title: Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis.
abstract: OBJECTIVE
  Intrathecal synthesis of immunoglobulin gamma (IgG) synthesis is frequently observed in patients with multiple sclerosis (MS). Whereas the extent of intrathecal IgG synthesis varies largely between patients, it remains rather constant in the individual patient over time. The aim of this study was to identify common genetic variants associated with the IgG index as a marker of intrathecal IgG synthesis in MS.
  
  
  METHODS
  We performed a genome-wide association study of the IgG index in a discovery series of 229 patients. For confirmation we performed a replication in 2 independent series comprising 256 and 153 patients, respectively. The impact of associated single nucleotide polymorphisms (SNPs) on MS susceptibility was analyzed in an additional 1,854 cases and 5,175 controls.
  
  
  RESULTS
  Significant association between the IgG index and 5 SNPs was detected in the discovery and confirmed in both replication series reaching combined p values of p = 6.5 × 10(-11) to p = 7.5 × 10(-16) . All identified SNPs are clustered around the immunoglobulin heavy chain (IGHC) locus on chromosome 14q32.33 and are in linkage disequilibrium (r(2) range, 0.71-0.95). The best associated SNP is located in an intronic region of the immunoglobulin gamma3 heavy chain gene. Additional sequencing identified the GM21* haplotype to be associated with a high IgG index. Further evaluation of the IGHC SNPs revealed no association with susceptibility to MS in our data set.
  
  
  CONCLUSIONS
  The extent of intrathecal IgG in MS is influenced by the IGHC locus. No association with susceptibility to MS was found. Therefore GM haplotypes might affect intrathecal IgG synthesis independently of the underlying disease.
authors.affiliation: Department of Neurology, Technische Universität München, Munich, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Buck
authors.forename: Eva
authors.initials: E
authors.lastname: Albrecht
authors.forename: Muhammad
authors.initials: M
authors.lastname: Aslam
authors.forename: An
authors.initials: A
authors.lastname: Goris
authors.forename: Natalie
authors.initials: N
authors.lastname: Hauenstein
authors.forename: Angela
authors.initials: A
authors.lastname: Jochim
authors.forename: Sabine
authors.initials: S
authors.lastname: Cepok
authors.forename: Verena
authors.initials: V
authors.lastname: Grummel
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Dubois
authors.forename: Achim
authors.initials: A
authors.lastname: Berthele
authors.forename: Peter
authors.initials: P
authors.lastname: Lichtner
authors.forename: Christian
authors.initials: C
authors.lastname: Gieger
authors.forename: Juliane
authors.initials: J
authors.lastname: Winkelmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000134:cerebrospinal fluid; D005260:Female; D056426:Genetic Loci / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D007074:Immunoglobulin G / Q000134:cerebrospinal fluid* / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000134:cerebrospinal fluid / Q000235:genetics*; D007142:Immunoglobulin gamma-Chains / Q000134:cerebrospinal fluid / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007142:Immunoglobulin gamma-Chains