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Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis


Buck, D and Albrecht, E and Aslam, M and Goris, A and Hauenstein, N and Jochim, A and Ban, M and Baranzini, S and Barcellos, L and Beecham, G and Beecham, A and Bernardinelli, L and Booth, D and Steffan, B and Bush, W and Comabella, M and Compston, A and Cotsapas, C and Cree, B and D'Alfonso, S and Daly, M and Damotte, V and Davis, M and de Bakker, P and De Jager, PL and Esposito, F and Fontaine, B and Gourraud, P-A and Green, T and Gulowsen Celius, E and Hadjixenofontos, A and Hafler, D and Haines, J and Harbo, HF and Hauser, S and Hawkins, C and Hillert, J and Hintzen, R and Horakova, D and Ivinson, AJ and Anu, K and Kira, J and Kockum, I and Lincoln, R and Martin, R and Martinelli Boneschi, F and McCauley, JL and Mero, I-L and Oksenberg, J and Olsson, T and Oturai, A and Aarno, P and Patsopoulos, N and Pericak-Vance, M and Rioux, J and Saarela, J and Sawcer, S and Schnetz-Boutaud, N and Finn, S and Soendergaard, H and Sorensen, PS and Spurkland, A and Stankovich, J and Stewart, G and Taylor, B and Ticca, A and West, S and Zipp, F and Cepok, S and Grummel, V and Dubois, B and Berthele, A and Lichtner, P and Gieger, C and Winkelmann, J and Hemmer, B, Wellcome Trust Case Control Consortium, Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis, Annals of Neurology, 73, (1) pp. 86-94. ISSN 0364-5134 (2013) [Refereed Article]

Copyright Statement

Copyright 2012 American Neurological Association

DOI: doi:10.1002/ana.23749


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. INTERPRETATION: 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.

Item Details

Item Type:Refereed Article
Research Division:Biomedical and Clinical Sciences
Research Group:Neurosciences
Research Field:Central nervous system
Objective Division:Health
Objective Group:Clinical health
Objective Field:Clinical health not elsewhere classified
UTAS Author:Stankovich, J (Dr Jim Stankovich)
UTAS Author:Taylor, B (Professor Bruce Taylor)
ID Code:89116
Year Published:2013
Web of Science® Times Cited:29
Deposited By:Menzies Institute for Medical Research
Deposited On:2014-02-25
Last Modified:2017-11-06

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