Carrier frequency of HLA-DQB1*02 allele in patients affected with celiac disease: A systematic review assessing the potential rationale of a targeted allelic genotyping as a first-line screening

Table 1 Original articles selected and included in this systematic review

Ref.	Country	Total number of CD patients	1Age (yr)	Sex ratio (M/F)	HLA-DQB1*02 carriers	Non-HLA-DQB1*02 carriers	2Notes	Clinical Background	3DM1 patients (< 3%)
Congia et al[15], 1994	Italy	62	Group I	24/38	61	1	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[12]	Symptomatic patients classified as classic (group I) or atypical (group II) CD	+
			(3.08 ± 2.05)
			Group II
			(5.7 ± 3.1)
Herrera et al[16],1994	Argentina	62	Children	12/50	51	2	HLA-DQ genotyping of 53 patients previously diagnosed with CD (ESPGHAN criteria)[12]	NA. Patients were diagnosed at the gastroenterology unit	?
Fernández-Arquero et al[17], 1995	Spain	70	1.7	NA	67	3	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[12]	NA	?
			(NA)
Polvi et al[18], 1996	Finland	49	Index cases: 8 (1-34)	25/24	49	0	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	35 patients diagnosed on a clinical basis (not specified) and 14 FDR diagnosed by case-finding screening	+
			FDR: (NA)
Catassi et al[19], 2001	Algeria	79	8	33/44	68	1	HLA-DQ genotyping of 69 patients previously diagnosed with CD (confirmed with intestinal biopsy)	NA	?
			(2-37)
Kaur et al[20], 2002	India	35	8.42	18/17	35	0	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	Symptomatic patients with consistent GI or extra-GI symptoms	+
			(1.5-15.6)
Zubillaga et al[21], 2002	Spain	133	3.1	59/74	132	1	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	Patients with classic (71.4%) or non-classic (21.8%) CD. Nine asymptomatic patients diagnosed by case-finding screening (5 FRD, 3 DS, 1 DM1)	+
			(0.5-18)
Mustalahti et al[22], 2002	Finland	56	NA	18/38	49	0	HLA-DQ genotyping of symptomatic patients previously diagnosed with CD. Seven patients did not undergo the intestinal biopsy (and, thus, have been excluded)	Twenty-eight symptomatic patients with consistent GI or extra-GI symptoms; and 28 asymptomatic siblings by case-finding screening	+
Karinen et al[23], 2006	Finland	54	43.7 ± 14.7	NA	53	1	HLA-DQ genotyping of patients previously diagnosed with CD (confirmed with intestinal biopsy)	NA (based on clinical symptoms)	+
			(1-79)
Catassi et al[24], 2007	United States	22	(19-83)	18/4	21	0	HLA-DQ genotyping in the context of a multicenter and prospective study (ESPGHAN criteria). HLA-DQ genotyping not done in only one of the 22 new CD diagnoses	Patients enrollment based on specific GI/extra-GI symptoms; or criteria for case-finding screening. Only 1 CD patients with DM1	?
Murray et al [25], 2007	United States	84	(26-68)	35/49	80	4	HLA-DQ genotyping of patients previously diagnosed with CD (confirmed with intestinal biopsy)	Patients with consistent GI and/or extra-GI symptoms	+
Dezsofi et al [26], 2008	Hungary	100	16	47/53	96	4	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	NA. Anyway, this group was declared as not affected with DM1	+
			(3-40)
Megiorni et al[27], 2009	Italy	437	5.7	NA	392	45	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	“Patients were divided on the basis of the clinical manifestations and gastrointestinal symptoms in typical, atypical, and silent forms”. No further numerical information is provided and, thus, it cannot be estimated number of DM1 patients	?
			(NA; only children)
Thomas et al[28], 2009	United Kingdom	384	44	102/282	346	14	HLA-DQ genotyping available for 360 patients previously diagnosed with CD (confirmed with intestinal biopsy)	Patients with consistent GI and/or extra-GI symptoms. Only 7 patients were affected with DM1 as well	+
			(16-84)
Martins et al[29], 2010	Brazil	90	15.5	35/55	84	6	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	NA. Patients were diagnosed at the gastroenterology unit	?
			(1-55)
Srivastava et al[30], 2010	India	30	9.5	15/16	29	1	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	NA. Patients were diagnosed at the gastroenterology unit	?
			(3-17)
El-Akawi et al[31], 2010	Jordan	44	13.5	12/32	44	0	HLA-DQ genotyping available for 360 patients previously diagnosed with CD (confirmed with intestinal biopsy)	NA	?
			(1-39)
Alarida et al[32], 2010	Libya	31	9.2	9/22	29	2	HLA-DQ genotyping of patients diagnosed with CD (confirmed with intestinal biopsy)	School children undergone mass screening through anti-TG IgA	?
			(5-18)
Castro-Antunes et al[33], 2011	Brazil	73	NA	37/36	60	13	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]; One patient did not undergo HLA analysis	Patients enrollment based on specific GI/extra-GI symptoms; or criteria for case-finding screening (15: FDR or DM1, whose proportion is not specified)	-
			(Children and adults)
Mubarak et al[34], 2012	the Netherlands	70	5.7	20/50	70	0	HLA-DQ genotyping of patients diagnosed with CD (confirmed with intestinal biopsy)	NA	?
			(NA; only children)
Mubarak et al[34], 2012	the Netherlands	85	6.2	25/60	81	4	HLA-DQ genotyping performed in all consecutive CD patients (confirmed with intestinal biopsy) at the time of the diagnosis	NA	?
			(NA; only children)
Piccini et al[35], 2012	Italy	89	NA	27/62	81	8	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	NA	?
			(< 18)
Krini et al[36], 2012	Greece	118	NA	NA	105	13	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	NA	?
