Association between DPP6 polymorphism and the risk of progressive multiple sclerosis in Northern and Southern Europeans.
BACKGROUND
In this study, we investigated the role of the dipeptidyl-peptidase-6 (DPP6) gene in the etiopathogenesis of progressive forms of multiple sclerosis (PrMS). This gene emerged as a candidate gene in a genome-wide association study (GWAS) performed in an Italian sample of PrMS and controls in which two SNPs located in the gene (rs6956703 and rs11767658) showed evidence of association (nominal p-value<10(-4)) (Martinelli-Boneschi et al.) [18]. Moreover, the gene is highly expressed in the central nervous system, and it has been found to be associated with sporadic cases of amyotrophic lateral sclerosis which shares some feature with PrMS.


METHODS
We genotyped 19 SNPs selected using a direct and tagging approach in 244 Italian PrMS and 225 controls, and we measured the expression levels of the gene in 13 PrMS cases and 25 controls.


RESULTS
Five out of 19 SNPs were found to be associated with the disease (adjusted p<0.05), and they have been tested in an independent sample of 179 primary progressive MS and 198 controls from Northern Europe. None of the SNPs was replicated, but combined analysis confirmed the presence of association for rs2046748 (p=2.5×10(-3),OR=1.82, 95%CI=1.24-2.69).


CONCLUSIONS
These results, inflated by the limited sample size determined by the rarity of this condition, suggest a possible role of this gene in the susceptibility to PrMS, at least in Southern Europeans. Moreover, DPP6 was over-expressed in PrMS patients compared to controls.
Institute of Experimental Neurology and Department of Neurology, San Raffaele Scientific Institute, 20132 Milan, Italy.
Paola
P
Brambilla
Federica
F
Esposito
Eva
E
Lindstrom
Melissa
M
Sorosina
Giacomo
G
Giacalone
Ferdinando
F
Clarelli
Mariaemma
M
Rodegher
Bruno
B
Colombo
Lucia
L
Moiola
Angelo
A
Ghezzi
Ruggero
R
Capra
Laura
L
Collimedaglia
Gabriella
G
Coniglio
Elisabeth G
EG
Celius
Daniela
D
Galimberti
Per Soelberg
PS
Sørensen
Vittorio
V
Martinelli
Annette B
AB
Oturai
Hanne F
HF
Harbo
Jan
J
Hillert
Giancarlo
G
Comi
Filippo
F
Martinelli-Boneschi
D000328:Adult; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000453:epidemiology* / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015221:Potassium Channels / Q000235:genetics*; D015995:Prevalence; D018570:Risk Assessment
D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; C503535:DPP6 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases