HLA-DQ genetics in children with celiac disease: a meta-analysis suggesting a two-step genetic screening procedure starting with HLA-DQ β chains

BACKGROUND: Specific HLA-DQ genes have been recognized as necessary - but not sufficient - factors for the occurrence of Celiac Disease (CD). Through a meta-analysis, evaluating the distribution of CD-related HLA genotypes in children, we aimed at providing insights for a potential widened screening strategy. METHODS: After a systematic search on the association between class II HLA genes and CD in children, 46 publications were obtained and assessed for eligibility. A total of 13 eligible studies were submitted to data extraction and analysis (10 case-control studies and 3 cohort studies). Case-control studies collectively enrolled 740 CD patients and 943 controls. RESULTS: In the population-stratified analysis, the following alleles conferred a significantly increased risk for CD: HLA-DQB1*02 (odds ratio [OR] = 10.28) and HLA-DQB1*03:02 (OR = 2.24). By drafting a risk gradient to develop CD according to HLA genetic background, the highest risk is confirmed to exist for DQ2/DQ2 homozygous subjects, regardless of the ethnicities (OR = 5.4). Actually, the genotype DQ2/beta 2 showed basically the same risk (OR = 5.3). Indeed, no differences have been found in CD risk between DQ2/beta 2 and DQ2/DQ2, as well as between DQ8/beta 2 and DQ2/DQ8, and between beta 2/DQX and DQ2/X. CONCLUSION: The HLA-DQB1*02:01 allele is present in more than 90% CD children. In the perspective of a widened pediatric population screening for CD, a double-step process might be suggested: HLA-DQB1*02:01 might be investigated first and, only if this result is positive, children might be candidate for a prospective serologic screening, as a second step.