Method for determining the risk of developing a neurological disease

Abstract

Methods and kits are provided for determining whether a subject is at risk of developing a neurological disease such as Alzheimer's disease and multiple sclerosis. The methods and kits are based on the detection of one or more nucleic acid variants in the MBL gene of the subject.

1 . A method for determining whether a subject is at risk of developing a neurological disease, comprising the step of detecting the presence or absence of one or more nucleic acid variants in the MBL genes of said subject.  
     
     
         2 . The method according to  claim 1 , comprising: 
 (a) detecting the presence or absence of one or more nucleic acid variants in the MBL genes of said subject; and    (b) determining, from the nucleic acid variants detected in step (a), whether the subject is at risk of developing a neurological disease, whereby the absence or presence of certain variant sequences in the MBL genes indicates that the subject is at risk of developing a neurological disease.    
     
     
         3 . The method according to any of  claims 1  to  2 , further characterized in that the neurological disease is selected from the following: Alzheimer's disease, Pick's disease, Parkinson's disease, dementia with Lewy bodies, Huntington disease, chromosome 13 dementias, Down's syndrome, cerebrovascular disease, multiple sclerosis, Rasmussen's encephalitis, viral meningitis, NPSLE, amyotrophic lateral sclerosis, Creutzfeldt-Jacob disease, Gerstmann-Straussler-Scheinker disease, transmissible spongiform encephalopathies, ischemic reperfusion damage (e.g. stroke), brain trauma, microbial infection and chronic fatigue syndrome.  
     
     
         4 . The method according to any of  claims 1  to  3 , further characterized in that the variant sequence in the MBL genes is detected in the promoter region, in the 5′ UTR and/or in exon 1 of the MBL2 gene.  
     
     
         5 . The method according to  claim 4 , further characterized in that the variant sequence in the MBL2 genes is detected in at least one of the positions −550, −221, +4, +154, +161 and/or +170 of the MBL2 gene.  
     
     
         6 . The method according to claims  5 , further characterized in that the variant is −550 (G>C), −221 (G>C), +4 (C>T), +154 (C>T), +161 (G>A) and/or +170 (G>A) of the MBL2 gene.  
     
     
         7 . The method according to  claim 6 , further characterized in that the absence of nucleotide T at position +154 (variant D), nucleotide A at position +161 (variant B) and nucleotide A at position +170 (variant C) indicates that the subject is at risk of developing Alzheimer's disease.  
     
     
         8 . The method according to  claim 7 , further characterized in that the absence of the haplotypes HYPD, LYPB and LYQC indicates that the subject is at risk of developing Alzheimer's disease.  
     
     
         9 . The method according to  claim 6 , further characterized in that the presence of nucleotide C at position −221 (variant X) indicates that the subject is at risk of developing Alzheimer's disease.  
     
     
         10 . The method according to  claim 9 , further characterized in that the presence of the haplotype LXPA indicates that the subject is at risk of developing Alzheimer's disease.  
     
     
         11 . The method according to  claim 6 , further characterized in that the presence of the haplotype LYPA indicates that the subject is at risk of developing multiple sclerosis.  
     
     
         12 . The method according to any of  claims 1  to  11 , further characterized in that the presence or absence of nucleic acid variants is detected by one of the following methods: hybridization, sequencing, PCR, primer extension and restriction site analysis.  
     
     
         13 . The method according to any of  claims 1  to  3 , further characterized in that the nucleic acid variants in the MBL genes are detected by their phenotype.  
     
     
         14 . The method according to  claim 13 , further characterized in that the concentration of one or more protein variants of the MBL product is measured.  
     
     
         15 . The method according to  claim 14 , comprising: 
 (a) measuring the concentration of one or more protein variants of the MBL product in said subject; and    (b) determining, from the measurement in step (a), whether the subject is at risk of developing a neurological disease, whereby a change in the concentration of a certain MBL protein variant indicates that the subject is at risk of developing a neurological disease.    
     
     
         16 . The method according to  claim 15 , further characterized in that the concentration of one or more protein variants of the MBL2 product is measured.  
     
     
         17 . The method according to  claim 16 , further characterized in that the MBL2 protein variant with C at amino acid position 52 (variant D), D at amino acid position 54 (variant B) or E at amino acid position 57 (variant C) is detected, whereby the absence of said MBL2 protein variants indicates that the subject is at risk of developing Alzheimer's disease.  
     
     
         18 . The method according to any of  claims 14  to  17 , further characterized in that the concentration of one or more MBL protein variants is measured by immunoassay.  
     
     
         19 . The method according to  claim 13 , further characterized in that the functional activity of the MBL product is measured.  
     
     
         20 . The method according to  claim 19 , comprising: 
 (a) measuring the functional activity of the MBL product in said subject;    (b) determining, from the measurement step (a), whether the subject is at risk of developing a neurological disease, whereby a change in the functional activity of the MBL product indicates that the subject is at risk of developing a neurological disease.    
     
     
         21 . The method according to any of  claims 1  to  20 , further characterized in that the presence or absence of a nucleic acid variant in the MBL gene is determined in vitro in a biological sample obtained from said subject.  
     
     
         22 . The method according to  claim 21 , further characterized in that the biological sample is a tissue sample or a body fluid sample.  
     
