CTLA4 polymorphism and primary Sjögren's syndrome
Arthritis Research & Therapy volume 9, Article number: 401 (2007)
The March 2007 issue of Arthritis Research and Therapy included a research article by Gottenberg and colleagues  that reports a failure to confirm our previous study  of a genetic association between CTLA4 and primary Sjögren's syndrome (pSS).
Similar to our study, the Gottenberg study analysed both CTLA4 CT60 and +49A/G single nucleotide polymorphisms (SNPs). They observed an association with the +49A/G SNP in one pSS cohort; however, this failed to replicate in a second cohort. We unreservedly agree with the authors' conclusions regarding the importance of replication cohorts. However, we disagree that their results can be interpreted meaningfully against our study.
The CTLA4 CT60 and +49A/G SNPs are haplotype tags for three common, extended CTLA4 haplotypes [3, 4], and the main finding of our study was an association between the +49A:CT60G haplotype and autoantibody positive pSS. As we noted in our paper, the individual SNPs occur on multiple haplotypes, and an individual SNP analysis, such as that reported by Gottenberg and colleagues, may result in negative studies or inconsistent findings between studies, particularly if the haplotype frequencies vary between study populations.
In addition to our finding of an association with pSS, the CTLA4 +49A:CT60G haplotype is also associated with systemic lupus erythematosus , which shares a number of clinical, serological and genetic features with pSS. A more recent study has identified several haplotype blocks across the extended CD28-CTLA4-ICOS region, with systemic lupus erythematosus associations observed in the distal 3' flanking region of CTLA4 on a haplotype that includes variants in the promoter of ICOS . Therefore, the balance of evidence supports a genetic association between this region and systemic autoimmune disease, although the precise nature, definition and boundaries of the haplotypes involved remain to be fully defined.
= primary Sjögren's syndrome
= single nucleotide polymorphism.
Gottenberg JE, Loiseau P, Azarian M, Chen C, Cagnard N, Hachulla E, Puechal X, Sibilia J, Charron D, Mariette X, Miceli-Richard C: CTLA-4 +49A/G and CT60 gene polymorphisms in primary Sjögren syndrome. Arthritis Res Ther. 2007, 9: R24-10.1186/ar2136.
Downie-Doyle S, Bayat N, Rischmueller M, Lester S: Influence of CTLA4 haplotypes on susceptibility and some extraglandular manifestations in primary Sjogren's syndrome. Arthritis Rheum. 2006, 54: 2434-2440. 10.1002/art.22004.
Amundsen SS, Naluai AT, Ascher H, Ek J, Gudjonsdottir AH, Wahlstrom J, Lie BA, Sollid LM: Genetic analysis of the CD28/CTLA4/ICOS (CELIAC3) region in coeliac disease. Tissue Antigens. 2004, 64: 593-599. 10.1111/j.1399-0039.2004.00312.x.
Munthe-Kaas MC, Carlsen KH, Helms PJ, Gerritsen J, Whyte M, Feijen M, Skinningsrud B, Main M, Kwong GN, Lie BA, et al: CTLA-4 polymorphisms in allergy and asthma and the TH1/TH2 paradigm. J Allergy Clin Immunol. 2004, 114: 280-287. 10.1016/j.jaci.2004.03.050.
Torres B, Aguilar F, Franco E, Sanchez E, Sanchez-Roman J, Jimenez Alonso J, Nunez-Roldan A, Martin J, Gonzalez-Escribano MF: Association of the CT60 marker of the CTLA4 gene with systemic lupus erythematosus. Arthritis Rheum. 2004, 50: 2211-2215. 10.1002/art.20347.
Graham DS, Wong AK, McHugh NJ, Whittaker JC, Vyse TJ: Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus in a family-based study. Hum Mol Genet. 2006, 15: 3195-3205. 10.1093/hmg/ddl395.
The authors declare that they have no competing interests.
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Lester, S., Downie-Doyle, S. & Rischmueller, M. CTLA4 polymorphism and primary Sjögren's syndrome. Arthritis Res Ther 9, 401 (2007). https://doi.org/10.1186/ar2196
- Systemic Lupus Erythematosus
- Genetic Association
- Haplotype Frequency
- Haplotype Block
- Systemic Autoimmune Disease