Abstract
Multiple Sclerosis (MS) displays a heterogeneous clinical onset and progression, which are mostly unpredictable, but demyelination of the central nervous system (CNS) leads to substantial deficits of sensory, motor, autonomic, and neurocognitive functions. Considering all genetic studies on MS, including the advanced genome-wide association studies, the risk linked to HLA alleles remains the highest among other susceptibility genetic variants. However, given the genetic variability of HLA alleles in different ethnic groups, we conducted a systematic review of reviews and meta-analyses aiming at summarizing all the results on the association between MS and HLA class II genes. We systematically searched meta-analyses and systematic reviews dealing with MS and HLA in all ethnicities. From 154 records, we included 5 articles collecting HLA data from 15,232 MS patients and 24,194 ethnically matched controls. DRB1∗15 (OR ranging from 1.39 in Chinese Han to 2.59 in Caucasians) and DQB1∗06:02 (OR ranging from 1.91 in Caucasians to 2.49 in Colombian) alleles confer an increased risk for MS transethnically (Caucasians, Chinese, South Americans, Carribeans, Middle Easterners, Japanese, and North Africans). DRB1∗01, DRB1∗09, DRB1∗11, DRB1∗12, and DRB1∗16 alleles were protective, in agreement with the type of amino-acidic (aa) residues (ranging from position 9 to 90) included in pockets 1, 4, 6, 7, and 9, which are most involved in peptide presentation. Changes in aa residues affect the capability of HLA molecules in binding myelin peptides. DQB1∗06:02 risk allele seems to be the most interesting target as humanized mice expressing only DQB1∗06:02 develop MS-like disease mediated by autoimmune reactions against myelin oligodendrocytic basic protein that stabilizes the myelin. Our summary of results from a high number of patients and controls suggests that allelic variants from both DQB1 and DRB1 genes are equally involved in MS susceptibility/protection transethnically.
Highlights
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that can lead to substantial deficits of sensory, motor, autonomic, and neurocognitive functions
On 21 December 2017, the protocol entitled “Association between Human Leukocyte Antigen (HLA) Class II (DRB1) Polymorphisms and Multiple Sclerosis: A Review of Systematic Reviews” was published in the PROSPERO International prospective register of systematic reviews (PROSPERO CRD42017076831), and from that date forward, it is available from https://www.crd.york.ac.uk/ PROSPERO/display_record.php?RecordID=76831
5 publications were deemed eligible for inclusion and were submitted to data extraction: 4 meta-analyses [14,15,16,17] and 1 systematic review [18]
Summary
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that can lead to substantial deficits of sensory, motor, autonomic, and neurocognitive functions. The disease is known to display a heterogeneous clinical onset and progression, which are mostly unpredictable [1]. Current data support the view of MS as a multifaceted disease caused by complex interactions between environmental factors and genetic susceptibility [3]. Ethnicity, geographical location, and environmental factors (such as vitamin D, smoke, infections, and air pollutions) influence both incidence and prevalence; on the other hand, Disease Markers due to an increased frequency of MS among first-degree relatives of affected subjects, a genetic background has been invoked to explain family aggregation [4]
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