Non-synonymous single nucleotide polymorphisms in genes for immunoregulatory galectins: Association of galectin-8 (F19Y) occurrence with autoimmune diseases in a Caucasian population

• Published in: Biochimica et biophysica acta Vol. 1820; no. 10; pp. 1512 - 1518
• Main Authors: Pál, Zsuzsanna, Antal, Péter, Srivastava, Sanjeev Kumar, Hullám, Gábor, Semsei, Ágnes F., Gál, János, Svébis, Mihály, Soós, Györgyi, Szalai, Csaba, André, Sabine, Gordeeva, Elena, Nagy, György, Kaltner, Herbert, Bovin, Nicolai V., Molnár, Mária Judit, Falus, András, Gabius, Hans-Joachim, Buzás, Edit Irén
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2012
• Subjects: Adolescent; Adult; Aged; Allele; Amino Acid Substitution - genetics; antibodies; apoptosis; Autoimmune Diseases - epidemiology; Autoimmune Diseases - ethnology; Autoimmune Diseases - genetics; Autoimmunity; carbohydrate binding; Case-Control Studies; European Continental Ancestry Group - genetics; European Continental Ancestry Group - statistics & numerical data; Female; Galectins - genetics; Galectins - physiology; genes; Genetic Association Studies; Genetics, Population; genotype; Humans; Immunologic Factors - genetics; Immunologic Factors - physiology; Lectin; lectins; Male; Middle Aged; mutants; Mutation, Missense - physiology; Neoglycoconjugate; patients; Phenylalanine - genetics; pleiotropy; polymorphism; Polymorphism, Single Nucleotide - physiology; rheumatoid arthritis; risk assessment; Sialylation; single nucleotide polymorphism; synovial fluid; T-lymphocytes; thymocytes; Tyrosine - genetics; Whites; Young Adult; Autoimmunity; Lectin; Neoglycoconjugate; BSA; SD; AChR; SE; SNP; ANOVA; OD; HWE; MG; LGALS8; Sialylation; BMLA; PBS; CD; OR; CI; PBMC; RA; CCP; Allele; ELLA; HLA; Exp(B); ELISA
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.05.015

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. 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. 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. 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. ► Focuses on a polymorphism in the coding region of the galectin-8 gene. ► Reveals clinical association with rheumatoid arthritis and also myasthenia gravis. ► Directs attention to functional study beyond trisaccharide recognition.