Associations of non-HLA gene polymorphisms with celiac disease in India

Celiac disease (CD) is highly prevalent in the wheat eating population of India. While HLA-DQ genotype is the strongest genetic determinant of CD, other genetic factors are likely contribute to genesis of CD. In this case-control study, we determined the frequencies of single nucleotide polymorphisms (SNP) in non-HLA candidate genes that influence the development of CD. DNA obtained from peripheral blood of 376 patients with CD and 736 controls was used for the studies. Fifty-one candidate gene polymorphisms were identified for evaluation. Competitive allele-specific polymerase chain reactions were designed to genotype biallelic SNPs at the selected loci. The genotype and allelotype was determined using KASP genotyping technology in a real-time PCR instrument. Eighteen of the 51 SNPs tested associated strongly with CD. The strongest association was found with the HLA DQ2.5 haplotype. HLA DQ2.2 haplotype and HLA-DQ8 haplotype were also strongly associated with CD. Non-HLA genes that were significantly associated with CD included those associated with T cell receptor signaling and T cell activation - CD247, CD80, CD28, PRKCQ, TNFAIP3, UBASH3 and ARHGAP31; genes involved in inflammatory cell migration - CCR3 and CCR4; those involved in epithelial protection - GATD3, PARK7 and INAVA (C1orf106); and those influencing RNA - DDX6 and PUS10. We concluded that the non-HLA genes associated with CD in this Indian population were mostly those associated with molecules involved in the T cell receptor signaling pathway downstream to HLA-DQ2/8, which lead to immune and subsequent inflammatory activation.