MHC Class I Chain-Related Gene B Promoter Polymorphisms and Celiac Disease

The possibility that susceptibility to celiac disease (CD) might be influenced by the MHC class I chain-related gene family, MICA and MICB, has been previously reported. In this study, we analyzed the MICB promoter and examined the association of the polymorphisms found within such in a group of CD patients. To study the MICB promoter we sequenced the 5′ flanking region of MICB gene in DNA from homozygous B-lymphoblastoid cell lines corresponding to the most frequent MICB alleles found in our population (MICB*00502, MICB*002, MICB*004, and MICB*008). DNA from a MICB*003 homozygous individual was also analyzed. Sequence analysis revealed six single nucleotide polymorphisms located at positions 45860 C/A, 45862 G/C, 45877 C/G, 46113 A/C, 46219 G/C, and 46286 G/C and an insertion of 2 bp --/AG at position 45944 according to the published genomic sequence. Those polymorphisms were found to be associated in four different haplotypes corresponding to different MICB alleles. Subsequently, 126 CD subjects and 117 healthy controls were typed by polymerase chain reaction using sequence-specific primers for these polymorphisms. MICB promoter polymorphism haplotypes were also found in our population and showed strong linkage disequilibrium with MICB alleles. MICB promoter polymorphism Haplotype 3, included in MICB*002 and MICB*008 alleles, was found to be overrepresented in CD patients (79.4% CD patients vs 45.3% healthy controls; pc < 0.0001; OR = 4.64; CI 95% = 2.64–8.16). Both MICB*008 and MICB*002 alleles were found as part of the CD susceptibility extended haplotypes B8/DR3/DQ2, B18/DR3/DQ2, and DR4/DQ8.