Contributions
Abstract: P1212
Type: Poster
Abstract Category: Therapy - disease modifying - 29 Risk management for disease modifying treatments
Background: JC polyomavirus (JCV) is known to cause progressive multifocal leukoencephalopathy (PML) during immunosuppression which can occur during immunomodulatory treatment
(e.g. natalizumab, rituximab) for multiple sclerosis (MS). Risk for PML development particularly before treatment is often assessed by level of JCV titers in plasma. In this study, we conducted a genome-wide association analysis to determine host genetic factors that are associated with JCV antibody levels.
Methods: JCV IgG antibody levels were measured in the plasma of 6,872 MS cases and 5,780 matched controls obtained from multiple Swedish MS cohort studies. Antibody levels were measured using a Luminex bead-based assay combined with glutathione-GST protein capture for the JC viral capsid protein (VP1). Seropositivity was determined in comparison to second generation STRATIFY JCV ELISA. Genotyping of approximately ~600,000 single nucleotide polymorphisms (SNPs) were measured using an Illumina Omniexpress BeadChip array.
Results: Analysis showed strong association of JCV seropositivity to three regions on chromosome 6, 9, and 19. Association on chromosome 6 was due to the highly polymorphic HLA genes as was described in previous studies. Top non-HLA associations were with rs687289 and rs601338 (P< 10-8 and P< 10-19, respectively). These two SNPs are associated with ABO blood type (ABO gene) and secretion status (FUT2 gene) where secretion status refers to the expression of the ABH and Lewis antigens in the mucous. Subjects who had blood type O and (-) secretor status were at a higher risk for JCV seropositivity in comparison to AB type and (+) secretor status (OR= 1.39, 95% CI= 1.19-1.61).
Conclusion: Our findings showed an interaction between JCV seropositivity and both ABH secretor status and ABO blood groupings. This suggests a possible neutralization effect due to interaction between the ABH antigens and JCV receptors resulting in protection against infection and lower rates of seropositivity. However, further studies are necessary to determine mechanism of interaction. Clinical implications may include the additional usage of blood antigen phenotypes in determining the risk for PML development.
Disclosure: This study is supported by the PML consortium.
Jesse Huang, Izaura Lima Bomfim, Angelika Michel, Mohsen Khademi, Tim Waterboer has nothing to disclose.
Jenny Link received support from Neuro Sweden.
Clemens Warnke has received consultancy or speaking fees from Novartis, Bayer, Biogen and Teva.
Jan Hillert has received honoraria for serving on advisory boards for Biogen and Novartis and speaker´s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Merck-Serono, Sanofi-Genzyme, and Novartis.
Lars Alfredsson received speaker´s fee from Biogene and Teva and receives research support from the Swedish Medical Research Council (Dnr 521-2012-2917), Swedish Council for Health, Working Life and Welfare (Dnr 2012-0325), and Swedish Brain Foundation.
Tomas Olsson has received lecture and/or advisory board honoraria, and unrestricted MS research grants from Astrazeneca, Biogen, Novartis, Allmiral and Genzyme. Ingrid Kockum received speaker honoraria from Merck Serono and receives research support from the Swedish Brain Foundation and Horizon2020.
Abstract: P1212
Type: Poster
Abstract Category: Therapy - disease modifying - 29 Risk management for disease modifying treatments
Background: JC polyomavirus (JCV) is known to cause progressive multifocal leukoencephalopathy (PML) during immunosuppression which can occur during immunomodulatory treatment
(e.g. natalizumab, rituximab) for multiple sclerosis (MS). Risk for PML development particularly before treatment is often assessed by level of JCV titers in plasma. In this study, we conducted a genome-wide association analysis to determine host genetic factors that are associated with JCV antibody levels.
Methods: JCV IgG antibody levels were measured in the plasma of 6,872 MS cases and 5,780 matched controls obtained from multiple Swedish MS cohort studies. Antibody levels were measured using a Luminex bead-based assay combined with glutathione-GST protein capture for the JC viral capsid protein (VP1). Seropositivity was determined in comparison to second generation STRATIFY JCV ELISA. Genotyping of approximately ~600,000 single nucleotide polymorphisms (SNPs) were measured using an Illumina Omniexpress BeadChip array.
Results: Analysis showed strong association of JCV seropositivity to three regions on chromosome 6, 9, and 19. Association on chromosome 6 was due to the highly polymorphic HLA genes as was described in previous studies. Top non-HLA associations were with rs687289 and rs601338 (P< 10-8 and P< 10-19, respectively). These two SNPs are associated with ABO blood type (ABO gene) and secretion status (FUT2 gene) where secretion status refers to the expression of the ABH and Lewis antigens in the mucous. Subjects who had blood type O and (-) secretor status were at a higher risk for JCV seropositivity in comparison to AB type and (+) secretor status (OR= 1.39, 95% CI= 1.19-1.61).
Conclusion: Our findings showed an interaction between JCV seropositivity and both ABH secretor status and ABO blood groupings. This suggests a possible neutralization effect due to interaction between the ABH antigens and JCV receptors resulting in protection against infection and lower rates of seropositivity. However, further studies are necessary to determine mechanism of interaction. Clinical implications may include the additional usage of blood antigen phenotypes in determining the risk for PML development.
Disclosure: This study is supported by the PML consortium.
Jesse Huang, Izaura Lima Bomfim, Angelika Michel, Mohsen Khademi, Tim Waterboer has nothing to disclose.
Jenny Link received support from Neuro Sweden.
Clemens Warnke has received consultancy or speaking fees from Novartis, Bayer, Biogen and Teva.
Jan Hillert has received honoraria for serving on advisory boards for Biogen and Novartis and speaker´s fees from BiogenIdec, Merck-Serono, Bayer-Schering, Teva and Sanofi-Aventis. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Merck-Serono, Sanofi-Genzyme, and Novartis.
Lars Alfredsson received speaker´s fee from Biogene and Teva and receives research support from the Swedish Medical Research Council (Dnr 521-2012-2917), Swedish Council for Health, Working Life and Welfare (Dnr 2012-0325), and Swedish Brain Foundation.
Tomas Olsson has received lecture and/or advisory board honoraria, and unrestricted MS research grants from Astrazeneca, Biogen, Novartis, Allmiral and Genzyme. Ingrid Kockum received speaker honoraria from Merck Serono and receives research support from the Swedish Brain Foundation and Horizon2020.