Non-synonymous single nucleotide polymorphisms in genes for immunoregulatory galectins: association of galectin-8 (F19Y) occurrence with autoimmune diseases in a Caucasian population.
BACKGROUND
Galectins are potent immune regulators, with galectin-8 acting as a pro-apoptotic effector on synovial fluid cells and thymocytes and stimulator on T-cells. To set a proof-of-principle example for risk assessment in autoimmunity, and for a mutation affecting physiological galectin sensor functions, a polymorphism in the coding region of the galectin-8 gene (rs2737713; F19Y) was studied for its association with two autoimmune disorders, i.e. rheumatoid arthritis and myasthenia gravis.


METHODS
A case-control analysis and a related quantitative trait-association study were performed to investigate the association of this polymorphism in patients (myasthenia gravis 149, rheumatoid arthritis 214 and 134 as primary and repetitive cohorts, respectively) and 365 ethnically matched (Caucasian) healthy controls. Distribution was also investigated in patients grouped according to their antibody status and age at disease onset. Comparative testing for lectin activity was carried out in ELISA/ELLA-based binding tests with both wild-type and F19Y mutant galectin-8 from peripheral blood mononuclear cell lysates of healthy individuals with different genotypes as well as with recombinant wild-type and F19Y mutant galectin-8 proteins.


RESULTS
A strong association was found for rheumatoid arthritis, and a mild one with myasthenia gravis. Furthermore, the presence of the sequence deviation also correlated with age at disease onset in the case of rheumatoid arthritis. The F19Y substitution did not appear to affect carbohydrate binding in solid-phase assays markedly.


CONCLUSIONS
This is the first report of an association between a galectin-based polymorphism leading to a mutant protein and autoimmune diseases, with evidence for antagonistic pleiotropy.
Center for Molecular Neurology, Department of Neurology, Semmelweis University, Budapest, Hungary.
Zsuzsanna
Z
Pál
Péter
P
Antal
Sanjeev Kumar
SK
Srivastava
Gábor
G
Hullám
Agnes F
AF
Semsei
János
J
Gál
Mihály
M
Svébis
Györgyi
G
Soós
Csaba
C
Szalai
Sabine
S
André
Elena
E
Gordeeva
György
G
Nagy
Herbert
H
Kaltner
Nicolai V
NV
Bovin
Mária Judit
MJ
Molnár
András
A
Falus
Hans-Joachim
HJ
Gabius
Edit Irén
EI
Buzás
D000293:Adolescent; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D001327:Autoimmune Diseases / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D037161:Galectins / Q000235:genetics* / Q000502:physiology; D056726:Genetic Association Studies; D005828:Genetics, Population; D006801:Humans; D007155:Immunologic Factors / Q000235:genetics* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000502:physiology; D010649:Phenylalanine / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D014443:Tyrosine / Q000235:genetics; D044465:White People / Q000235:genetics* / Q000706:statistics & numerical data; D055815:Young Adult
D037161:Galectins; D007155:Immunologic Factors; C091991:LGALS8 protein, human; D014443:Tyrosine; D010649:Phenylalanine