A new risk variant for multiple sclerosis at the immunoglobulin heavy chain locus associates with intrathecal IgG, IgM index and oligoclonal bands.
BACKGROUND
Recent findings have shown a correlation between the intrathecal IgG index and variants at the immunoglobulin heavy chain (IGHC) locus in patients with multiple sclerosis (MS).


OBJECTIVE
The objective of this paper is to analyse the association of the locus with MS susceptibility and its relationship with intrathecal immunoglobulin (Ig) parameters.


METHODS
We genotyped the rs11621145 variant, located at the IGHC locus, in 2726 patients with MS and 2133 healthy controls. Associations of intrathecal IgG and IgM indexes with rs11621145 were analysed by linear regression analysis in 538 MS patients.


RESULTS
We found that rs11621145 showed statistically significant evidence for association with susceptibility to MS (odds ratio = 0.69, p = 1.053E-09), though validation of this result in additional cohorts would be desirable. We confirmed the association between the IgG index and the rs11621145 (p = 6.85E-07, Beta = 0.207). Furthermore, rs11621145 was inversely correlated with IgM index (p = 7.24E-04, Beta = -0.277), and therefore marks a decreased likelihood of presenting IgM oligoclonal bands (odds ratio = 0.38, p = 2.35E-06).


CONCLUSIONS
Our results suggest that the polymorphism of the IGHC locus could be altering the switching of the Ig isotype in B cells and it may be interfering with T-dependent and T-independent antibody responses.
Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain/These authors contributed equally to this work.
Mercedes
M
Delgado-García
Departamento de Biología Celular e Inmunología, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), Consejo Superior de Investigaciones Científicas CSIC, 18016 Granada, Spain/These authors contributed equally to this work lindo@ipb.csic.es.
Fuencisla
F
Matesanz
Departamento de Biología Celular e Inmunología, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), Consejo Superior de Investigaciones Científicas CSIC, 18016 Granada, Spain.
Antonio
A
Alcina
Departamento de Biología Celular e Inmunología, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), Consejo Superior de Investigaciones Científicas CSIC, 18016 Granada, Spain.
María
M
Fedetz
Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain.
María Isabel
MI
García-Sánchez
Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain.
Juan Luis
JL
Ruiz-Peña
Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain.
Óscar
Ó
Fernández
Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain.
María Jesús
MJ
Pinto Medel
Unidad de Gestión Clínica de Neurociencias, Instituto de Biomedicina de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Málaga, Spain.
Laura
L
Leyva
Servicio de Neurología, Hospital Virgen de las Nieves, Granada, Spain.
Carmen
C
Arnal
Centro Regional de Transfusión Sanguínea Granada-Almería, Ganada, Spain.
Concepción
C
Delgado
Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Madrid, Spain.
José Antonio
JA
López Guerrero
Centro Andaluz de Estudios Bioinformáticos (CAEBi), Sevilla, Spain.
Antonio
A
González-Pérez
Centro Andaluz de Estudios Bioinformáticos (CAEBi), Sevilla, Spain.
María E
ME
Sáez
Hospital Ramon y Cajal, Departments of Immunology and Neurology, MS Unit, (IRYCIS), Madrid, Spain.
Luisa María
LM
Villar
Hospital Ramon y Cajal, Departments of Immunology and Neurology, MS Unit, (IRYCIS), Madrid, Spain.
José Carlos
JC
Álvarez-Cermeño
Hospital Ramon y Cajal, Departments of Immunology and Neurology, MS Unit, (IRYCIS), Madrid, Spain.
Carmen
C
Picón
Multiple Sclerosis Unit, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
Rafael
R
Arroyo
ImmunologyDepartment, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico S. Carlos (IdISSC), Madrid, Spain.
Jezabel
J
Varadé
ImmunologyDepartment, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico S. Carlos (IdISSC), Madrid, Spain.
Elena
E
Urcelay
Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, Spain/These authors contributed equally to this work.
Guillermo
G
Izquierdo
Servicio de Biología Molecular, Hospital Universitario Virgen Macarena, Facultad de Medicina, Sevilla, Spain/These authors contributed equally to this work.
Miguel
M
Lucas
D000328:Adult; D005260:Female; D050438:Genes, Immunoglobulin Heavy Chain / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007074:Immunoglobulin G / Q000134:cerebrospinal fluid; D007075:Immunoglobulin M / Q000134:cerebrospinal fluid; D007525:Isoelectric Focusing; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000235:genetics* / Q000276:immunology; D043025:Oligoclonal Bands / Q000134:cerebrospinal fluid; D020641:Polymorphism, Single Nucleotide
D007074:Immunoglobulin G; D007075:Immunoglobulin M; D043025:Oligoclonal Bands
Multiple sclerosis (MS); SNP variant; association; immunoglobulin heavy chain (IGHC) locus; intrathecal IgG/IgM index; oligoclonal bands (OCBs)