The possible role of LINGO1 in the pathogenesis of MS makes it reasonable to analyse the possible relationship between LINGO1 polymorphisms and the risk of MS. In the present study, we found no significant differences in allele genotypes, or haplotypes frequencies for the rs9652490 and rs11856808 polymorphisms when comparing patients with MS and healthy control subjects. Nor were these polymorphisms related with the age at onset of MS or with the evolutive type of MS. The findings obtained, though negative, are novel and represent an incremental advance in the knowledge of the clinical implications of the LINGO1 gene polymorphism.
Some experimental data suggest a possible role of LINGO1 in the pathogenesis of MS: (a) Nogo-A expression has been found to be enhanced in surviving oligodendrocytes, while NgR has been found to be up-regulated in reactive astrocytes and macrophages/microglia in chronic active demyelinating lesions of MS , (b) TROY has been found to be up-regulated, whereas LINGO1 expression has been found to be reduced, in MS brains , (c) LINGO1 knockout mice have shown earlier onset of myelination of CNS axons than the wild-type, and greater resistance to the development of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) ; (d) Treatment with antibody antagonists against LINGO1 function induces functional recovery and increases integrity of axons in MOG-induced EAE , and promotes oligodendrocyte precursor cell differentiation and remyelination in different experimental models of demyelination and remyelination .
The LINGO1 SNPs analyzed in this study have been studied as putative risk biomarkers for other movement disorders. A recent meta-analysis, which included 3,972 essential tremor (ET) patients and 20,714 controls for the LINGO1 rs9652490 polymorphism, and 2,076 ET patients and 18,792 controls for the rs11856808 polymorphism, concluded that the rs11856808 polymorphism was related with increased risk for both total and familial ET, whereas the rs9652490 polymorphism was related with increased risk for familial ET . With regard to Parkinson’s disease, another recent meta-analysis including 5,541 patients and 5,647 controls for the rs9652490 polymorphism and 3,276 patients and 3,371 controls for the rs11856808 polymorphism concluded that these polymorphisms could not be considered as major risk factors for susceptibility to PD .
Several SNPs have been described within the LINGO1 gene and in the 3’ flanking region (Figure 1). It is to be noted that most genetic association studies on LINGO1 focused on the same SNPs which were analyzed in the present study [17–19, 21–24, 37–50]. Although several LINGO1 nonsynonymous SNPs have been described, namely rs113329801, rs201732477, rs112205560, rs150289554, rs113096707, rs188738703, rs200688402, rs200463885, rs9855, rs201517725, rs184237450, rs77436810, rs193100227, rs111741384, rs202233236, rs199976207, rs199628078, rs201438433, rs140914739, rs200528664, rs111605415 and rs202223502, none of these SNPs show a minor allele frequency over 0.0005 (see the website http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?showRare=on&chooseRs=all&go=Go&locusId=84894). Therefore, the identification of one heterozygous individual out of 1000 individuals studied is to be expected. This precluded the analysis of these nonsynonymous SNPs as putative risk factors. Nevertheless, the two SNPs studied are linked with other SNPs within the coding region of the LINGO1 gene. Figure 1 show that linkage varies depending on the population studied, being low in individuals of African descent, high in individuals of Oriental descent or in related populations (of Amerindian descent), and intermediate in individuals of Caucasian descent. The Italian Tuscany population shows a higher linkage than other Caucasian individuals, probably due to genetic admixture with other Mediterranean populations. This admixture took also place in Spain. The Figure indicates that the two SNPs analyzed in this study are linked to the rest of the SNPs shown in the Figure.
The present study has some limitations. First, the size of analyzed cohorts may not be sufficient for strict conclusions about LINGO1 role in MS. As was shown in a previous publication about the role of LINGO1 in essential tremor risk, individual studies of small number of patients gave very contradictory results . Second, although the sample size is adequate to detect an OR as small as 1.5, a more modest association would not be detected. Third, because EDSS or progression index are not completely adequate measures of disease severity, the negative association observed in this study does not rule out a putative association with disease severity. Moreover, because the cohort study included MS patients with different degrees of severity, it is not adequate for the investigation of the influence of LINGO1 genotypes on the disability or severity of MS (the ideal study for this purpose should include genotyping of patients with a recent diagnosis of MS with similar follow-up periods).