     
         23 . The method according to  claim 22 , further characterized in that the biological sample is a brain, blood, plasma, saliva or cerebrospinal fluid sample.  
     
     
         24 . The method according to any of  claims 1  to  23 , further characterized in that the presence or absence of a nucleic acid variant in the MBL genes is determined in combination with the detection of one or more other risk factors.  
     
     
         25 . The method according to  claim 24 , further characterized in that the other risk factor is the ApoE genotype, the presenilin-1 genotype, the presenilin-2 genotype, a mutation in the APP gene or a CYP46 polymorphism.  
     
     
         26 . A method for the treatment or prevention of a neurological disease in a subject comprising the following: 
 (a) detecting the presence or absence of one or more nucleic acid variants in the MBL genes of said subject; and    (b) administering to the subject a suitable therapeutic agent, based on the nucleic acid variant detected in step (a).    
     
     
         27 . A kit for determining whether a subject is at risk of developing a neurological disease, comprising: 
 (a) a means for detecting the presence or absence of one or more nucleic acid variants in the MBL genes of said subject, for measuring the concentration of one or more MBL protein variants in said subject and/or for measuring the MBL functional activity in said subject; and    (b) a means for determining, from the nucleic acid variants, the protein variant concentration and/or the functional activity detected with the means of step (a), whether the subject is at risk of developing a neurological disease.    
     
     
         28 . The kit according to  claim 27 , comprising: 
 (a) a means for detecting the presence or absence of one or more nucleic acid variants at nucleic acid positions +154 (C>T), +161 (G>A) and/or +170 (G>A) of the MBL2 genes of said subject; and    (b) a means for determining, from the nucleic acid variants detected with the means of step (a), whether the subject is at risk of developing a neurological disease, whereby the absence of nucleotide T at position +154 (variant D), nucleotide A at position +161 (variant B) and nucleotide A at position +170 (variant C) of the MBL2 gene indicates that the subject is at risk of developing Alzheimer's disease.    
     
     
         29 . The kit according to  claim 28 , comprising: 
 (a) a means for detecting the MBL haplotype of said subject; and    (b) a means for determining, from the haplotypes detected with the means of step (a), whether the subject is at risk of developing a neurological disease, whereby the absence of the haplotypes HYPD, LYPB and LYQC indicates that the subject is at risk of developing Alzheimer's disease.    
     
     
         30 . The kit according to  claim 27 , comprising: 
 (a) a means for detecting the presence or absence of one or more nucleic acid variants at position −221 (G>C) of the MBL2 genes of said subject; and    (b) a means for determining, from the nucleic acid variants detected with the means of step (a), whether the subject is at risk of developing a neurological disease, whereby the presence of a nucleotide C at position −221 (variant X) of the MBL2 gene indicates that the subject is at risk of developing Alzheimer's disease.    
     
     
         31 . The kit according to  claim 30 , comprising: 
 (a) a means for detecting the MBL haplotype of said subject; and    (b) a means for determining, from the haplotypes detected with the means of step (a), whether the subject is at risk of developing a neurological disease, whereby the presence of the haplotype LXPA indicates that the subject is at risk of developing Alzheimer's disease.    
     
     
         32 . The kit according to  claim 27 , comprising: 
 (a) a means for detecting the MBL haplotype of said subject; and    (b) a means for determining, from the haplotypes detected with the means of step (a), whether the subject is at risk of developing a neurological disease, whereby the presence of the haplotype LYPA indicates that the subject is at risk of developing multiple sclerosis.    
     
     
         33 . The kit according to  claim 27 , comprising: 
 (a) an antibody that specifically recognizes the MBL protein variant that is measured; and    (b) a means for determining, from the MBL protein variant concentration measured with the means of step (a), whether the subject is at risk of developing a neurological disease.    
     
     
         34 . The kit according to  claim 33 , comprising: 
 (a) an antibody that specifically recognizes the MBL2 protein variant with C at amino acid position 52 (variant D), D at amino acid position 54 (variant B) and/or E at amino acid position 57 (variant C); and    (b) a means for determining, from the MBL protein variant concentration measured with the means of step (a), whether the subject is at risk of developing a neurological disease, whereby the absence of the MBL2 protein variant with C at amino acid position 52 (variant D), D at position 54 (variant B) and E at position 57 (variant C) indicates that the subject is at risk of developing Alzheimer's disease.    
     
     
         35 . The kit according to any of  claims 27  to  34 , further characterized in that the means for determining whether the subject is at risk of developing a neurological disease comprises a predisposition risk algorithm taking into account at least one of the following: the MBL nucleic acid variants or haplotypes, the MBL protein variant concentration and/or the MBL functional activity, to determine the risk for developing a neurological disease.  
     
     
         36 . A kit for determining whether a subject is at risk of developing a neurological disease, comprising: 
 (a) a means for detecting the presence or absence of one or more nucleic acid variants in the MBL gene of said subject, for measuring the concentration of one or more MBL protein variants in said subject and/or for measuring the MBL functional activity in said subject; and    (b) a means for detecting the ApoE genotype, the presenilin-1 genotype, the presenilin-2 genotype, a mutation in the APP gene and/or a CYP46 polymorphism in said subject.