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.
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.
Authors: B G Weinshenker; P C O'Brien; T M Petterson; J H Noseworthy; C F Lucchinetti; D W Dodick; A A Pineda; L N Stevens; M Rodriguez Journal: Ann Neurol Date: 1999-12 Impact factor: 10.422
Authors: Laura Piccio; Robert T Naismith; Kathryn Trinkaus; Robyn S Klein; Becky J Parks; Jeri A Lyons; Anne H Cross Journal: Arch Neurol Date: 2010-06
Authors: Andrew M Waterhouse; James B Procter; David M A Martin; Michèle Clamp; Geoffrey J Barton Journal: Bioinformatics Date: 2009-01-16 Impact factor: 6.937
Authors: Stephen L Hauser; Emmanuelle Waubant; Douglas L Arnold; Timothy Vollmer; Jack Antel; Robert J Fox; Amit Bar-Or; Michael Panzara; Neena Sarkar; Sunil Agarwal; Annette Langer-Gould; Craig H Smith Journal: N Engl J Med Date: 2008-02-14 Impact factor: 91.245
Authors: An Goris; Ine Pauwels; Marte W Gustavsen; Brechtje van Son; Kelly Hilven; Steffan D Bos; Elisabeth Gulowsen Celius; Pål Berg-Hansen; Jan Aarseth; Kjell-Morten Myhr; Sandra D'Alfonso; Nadia Barizzone; Maurizio A Leone; Filippo Martinelli Boneschi; Melissa Sorosina; Giuseppe Liberatore; Ingrid Kockum; Tomas Olsson; Jan Hillert; Lars Alfredsson; Sahl Khalid Bedri; Bernhard Hemmer; Dorothea Buck; Achim Berthele; Benjamin Knier; Viola Biberacher; Vincent van Pesch; Christian Sindic; Annette Bang Oturai; Helle Bach Søndergaard; Finn Sellebjerg; Poul Erik H Jensen; Manuel Comabella; Xavier Montalban; Jennifer Pérez-Boza; Sunny Malhotra; Jeannette Lechner-Scott; Simon Broadley; Mark Slee; Bruce Taylor; Allan G Kermode; Pierre-Antoine Gourraud; Stephen J Sawcer; Bettina Kullle Andreassen; Bénédicte Dubois; Hanne F Harbo Journal: Brain Date: 2015-01-22 Impact factor: 13.501
Authors: Inger-Lise Mero; Marte W Gustavsen; Hanne S Sæther; Siri T Flåm; Pål Berg-Hansen; Helle B Søndergaard; Poul Erik H Jensen; Tone Berge; Anja Bjølgerud; Aslaug Muggerud; Jan H Aarseth; Kjell-Morten Myhr; Elisabeth G Celius; Finn Sellebjerg; Jan Hillert; Lars Alfredsson; Tomas Olsson; Annette Bang Oturai; Ingrid Kockum; Benedicte A Lie; Bettina Kulle Andreassen; Hanne F Harbo Journal: PLoS One Date: 2013-03-05 Impact factor: 3.240