THERE IS NO ASSOCIATION BETWEEN THE –318 (C→T) AND +49 (A→G)
CTLA4 GENE POLYMORPHISMS AND THE COELIAC CONDITION
IN THE MALTESE POPULATION
Borg J1,*, Scerri CA1,3, Vidal C2, Xuereb Anastasi A1,2 *Corresponding Author: Joseph Borg, B.Sc (Hons) MLS, Laboratory of Molecular Genetics, Department of Physiology and Biochemistry, Biomedical Science Building, University of Malta, Msida, Malta; Tel.: +356-2340-2774, Fax: +356-2134-3535, E-mail: joseph.borg@biotech.um.edu.mt
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DISCUSSION
Although the pathogenesis of CD is still unknown, there is evidence [4,5] of an association with the major histocompatibility (HLA)-DQ2 and DQ8 that are found on antigen presenting cells enabling the recognition of deamidated gliadin. The HLA-linked markers contribute about 35% to the genetic predisposition for CD. Thus, other non HLA-linked genes play a major role in the pathogenesis of CD.
The CTLA4 gene is a candidate gene for the susceptibility of T-cell-mediated diseases. Polymorphisms within this gene have been reported in association with a large number of autoimmune diseases, including type I diabetes mellitus, CD, multiple sclerosis and autoimmune thyroid disease [6]. Although the exact pathological polymorphism has not been identified, it has been shown that individuals who carry thymine at position –318 (C→T) of the CTLA4 promoter and individuals who are homozygous for adenine at position +49 (A→G) in exon 1, have significantly increased expression of CTLA4 mRNA and cell-surface CTLA4. As documented in various other studies [7,8], the C allele in the –318 (C→T) locus is in linkage disequilibrium with the A allele in the +49 (A→G) locus, indicating that the initial allele framework was one of C at the –318 locus and an A at the +49 locus.
In both of our coeliac and control groups, the alleles for both polymorphisms were in Hardy-Weinberg equilibrium. In addition, no association was found between the single alleles and CD and between haplotypes and CD. This contrasts with results reported in some studies conducted on Italian, English and Scandinavian countries [9-14] where a positive association was found between the A allele at the +49 (A→G) polymorphism, while it is in agreement with two other studies done on Italian and Tunisian coeliac patients [15] and North American coeliac patients [16]. In a recent study [8] on various European populations, the association between the +49 A allele and CD was identified only in the Norwegian/Swedish populations. In the same study, the –318 T polymorphism was associated with CD, again only in Norwegian/Swedish populations.
These differences in results among different European populations could be explained either by statistical anomalies arising from small sample size or because the causative polymorphism is linked to CTLA4 polymorphism in some populations but not in others, or because of different pathophysiological causes for CD. Our results indicate that the Maltese population is genetically nearer to the Italian and Tunisian than to the Northern European populations. This closeness to the Italian population has been shown in a Mediterranean study on the Y-chromosome [17]. In contrast, our results could be due to founder effects present in the Maltese population which could result in a different pathogenesis for this condition in this population. This has been effectively shown in single gene disorders for which a single mutation is predominant and was not common in the Mediterranean Basin [18-20]. The Maltese population numbered about 17,000 in 1530 AD, and gradually increased to reach about 100,000 by 1800 AD. Demographic data of the Maltese Islands for this period show that the increase was not due to immigration [21]. Thus, hypotheses that within this population there exists a founder effect for CD is also plausible.
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