Association between HLA alleles and risk of celiac disease in Iranian patients

Abstract

Celiac disease (CD) is a common autoimmune disease that is manifested by inflammation of the small intestine and varying extra intestinal symptoms, also considered to be associated with human HLA-DQ genes. In this study, 40 patients of CD and 40 healthy control samples were genotyped for HLA-DQB1 and 14 patients of CD and 14 healthy control samples were genotyped for HLA-DQA1genes using the SSP-PCR technique and a commercial kit.

The DQA1*05 allele had the highest frequency among the patient group (42.86%). The frequency of this allele was 28.57% in healthy controls, and there was no statistically significant difference in this case ( $p=$ 0.771).

The DQB1*02 allele was the most common in patients (33.75%) followed by the DQB1*03 allele (31.25%).

The difference in frequency of the HLA-DQB1*02 allele in the patient and control groups was statistically significant ( $P=$ 0.0002, OR $=$ 4.72). The remarkable differences in the distribution of HLA-DQ2 in Iranian patients compared to controls and relative risks signified the role of these alleles in the development of CD in Iranian patients and confirmed the likelihood of using HLA-DQ typing in the substantiation of the disease.

Keywords

Celiac disease HLA immune response

1. Introduction

The autoimmune and inflammatory processes that distinguish celiac disease are caused by gluten in genetically predisposed individuals, particularly with the appearance of environmental aggression that intervenes with the integrity of the small intestine [1]. Of the genetic markers currently known, the HLAgenes have the greatest influence on this disease and its development [2]. It is assumed that HLA molecules present gluten antigens to T-cells, and thus cause damage to the tissue. As proposed by numerous authors, the HLA genotypes DQ2 and DQ8 are not merely indicators of genetic vulnerability, but they might also be considered to diagnose celiac disease in certain conditions such as patients that remain undefined even after biopsy [3, 4]. As indicated in a study by Anderson et al., a combination of human leukocyte antigen (HLA) typing and confirmatory serology could reduce the number of times unnecessary endoscopies take place [5].

The HLA-DQ2 heterodimer, as coded by alleles DQA1*05 and DQB1*02, exists in a great number of CD patients, taking about 95% of CD patients of Northern-European origin into consideration [5].

The application of HLA testing as a screening test for CD is negligible since 30–35% of the general population in Western countries carries HLA-DQ2 and/or DQ8, but only a portion of them actually develop CD. However, the highly negative predictive value of HLA typing tests reveals that the absence of HLA-DQ2/DQ8 can eliminate the possibility or future development of CD with approximately 100% assurance [6, 7, 8, 9]. As HLA genes are enduring stable markers, this test is uniquely positioned in order to discriminate individuals who are genetically CD susceptible or not susceptible prior to the appearance of any clinical or serological symptoms. Hence, the HLA test is progressively being considered as a substantial support in the diagnostic algorithm of CD [10].

In the present study, an attempt is made to examine the HLA-DQA1 and -DQB1 genotype and haplotype in Iranian diagnosed celiac patients.

2. Material and methods

2.1 Patients and controls

Forty CD patients (19 males and 21 females; mean age, 21.07 years; range, 1–60 years) and 40 healthy controls (21 males and 19 females; mean age, 35.87 years; range, 4–54 years) with no history of CD and autoimmune diseases participated in this study.

HLA-DQB1 genotyping was carried out for 40 patients (8 males and 8 females; mean age 3–34 years; mean age range of 13.78 years) and HLA-DQA1 genotyping was done for 14 patients in the control group (6 males and 8 females; mean age, 34.07 years; range, 18–49 years) and the haplotype HLA-DQA1-DQB1 was assessed.

The data collection was carried out with the assistance of patients referred to Tehran medical genetics laboratory during 2018. All participants who took part in the study were required to fill out consent forms. In addition, the ethical committee of Shahid Beheshti University of Medical Sciences has endorsed the study protocol.

2.2 HLA-DQA1 and DQB1 genotyping

Genomic DNA was extracted from the peripheral blood of both subject and control groups by using the GeneAll Exgene cell SVmini DNA kit (cat no 106–152). Subsequently, the purity and concentration of extracted DNA were measured using the WPA Biowave II UV/Visible Spectrophotometer (serial no 80-3003-75) as proposed in the manual. HLA alleles were genotyped by the low-resolution HLA-ABDR SSP kit (HLA-A-B-DR SSP Combi Tray, Olerup Diagnostic Gmbh, Germany). Briefly, the genomic regions corresponding to HLA alleles were amplified with sequence-specific primers. PCR products were electrophoresed on 2.0% agarose gel, stained with safety dye and detected under UV transilluminator. The resolution of the method was equal to the serologic analysis of HLA-A, HLA-B and DRB1 loci. Evaluation of the results was carried out using the SCORE software provided by the company. HLA-A/B/DRB1 haplotypes were identified based on the recognized linkage disequilibrium of HLA-A, -B and -DRB1 alleles via the expectation-maximization (EM) algorithm in the R statistical software.

