A linkage analysis of the Gm locus and multiple sclerosis

Haile, Robert W.; Goldstein, Alisa M.; Field, L. Leigh; Marazita, Mary L.; Rao, D. C.

doi:10.1002/gepi.1370020104

Cited by 10 publications

(4 citation statements)

References 13 publications

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“…Although the Gm21* haplotype is not associated with higher IgG serum levels, 35 we cannot exclude that it goes along with a higher IgG synthesis of plasma cells and plasmablasts infiltrating the CNS compartment. 10 Conflicting results have been reported for the correlation of the GM allotype with susceptibility, severity, and course of MS as well as with absolute CSF IgG levels in MS. [35][36][37][38][39][40] SNPs of the IGHC locus have not been analyzed in the latest MS GWASs, 8 because they have not been adequately genotyped in all controls. In the present study, analysis of the identified candidate SNPs in a subset of cases and controls revealed no evidence of association of the IGHC locus with susceptibility to MS.…”

Section: Discussionmentioning

confidence: 99%

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

Buck

Albrecht

Aslam

et al. 2012

Annals of Neurology

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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 (r2 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

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Section: Discussionmentioning

confidence: 99%

“…Conflicting results have been reported for the correlation of the GM allotype with susceptibility, severity, and course of MS as well as with absolute CSF IgG levels in MS 35–40. SNPs of the IGHC locus have not been analyzed in the latest MS GWASs,8 because they have not been adequately genotyped in all controls.…”

Section: Discussionmentioning

confidence: 99%

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

Buck

Albrecht

Aslam

et al. 2012

Annals of Neurology

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“…Geographical stratification and local variation in ethnic composition has been suggested as a possible explanation, as well as the possibility that different environmental factors may involve different MS susceptibility loci. However, as different results in association studies between MS and the CH region have been reported for MS patients from the same geographical regions (28,57,61,62), other explanations including incompatible control groups, may be more probable.…”

Section: Resultsmentioning

confidence: 90%

“…Several studies reported an elevation of the IgG marker Gm"'7;21 haplotype in MS patients (57)(58)(59). However, Bulman et al (60) found no association and Haile et al (61) found no linkage between Gm markers and MS. Gaiser et al (28) reported an association between a DNA polymorphism of IgG3 and MS, but found no association between IgG1 and MS. Furthermore, the IgG3 association was with the opposite allele of IgG3 reported elevated in MS patients in the previous studies (57)(58)(59).…”

Section: Resultsmentioning

confidence: 99%

Susceptibility to multiple sclerosis is associated with the proximal immunoglobulin heavy chain variable region.

Walter¹,

Gibson²,

Ebers³

et al. 1991

J. Clin. Invest.

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15 immunoglobulin heavy chain constant (CH) and variable region (VH) polymorphisms were selected to span the entire length of the heavy chain cluster. These polymorphisms were examined in 34 sib pairs concordant for multiple sclerosis (MS) and in 23 sporadic MS patients. Allele frequencies were calculated for the 2 MS patient groups and compared with those found in a control population from the same geographical location and of similar ethnic background. No significant association was found between MS and the 7 CH region polymorphisms examined. However, a significant correlation between the MS phenotype and a VH2 family polymorphism was observed in both MS patient populations (familial MS patients x2 = 8.16, P < 0.005; sporadic MS patients x2 = 8.90, P < 0.005). One allele of the VH2-5 gene segment was found to be overrepresented in both MS groups. VH2-5 has recently been physically mapped close to the CH region, between 180 and 360 kb away. These results indicate that a locus near or within the CH-proximal VH region is associated with increased susceptibility to MS. (J. Clin.

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