			(< 18)
Fernández-Cavada-Pollo et al[37], 2013	Spain	355	NA	NA	335	20	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	Patients with consistent GI and/or extra-GI symptoms	+
			(0.5-76; children: n = 214, adults: n = 141)
Delgado et al[38], 2014	Spain	91	6.9	23/68	88	3	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[14]	Patients with consistent GI and/or extra-GI symptoms; or with an affected FDR	+
			(NA; only children)
Cilleruelo et al[39], 2014	Spain	513	NA	NA	496	17	HLA-DQ genotyping in the context of a multicenter and prospective study (ESPGHAN criteria)[13]	Patients enrollment based on classic or atypical symptoms consistent with CD; or criteria for case-finding screening. DM1 is reported in 2.2% (n = 11) of CD patients	+
			(0.5-15)
Stanković et al[40], 2014	Serbia	73	12	19/54	71	2	HLA-DQ genotyping in the context of a multicenter and prospective study (ESPGHAN criteria)[13]	NA	?
			(1-22)
Uenishi et al[41], 2014	Brazil	5	NA	1/4	5	0	HLA-DQ genotyping of patients diagnosed with CD (confirmed with intestinal biopsy)	FDR case-finding screening	+
			(7-75)
Oliveira et al[42], 2014	Portugal	39	1.8	18/21	37	1	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[14]. One patient did not undergo HLA typing	Patients with consistent GI and/or extra-GI symptoms	+
			(0.5-17)
Almeida et al[43], 2016	Brazil	237	22	73/164	222	15	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	NA	?
			(1-75)
Viken et al[44], 2017	Norway	327	NA	NA	310	17	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	NA. Patients with DM1 have been excluded	+
			(Both children and adults)
Murad et al[45], 2018	Syria	49	9.5	14/35	45	4	HLA-DQ genotyping of patients diagnosed with CD (confirmed with intestinal biopsy)	NA	?
			(1-18)
Martínez-Ojinaga et al[46], 2019	Spain	463	2.6	NA	454	9	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13,14]	Patients with consistent GI/extra-GI symptoms; or criteria for case-finding screening (not specified)	+
			(0.6-14)
Poddighe et al[47], 2019	Italy	184	NA	70/114	179	5	HLA-DQ genotyping of 184 patients previously diagnosed with CD (ESPGHAN criteria)[13,14]	Patients with consistent GI (n = 75) or extra-GI (n = 69) symptoms; or criteria for case-finding screening (n = 40)	+
			(1-16)
Kauma et al[48], 2019	Finland	100	CD index cases	19/81	64	2	HLA-DQ genotyping was available for 132 patients diagnosed with CD (confirmed with intestinal biopsy) in the context of a research study considering pairs of siblings both affected with CD	Patients with consistent GI/extra-GI symptoms. There is only one patient with IDDM among CD index cases	+
			(3.08 ± 2.05)
Kauma et al[48], 2019	Finland	100	CD siblings	37/63	59	7	See previous notes (same study/article)	Patients with consistent GI/extra-GI symptoms. There are 4 patients with DM1 among sibling CD cases	-
			(5.7 ± 3.1)
4Lopes et al[49-51], 2019	Brazil	7	7.5	NA	7	0	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13]	FDR case-finding screening. 7 CD cases out of 114 screened FDR	+
			(6-12)
4Bajor et al[52-54], 2019	Hungary	105	31.2	32/73	97	8	HLA-DQ genotyping of patients diagnosed with CD (confirmed with intestinal biopsy)	Patients with consistent GI or extra-GI symptoms; or criteria for case-finding screening. No CD patients with DM1	+
			(0.5-78)
Al-Hussaini et al[55], 2019	Saudi Arabia	100	Group 1	19/27	43	3	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13,14]	Patients with consistent GI or extra-GI symptoms (Group 1, n = 46). No data about comorbidity (e.g., DM1)	+
			(7 ± 3.2)
Al-Hussaini et al[55], 2019	Saudi Arabia	100	Group 2	11/43	45	9	Refer to the previous notes (same study/ article)	Patients diagnosed through a mass screening among school children (Group 2, n = 54). No data about comorbidity (e.g., DM1)	-
			(11.3 ± 2.5)
Ramosaj-Morina et al[56], 2019	Kosovo	60	5.5	20/40	55	5	HLA-DQ genotyping of patients previously diagnosed with CD (ESPGHAN criteria)[13,14]	NA	?
			(1.5-18)

¹This column describe the age of the patients, in terms of mean ± SD or median (age range).

²This column describes the version of ESPGHAN guidelines that each article refers to, if provided: If a superscript number is present, it refers to the specific reference. Anyway, all articles included in this systematic review based the final celiac disease (CD) diagnosis on the duodenal biopsy, even if no specific guidelines are reported in the original article (in this case, no superscript number is present).

³This column assesses the presence of patients affected with type 1 diabetes mellitus (DM1) in the population of CD patients included in the respective article (+: it indicates that the study includes or is estimated to include < 3% of CD patients with DM1; ?: it indicates that the article provided no data to estimate the actual percentage of CD patients affected with DM1; -: it indicates that the study clearly indicates the number of CD patients with DM1 and those are at least 3% of the study cohort).

⁴These articles have been completed with additional references, in order to provide all necessary information about the HLA-DQB1*02 carrier status in the CD patients included in the respective studies. List of abbreviations. CD: Celiac disease; DM1: Type 1 diabetes mellitus; FDR: First degree relative; TG: Transglutaminase; DS: Down syndrome; GI: Gastrointestinal; NA: Not available.