Contributions
Abstract: P958
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Background: Clinical, radiological and neuropathological heterogeneity of Multiple Sclerosis (MS) suggests that different pathogenic mechanisms are involved in subgroups of MS patients. Single Nucleotide Polymorphisms (SNPs) show a relation with MRI outcome and disease severity in Genome Wide Association Studies (GWAS). We hypothesize that in subgroups of MS patients SNPs cause (in)activation of different pathogenic mechanisms, resulting in differences in pathological outcome, clinical disease course and response to immunomodulatory therapy.
Objective: identify SNPs that correlate with MS pathology in MS cohort of Netherlands Brain Bank (NBB).
Methods: 198 MS patients were included. From all archived tissue (n=3562) lesions were characterized with HLA-PLP immunohistochemistry. Lesion types were scored according to demyelination and microglia morphology. Reactive, active, chronic active, inactive and shadow plaques were distinguished in white matter and demyelination in cortical grey matter lesions. 104 SNPs were selected based on previous association with MRI measures or disease severity in GWAS and pathology in gene expression studies. DNA was isolated from leukocytes or cerebellum tissue. Competitive allele specific polymerase chain reaction (PCR) was performed for 104 SNPs. Statistical analysis of SNPs with total white matter lesion load, proportions of lesion types, cortical lesion presence and disease duration was performed in R.
Results: The most significant SNPs all showed a relation with proportion of reactive sites, indicating higher proportion of reactive microglia in normal appearing white matter; MIF (p=0,0001), MET (p=0,001), SKA1 (p=0,002) and AGBL4 (p=0,002). Analysis stratified by sex showed in males (n=66) most significant are MIF (p=0,0008) with proportion of reactive sites and RFK (p=0,0004) with proportion of active lesions. In females (n=103) most significant are SKA1 (p=0,001) with proportion of reactive sites, IGF2R (p=0,001) with total white matter lesion load.
Discussion: This exploratory study shows that in the NBB cohort SNPs are predicting pathological outcome of MS. This analysis suggests an important role for SNPs in predicting activation of microglia-macrophages. Validation of these SNPs in another post-mortem cohort of MS patients is needed. Further functional experiments on the effects of these SNPs on MS pathology will be conducted to better understand the different pathogenic mechanisms causing heterogeneity in MS.
Disclosure: N.L. Fransen; nothing to disclose
M. Mason; nothing to disclose
B. Crusius; nothing to disclose
C. van Eden; nothing to disclose
M. Mizee; nothing to disclose
S. Luchetti; nothing to disclose
I. Huitinga; nothing to disclose
Abstract: P958
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Genetics /Epigenetics and Pharmacogenetics
Background: Clinical, radiological and neuropathological heterogeneity of Multiple Sclerosis (MS) suggests that different pathogenic mechanisms are involved in subgroups of MS patients. Single Nucleotide Polymorphisms (SNPs) show a relation with MRI outcome and disease severity in Genome Wide Association Studies (GWAS). We hypothesize that in subgroups of MS patients SNPs cause (in)activation of different pathogenic mechanisms, resulting in differences in pathological outcome, clinical disease course and response to immunomodulatory therapy.
Objective: identify SNPs that correlate with MS pathology in MS cohort of Netherlands Brain Bank (NBB).
Methods: 198 MS patients were included. From all archived tissue (n=3562) lesions were characterized with HLA-PLP immunohistochemistry. Lesion types were scored according to demyelination and microglia morphology. Reactive, active, chronic active, inactive and shadow plaques were distinguished in white matter and demyelination in cortical grey matter lesions. 104 SNPs were selected based on previous association with MRI measures or disease severity in GWAS and pathology in gene expression studies. DNA was isolated from leukocytes or cerebellum tissue. Competitive allele specific polymerase chain reaction (PCR) was performed for 104 SNPs. Statistical analysis of SNPs with total white matter lesion load, proportions of lesion types, cortical lesion presence and disease duration was performed in R.
Results: The most significant SNPs all showed a relation with proportion of reactive sites, indicating higher proportion of reactive microglia in normal appearing white matter; MIF (p=0,0001), MET (p=0,001), SKA1 (p=0,002) and AGBL4 (p=0,002). Analysis stratified by sex showed in males (n=66) most significant are MIF (p=0,0008) with proportion of reactive sites and RFK (p=0,0004) with proportion of active lesions. In females (n=103) most significant are SKA1 (p=0,001) with proportion of reactive sites, IGF2R (p=0,001) with total white matter lesion load.
Discussion: This exploratory study shows that in the NBB cohort SNPs are predicting pathological outcome of MS. This analysis suggests an important role for SNPs in predicting activation of microglia-macrophages. Validation of these SNPs in another post-mortem cohort of MS patients is needed. Further functional experiments on the effects of these SNPs on MS pathology will be conducted to better understand the different pathogenic mechanisms causing heterogeneity in MS.
Disclosure: N.L. Fransen; nothing to disclose
M. Mason; nothing to disclose
B. Crusius; nothing to disclose
C. van Eden; nothing to disclose
M. Mizee; nothing to disclose
S. Luchetti; nothing to disclose
I. Huitinga; nothing to disclose