2.3 Statistical analysis

The proportions of HLA-A, HLA-B and DRB1 allele’s between patient and healthy control groups were compared using the Pearson chi-square test of independence. In addition, the Yates’ correction for continuity or Fisher’s exact test were applied to test small sample sizes. The Bonferroni correction was used to control the family wise error rates. Thus, considering the $m$ pair comparisons test, $p$ -values $\leqslant\alpha/m$ were considered as statistically significant. All data were analyzed using the ‘abd’ and ‘pairwise Nominal Independence’ packages in R3.5.1 environment.

3. Results

3.1 Distribution of DQA1 and DQB1 alleles between the patient and healthy controls

The DQA1 allele was determined for 14 patients and 14 healthy individuals from the control group as shown in Table 1. The results are as follows.

Table 1
Distribution of HLA-DQA1 alleles in Iranian celiac patients and healthy controls

HLA-DQA1	Patient $n=$ 28		Control $n=$ 28		Chi square				OR [95% CI for OR]
HLA-DQA1*01	8	(28.57)	14	(50)	1	.72	.18	.2	0.421 [0.12, 1.38]
HLA-DQA1*02	4	(14.28)	0	(0)	1	.95	.112	.237	Inf
HLA-DQA1*03	3	(10.71)	5	(17.86)	0	.129	.732	.091	0.62 [0.11, 2.97]
HLA-DQA1*04	1	(3.57)	0	(0)	0	.0001	.492	.091	Inf
HLA-DQA1*05	12	(42.86)	8	(28.57)	0	.648	.412	.136	1.81 [0.54, 6.35]
HLA-DQA1*06	0	(0)	1	(3.57)	0	.0001	.492	.091	0.0001 [0, 5.65]

${}^{\S}$ Adjusted Fisher $P$ -values.

The DQA1*01 allele was the most frequent allele observed in the control group (50%), while its frequency in the group of patients was 28.57%. However, this difference was not statistically significant ( $p=$ 0.557). The DQA1*05 allele had the highest frequency among patients (42.86%). The frequency rate of this allele was 28.57% in the control group, for which no statistically significant difference was observed ( $p=$ 0.771). The second and third alleles considering highest frequency were DQA1*01 (28.57) and DQA1*02 (14.28) in the patient group and DQA1*05 (28.57%) and DQA1*03 (17.86 %) in the control group, respectively.

For 40 patients and 40 individuals in the control group, the DQB1 alleles were determined as shown in Table 2. The results of analyses are as follows.

Table 2

Distribution of HLA-DQB1 alleles in Iranian celiac patients and healthy controls

HLA-DQB1	Patient $n=$ 80		Control $n=$ 80		Chi square		Adj. $P$ -value ${}^{\S}$			OR [95% CI for OR]
HLA-DQB1*02	27	(33.75)	7	(8.75)	13	.09	0	.0002	.296	4.72 [1.91, 12.9]
HLA-DQB1*03	25	(31.25)	38	(47.5)	3	.67	0	.056	.162	0.53 [0.26, 1.04]
HLA-DQB1*04	1	(1.25)	2	(2.5)	0		$>$ 0	.999	.039	0.98 [0.07, 13.92]
HLA-DQB1*05	14	(17.5)	21	(26.25)	1	.27	0	.187	.103	0.57 [0.24, 1.28]
HLA-DQB1*06	13	(16.25)	12	(15)	0		0	.831	.016	1.18 [0.46, 3.01]

${}^{\S}$ Adjusted Fisher $P$ -values.

In the control group, the most frequent HLA-DQB1 alleles were HLA-DQB1*02, allele 27 at (33.75%), DQB1*03, allele 25 at (31.25%), respectively. The difference in frequency for the HLA-DQB1*02 allele in the patients and healthy controls was statistically significant ( $P=$ 0.0002, OR $=$ 4.72).

In the control group, the DQB1*03 allele had the highest frequency at 38 (47.5%) and the second highest was DQB1*05 at 21 (26.25%). The difference in frequency in the DQB1*03 allele in the patient and healthy controls was at the borderline ( $p=$ 0.056).

3.1.1 Distribution of HLA-DQA1 genotypes in patients and healthy controls

The HLA-DQA1 genotype was determined for the 14 patients and 14 healthy controls (Table 3). The most frequent genotype observed in patients was HLA-DQA1*01/05 at a frequency of 35.71% in five patients and in the healthy controls, three individuals were observed with 21.43% ( $p=$ 0.714, OR $=$ 1.71).

