HLA-DR15 Haplotype and Multiple Sclerosis: A HuGE Review

Abstract

An association between multiple sclerosis (MS) and the human leukocyte antigen (HLA) complex, a dense cluster of genes on the short arm of chromosome 6, was first noted over 30 years ago. In Caucasian populations of Northern European descent, the DR15 haplotype (DRB1*1501-DQA1*0102-DQB1*0602) has been hypothesized to be the primary HLA genetic susceptibility factor for MS. However, studies of other populations have produced varying results. Thus, the authors reviewed the literature for articles on the association between the DR15 haplotype and MS. They identified 72 papers meeting the inclusion criteria: human genetic studies written in English that were published between 1993 and 2004 and that reported allele frequencies for HLA-DRB1*1501, HLA-DQA1*0102, or HLA-DQB1*0602 or the frequency of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. Most of the studies identified used a case-control design (n = 60), while the remainder used a family-based design (n = 22). In most of these papers, investigators reported a higher frequency of the DR15 haplotype and/or its component alleles among MS cases than among controls. However, the authors' confidence in these results is tempered by factors related to study design that may have biased the outcomes.

The HLA Class II Allele DRB1*1501 Is Over-Represented In Patients With Idiopathic Pulmonary Fibrosis

“…The present findings implicate immunoregulatory elements within the HLA Class II complex in the pathogenesis of IPF. These data are also consistent with the hypothesis that the development of IPF likely involves interactions between environmental agent(s) and genetic factors [34,35], a disease paradigm also common to many other disorders, notably including those caused by aberrant immune processes [19][20][21][22][23][24].…”

“…Two distinct mechanisms may account for the frequently observed associations between unique HLA polymorphisms and various disease syndromes [19][20][21][22][23][24]. First, HLA molecules are requisite effectors for presentations of peptide antigens to the Tcells that initiate adaptive immune responses, but each distinct HLA allele has a restricted peptide binding motif [25].…”

“…HLA allele frequencies are often aberrantly distributed among patients with immunologic disorders [19][20][21][22][23][24]. However, HLA characterizations of IPF populations have not been extensively pursued, particularly among disease cohorts that have been delineated by contemporaneous diagnostic criteria [1] and use of definitive, molecular allele typing.…”

Multiple sclerosis associates with LILRA3 deletion in Spanish patients

“…1 The strongest and the best characterized predisposing genetic factor for MS lies, as in many autoimmune diseases, in the major histocompatibility complex of chromosome 6: the HLA-DRB1*1501 allele. 2,3 Polymorphisms of other genes related to the immunological response, namely IL7R and IL2RA, also contribute, albeit more modestly, to the risk of suffering MS (odds ratio (OR) values: 1.18-1.34). [4][5][6][7] In Germans, 8 RR-MS is associated with deficiency of the A3 member of the leukocyte immunoglobulin (Ig)-like receptor family (LILRA3, CD85e), molecule earlier referred to as Ig-like transcript 6 (ILT6), leukocyte Ig-like receptor 4 (LIR-4) or HM43.…”

HLA DRB5*01 Association Survey with Multiple Sclerosis in Khuzestan Province of Iran

“…HLA genes have three groups: class I, class II, and class III. The present of antigens from outside of the cell to T-lymphocytes is the function of HLAs class II and it contains the classical alpha and beta chain genes including DP, DM, DOA, DOB, DQ , and DR. As Class II molecules can bind and present certain self-peptides, several studies indicated that HLAs class II have been associated to several autoimmune or immune mediated disorders, including MS [29]. An estimated 10-60% of the MS genetic risk appears to be conferred by the DR15 haplotype (DQB1*0602, DQA1*0102, DRB1*1501, DRB5*0101) [30].…”