Protein Antibodies and Rheumatoid Factor, Including IgA Isotypes, and Articular Manifestations in Ulcerative Colitis and Crohn’s Disease

“…In addition, bacterial antigens are hypothesized to contribute to ACPA development via molecular mimicry of self-antigens presented by predisposing HLA-DQ molecules [36]. However, HLA-associated genetic risk factors involved in IBD [37,38] are not involved in development of ACPA+ RA [39]. Therefore, we can speculate that due to the absence of these HLA-related risk factors, ACPA initiation in IBD is not followed by a maturation of the ACPA response and spreading of epitopes, which can be measured in the context of RA development.…”

Is celiac disease really associated with inflammatory bowel disease?

“…On the one hand, CD is positively associated with variants DR7 and DRB3*0301, as well as DQ4 among the Japanese population, and negatively associated with variants DR2 and DR3, whereas UC is associated with variants DR2, DR9, and DRB1*0103, with DR4 acting as a protective variant against UC (14). Despite the above association of various HLA variants with IBD, the exact molecular mechanisms and polymorphisms that promote its development, as well as the potential functional impact they may entail, are significantly difficult to interpret, partly because of linkage disequilibrium between genotypes (15). That is, since the DNA region coding for antigen-presenting molecules tends to be inherited in a non-random manner, for the various variants remain in one chromosome, understanding the actual effects of HLA on IBD becomes highly challenging.…”

“…That is, since the DNA region coding for antigen-presenting molecules tends to be inherited in a non-random manner, for the various variants remain in one chromosome, understanding the actual effects of HLA on IBD becomes highly challenging. Furthermore, the involvement of HLA in IBD is ambiguous as many variants contribute risk for CD and UC with colonic involvement whereas others predispose to ileal CD while protecting against UC and vice versa (15). Therefore, the HLA gene is known to play a key role in IBD, but one can only speculate about its role in aberrant responses to bacterial antigens, including those of commensal germs (15).…”

“…Furthermore, the involvement of HLA in IBD is ambiguous as many variants contribute risk for CD and UC with colonic involvement whereas others predispose to ileal CD while protecting against UC and vice versa (15). Therefore, the HLA gene is known to play a key role in IBD, but one can only speculate about its role in aberrant responses to bacterial antigens, including those of commensal germs (15).…”