Clinical settings in which human leukocyte antigen typing is still useful in the diagnosis of celiac disease

Table 1 Genetic terminology used in the present manuscript

Terminology	Explanation
Gene	A particular nucleotide DNA sequence at a specific locus
Allele	Polymorphisms in the sequence of a DNA at the same locus. In a diploid individual, at most two different alleles can be present
MHC and HLA	Major histocompatibility complex. A large region of vertebrate DNA containing a set of closely linked polymorphic genes encoding immune cell surface proteins called MHC molecules. In humans the region is called HLA
Center-telomeric	Refers to the known order of the HLA class II (DP, DM, DQ, and DR loci), class III (containing the C4 and TNF genes), and class I (B, C, E and A) genes, from centromere to telomere along the chromosome. Centromer is the constricted region of chromosome connecting the sister chromatids and creating a short arm (p) and a long arm (q) on the chromatids. The telomere is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of chromosomes
Polymorphism	Variations in the nucleotide sequence of a given locus (determines more than one allele at that locus)
Homozygous	Presence of alleles with the same nucleotide sequence at the same locus on homologous chromosomes (HLA-DQB1 02:01/HLA-DQB1 02:01)
Heterozygous	Presence of alleles with different nucleotide sequences at the same locus on homologous chromosomes (HLA-DQB1 02:01/HLA-DQB1 03:02)
Haplotype	Alleles inherited together on a certain chromosomal segment (HLA-DQA1 05:01/HLA-DQB1 02:01). In the MHC, due to a strong linkage disequilibrium, haplotypes sometimes extending from the A locus to the DQB1 locus are found quite frequently. A1, Cw7, B8, DR3, and DQ2 are present in Northern European populations, and A30, Cw5, B18, DR3, and DQ2 are present in the Sardinian population
Genotype	Genetic constitution of an individual (e.g., of an HLA genotype -A1, Cw7, B8, DR3, DQ2/-A30, Cw5, B18, DR3, DQ2)
Cis	Alleles at different loci located on the same chromosome (e.g., HLA-DQA1 03:01 HLA-DQB1 03:02, coding for the molecule HLA-DQ8)
Trans	Alleles located at different loci on opposite chromosomes (e.g., HLA-DQA1 05:05 HLA-DQB1 03:01/HLA-DQA1 02:01 HLA-DQB1 02:02; see also Figure 1)
Heterodimer	Protein complex consisting of two different subunits (e.g., α chain and β chain of HLA-DQ2), also named HLA-DQ molecule
Codominance	Both maternal and paternal alleles are expressed. This allows the formation of the HLA-DQ2 heterodimer in trans
Linkage disequilibrium	The nonrandom association of alleles of different loci within a population

HLA: Human leukocyte antigens; MHC: Major histocompatibility complex; TNF: Tumor necrosis factor.

Table 2 Human leukocyte antigen-DQ genotypes associated with celiac disease

HLA (genotype)	HLA (heterodimer)	CD (n = 746)	Controls (n = 627)	OR	P value	CI
HLA-DQA1 05 HLA-DQB1 02:01/HLA-DQA1 02:01 HLA-DQB1 02:02	-DQ2.5/-DQ2.2	111	17	6.3	1.1 × 10-14	3.7-10.6
HLA-DQA1 05 HLA-DQB1 02:01/HLA-DQA1 05 HLA-DQB1 02:01	-DQ2.5/-DQ2.5	153	33	4.6	2 × 10-16	3.1-6.9
HLA-DQA1 05 HLA-DQB1 02:01/HLA-DQA1 03:01 HLA-DQB1 03:02	-DQ2.5/-DQ8	57	21	2.4	6.2 × 10-4	1.4-4.0
HLA-DQA1 05 HLA-DQB1 03:01/HLA-DQA1 02:01 HLA-DQB1 02:02	-DQ2.5 trans	41	20	1.8	3.9 × 10-2	1.0-3.0
HLA-DQA1 05 HLA-DQB1 02:01/HLA-DQA1 X HLA-DQB1X	-DQ2.5 cis	271	165	1.6	7.2 × 10-5	1.3-2.0
HLA-DQA1 02:01 HLA-DQB1 02:02/HLA-DQA1 X HLA-DQB1 X	-DQ2.2/X	17	28	0.5	2.3 × 10-2	0.3-0.9
HLA-DQA1 03:01 HLA-DQB1 03:02/HLA-DQA1 X HLA-DQB1 X	-DQ8/X	15	38	0.3	1 × 10-4	0.2-0.6

HLA: Human leukocyte antigens; CD: Celiac disease; OR: Odd ratio; CI: Confidence intervals.

Table 3 Clinical settings where it is reasonable to propose human leukocyte antigen genotyping for celiac disease

Condition	HLA-DQ2 and HLA-DQ8 negativity
Before biopsy
First-degree relatives of a patient affected by CD	Allows the exclusion of serological monitoring in individuals not carrying any genetic risk
Individuals who have started a GFD without performing t-TG2-IgA measurement	Allows the exclusion of CD as the cause of gastrointestinal symptoms regardless of the clinical response to the GFD
Individuals with persistent low t-TG2-IgA titer	Allows unequivocal definition of the false positives, including first-degree relatives of a proband with reduced gluten intake
Individuals affected by IgA deficiency	Allows the exclusion of serological monitoring in individuals not carrying any HLA genetic risk
Patients with chromosomal pathologies associated with increased CD risk (Down syndrome, Turner syndrome, Williams syndrome)	Allows the limit of periodic serological follow-up exclusively to positive patients
Patients affected by Hashimoto’s thyroiditis	Allows the limit of the periodic serological follow-up exclusively to positive patients
After biopsy
Ineffectiveness of GFD in patients with CD	Allows exclusion of CD and suspect other pathologies. Could help in excluding refractory CD type II and enteropathy-associated T cell lymphoma
Dubious CD biopsy performed for other reasons	Allows exclusion of CD and suspect other pathologies

GFD: Gluten free diet; HLA: Human leukocyte antigens; CD: Celiac disease; t-TG2-IgA: Tissue transglutaminase type 2-IgA.