HLA genetics in multiple sclerosis

Multiple sclerosis (MS) is a chronic disease in which both genetic and environmental risk factors contribute to disease susceptibility. MS patients suffer from inflammatory lesions in the central nervous system which results in demyelination of nerve cells, reduced neuronal activity and finally neurodegeneration. The immune system has a central role in MS pathogenesis and human leukocyte antigen (HLA) molecules are key players. The genes encoding HLA class I and II molecules are highly polymorphic isotypically and allotypically which makes it problematic to identify which variants affect disease susceptibility.

The strongest genetic risk factor for MS is a haplotype of HLA class II alleles, DRB1*15:01,DRB5*01:01,DQA1*01:02,DQB1*06:02 (below referred to as DRB1*15) which increases the risk of MS 3-fold compared with the general Swedish population where the lifetime risk of MS is 0.2%. Our group pioneered the identification of a protective effect of the HLA class I region, by discovering that HLA-A*02 decreases the risk of MS by 40%. The main focus in this thesis has been to identify additional HLA factors, if any, that influence MS susceptibility.

In papers I and II we genotyped 1,784 Swedish and Norwegian MS patients and 1,660 controls, for HLA-DRB1, HLA-A, HLA-C, and eventually also HLA-B, and applied several statistical methods, mainly logistic regression analyses. We conclude that, in addition to the roles played by DRB1*15 and HLA-A*02, additional influence on susceptibility is exerted by HLA-DRB1*01, HLA-DRB1*07 and HLA-B*12, which are negatively associated with MS and HLA-B*14 which increases the risk of MS. Analysis based on haplotypes, rather than on alleles, showed that a haplotype carrying HLA-A*02, HLA-C*05 and HLA-B*12 is markedly protective, reducing the risk of MS 2.4-fold, also outweighing the risk of HLA-DRB1*15 when present on the same haplotype.

Paper III focuses on a possible interaction between genetic background (DRB1*15) and an environmental influence, a month-of-birth effect on MS risk. We demonstrate that patients born in April have a higher risk of being DRB1*15 positive. On the contrary, patients born in November have a lower risk of being DRB1*15 positive. We hypothesize that pregnancies exposed to a lower degree of sunlight thus lower levels of Vitamin D, confer an increased risk for a DRB1*15 positive child to later develop MS.

In paper IV the influence of HLA genes on the risk of developing neutralizing antibodies (NAbs) to interferon beta (IFN-β) treatment was studied. We show that the risk allele for MS, HLA-DRB1*15, is also a risk factor for development of NAbs in patients treated with high dose subcutaneously administered IFN-β 1-a, but not for IFN-β 1-b. DRB1*15 is also a risk factor for developing antibody titers high enough to abolish the effect of treatment. Thus, the genetic risk of NAbs varies with IFN-β formulation.

This thesis adds several pieces of information to the large MS genetics puzzle and suggests several roles of HLA genes and molecules that should be further investigated.

List of scientific papers

I. Two HLA class I genes independently associated with multiple sclerosis. LINK J, Lorentzen ÅR, Kockum I, Duvefelt K, Lie BA, Celius EG, Harbo HF, Hillert J, Brynedal B. J Neuroimmunol. 2010 Sep 14; 226(1-2):172-6.
https://doi.org/10.1016/j.jneuroim.2010.07.006

II. Importance of Human Leukocyte Antigen (HLA) class I and II Alleles on the Risk of Multiple Sclerosis. LINK J, Kockum I, Lorentzen ÅR, Lie BA, Celius EG, Westerlind H, Schaffer M, Alfredsson L, Olsson T, Brynedal B, Harbo HF, Hillert J. [Accepted]
https://doi.org/10.1371/journal.pone.0036779

III. HLA-DRB1 and month of birth in multiple sclerosis. Ramagopalan SV, LINK J, Byrnes JK, Dyment DA, Giovannoni G, Hintzen RQ, Sundqvist E, Kockum I, Smestad C, Lie BA, Harbo HF, Padyukov L, Alfredsson L, Olsson T, Sadovnick AD, Hillert J, Ebers GC. Neurology. 2009 Dec 15; 73(24):2107-11.
https://doi.org/10.1212/WNL.0b013e3181c679f3

IV. Human leukocyte antigen genes and interferon beta preparation influence on risk of developing neutralizing antibodies in multiple sclerosis. LINK J, Lundkvist M, Fink K, Hermanrud C, Brynedal B, Fogdell-Hahn A, Kockum I, Hillert J. [Manuscript]