MICA*A4 protects against ulcerative colitis, whereas MICA*A5.1 is associated with abscess formation and age of onset

Abstract

Ulcerative colitis (UC) is one of the two major forms of inflammatory bowel disease, the aetiology of which remains unknown. Several studies have demonstrated the genetic basis of disease, identifying more than 130 susceptibility loci. The major histocompatibility complex class I chain-related gene A (MICA) is a useful candidate to be involved in UC pathogenesis, because it could be important in recognizing the integrity of the epithelial cell and its response to stress. The aim of this study was to analyse the relationship between polymorphisms in the transmembrane domain of MICA and susceptibility to develop UC. A total of 340 patients with UC and 636 healthy controls were genotyped for MICA transmembrane polymorphism using a polymerase chain reaction (PCR) combined with fluorescent technology. Different MICA alleles were determined depending on the PCR product size. The allele MICA*A4 was less frequent in patients than in controls (P = 0·003; OR = 0·643), and this protective role is higher when it forms haplotype with B*27 (P = 0·002; OR = 0·294). The haplotype HLA-B*52/MICA*A6 was also associated with UC [P = 0·001; odds ratio (OR) = 2·914]. No other alleles, genotypes or haplotypes were related with UC risk. Moreover, MICA*A5.1 is associated independently with abscesses (P = 0·002; OR = 3·096) and its frequency is lower in patients diagnosed between ages 17 and 40 years (P = 0·007; OR = 0·633), meaning an extreme age on onset. No association with location, extra-intestinal manifestations or need for surgery was found.

Keywords: MHC; autoimmunity; cell surface molecules; inflammation; molecular biology.

Figure 1

Structure of the major histocompatibility complex class I chain‐related gene A (MICA). (a) View of a ribbon representation of the crystal structure of MICA. Only the extracellular region is shown, which consists of two structural domains: α1α2 platform and α3. The α1α2 platform consists of four α‐helices arranged on eight anti‐parallel β‐sheets. The α3 domain, a C‐type immunoglobulin‐like domain, is not in contact with the platform. Image from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB) (www.rcsb.org) (ID 1B3J) 18. (b) Diagram of the transmembrane region and the cytoplasmic tail of MICA. Full‐length MICA molecules (coded by MICA*A4, MICA*5, MICA*A6 and MICA*A9) are transmembrane (TM) proteins, whereas MICA*A5.1 attaches to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor and has no cytoplasmic tail. The sequence of amino acids of the TM region is shown in the lower box. The alleles differ in the number of trinucleotide GCT repetitions that code alanine (underlined); the frameshift in MICA*A5.1, due to a guanine insertion after the second GCT triplet, leads to a premature stop codon (black triangle).