Promoter polymorphisms of the CD14 gene in Italian patients with coeliac disease.

C oeliac disease (CD) is an autoimmune enteropathy triggered by ingestion of wheat gluten or related protein from rye and barley, and is one of the most frequently occurring, treatable, lifelong disorders. 2 Undetected or untreated CD may cause other, more severe, complications later, such as autoimmune diseases, osteoporosis, neurological disorders, and infertility. 4 Several studies have shown CD clusters in families with a sibling relative risk of 20–60 and high concordance between monozygotic twins (75%), which indicates a strong genetic component to coeliac disease. As expected in complex autoimmune diseases, human leukocyte antigen (HLA) linked genes are the main genetic factor involved in CD. More than 90% of patients suffering from CD share the major histocompatibility complex II class HLA-DQ2 haplotype. Most of the remainder present HLA-DQ8. However, there are patients who present neither HLA-DQ8 nor HLA-DQ2 on their antigen-presenting cells. These genetic findings strongly indicate the involvement of other genes in the pathogenesis of coeliac disease. So far, various genome-wide linkage analyses have been performed in order to identify non-HLA linked genes responsible for CD. A recent study by Greco et al. on Italian coeliac families demonstrated the existence of a genetic risk factor on chromosome 5 (5q31–33), which has been reported in other linkage studies in different populations. 11 This genomic region contains several candidate genes for CD, including the interleukin (IL12B) gene, the polymorphisms of which do not seem to be associated with CD, and the gene encoding for CD14. CD14 is a multifunctional receptor involved in the innate immune response. In fact, it is thought to be one of the most important receptors for lipopolysaccharide and other bacterial wall-derived components. However it is well known that CD14 has several other functions, 18 including the clearance of apoptotic cells. It is constitutively expressed, primarily on the surface of monocytes, macrophages, and neutrophils (mCD14); a soluble form, sCD14, has been isolated from serum and is derived both from secretion of CD14 and from enzymatically cleaved glycosyl-phosphatidylinositol anchored mCD14. 21 The serum levels of CD14, and thus the levels of mCD14, are genetically regulated. Four single nucleotide polymorphisms have been identified in the promoter region of the gene, and are thought to regulate the CD14 gene expression. Recently, different studies have correlated a CRT transition at position 2159 in the promoter region of the CD14 gene, with an increased risk of developing Crohn’s disease and ulcerative colitis; . Furthermore, a study by Holla et al. demonstrated an association between a GRT transversion at position 21359 and the severity of periodontitis. In our study the frequency of the two promoter polymorphisms was assessed in three selected populations in order to explore the influence of CD14 in coeliac disease, because the CD14 gene is located in a ‘‘hotbed’’ region for CD and is involved in the clearance of apoptotic cells, which could be important in CD, as already demonstrated by the findings of Boniotto et al.