3.1.2 Distribution of HLA-DQB1 genotype in patients and healthy controls

The HLA-DQB1 genotype was determined for 40 patients and 40 healthy controls (Table 4). Among the genotype patients, HLA-DQB1*02/-had the highest overall frequency as homozygote and heterozygote, with an overall of 61/65% in the patient group and 17.5% in the control group. The frequency distribution of the HLA-DQB1*02/03 genotype was statistically significant in the patient and healthy controls ( $p$ value $=$ 0.014). This genotype was observed in 10 of the patients (27.03%), while only one of the healthy controls had this genotype (2.71%). The HLA-DQB1*03/-had the highest frequency among the healthy controls as homozygote and heterozygote (67.23%, 26 individuals). The frequency of this genotype in patients was 35.21% (14 individuals).

Table 3
Distribution of HLA-DQA1 genotypes in Iranian celiac patients and healthy controls

HLA-DQA1	Patient $N=$ 14		Control $N=$ 14		Chi square		Adjusted $P$ -value ${}^{\S}$			OR [95% CI for OR]
HLA-DQA1*01/01	1	(7.14)	4	(28.57)	0	.79	0	.405	.22	0.43 [0.04, 3.46]
HLA-DQA1*01/03	0	(0)	3	(21.43)	1	.121	0	.105	.261	0 [0, 1.5]
HLA-DQA1*01/04	1	(7.14)	0	(0)	0		0	.486	.12	Inf
HLA-DQA1*01/05	5	(35.71)	3	(21.43)	0	.146	0	.714	.126	1.71 [0.33, 10.17]
HLA-DQA1*02/03	1	(7.14)	0	(0)	0		0	.486	.12	Inf
HLA-DQA1*02/05	3	(21.43)	0	(0)	1	.121	0	.105	.261	Inf
HLA-DQA1*03/05	2	(14.28)	2	(14.28)	0		$>$ 0	.999		1 [0.07, 15.39]
HLA-DQA1*05/05	1	(7.14)	1	(7.14)	0		$>$ 0	.999		1 [0.07, 15.29]
HLA-DQA1*05/06	0	(0)	1	(7.14)	0		0	.486	.12	0 [0, 5.58]

${}^{\S}$ Adjusted Fisher $P$ -values.

Table 4

Distribution of HLA-DQB1 genotypes in Iranian celiac patients and healthy controls

HLA-DQB1	Patient $N=$ 40		Control $N=$ 40		Chi square				OR [95% CI for OR]
HLA-DQB1*02/02	4	(8.11)	0	(0)	1	.91	.117	.191	Inf
HLA-DQB1*02/03	10	(27.03)	1	(2.71)	6	.13	.015	.289	6.14 [1.2, 61.17]
HLA-DQB1*02/05	3	(5.41)	2	(2.71)	0		.677	.044	2.04 [0.28, 23.56]
HLA-DQB1*02/06	6	(16.22)	4	(10.82)	0	.11	.739	.067	1.57 [0.35, 8.14]
HLA-DQB1*03/03	1	(2.71)	11	(29.73)	7	.25	.008	.31	0.14 [0.02, 0.66]
HLA-DQB1*03/04	0	(0)	2	(5.41)	0	.35	.495	.122	0 [0, 5.31]
HLA-DQB1*03/05	7	(16.22)	9	(24.33)	0	.08	.794	.056	0.77 [0.24, 2.42]
HLA-DQB1*03/06	6	(16.22)	3	(8.11)	0	.45	.523	.104	1.61 [0.36, 8.32]
HLA-DQB1*03/15	0	(0)	1	(2.71)	0		.495	.075	0 [0, 5.43]
HLA-DQB1*04/05	1	(2.71)	0	(0)	0		.495	.075	Inf
HLA-DQB1*05/05	1	(2.71)	3	(2.71)	0	.22	.677	.096	0.49 [0.05, 3.56]
HLA-DQB1*05/06	1	(2.71)	3	(8.11)	0	.22	.677	.096	0.49 [0.05, 3.56]
HLA-DQB1*06/06	0	(0)	1	(2.71)	0		.495	.075	0 [0, 5.43]

${}^{\S}$ Adjusted Fisher $P$ -values.

Table 5

Distribution of HLA-DQA1-DQB1haplotypes in Iranian celiac patients and healthy controls

HLA-DQA1-DQB1	Patient $n=$ 28		Control $n=$ 28		Chi square		Adjusted $P$ -value ${}^{\S}$			OR [95% CI for OR]
HLA-DQA101-DQB105	5	(17.86)	10	(35.71)	1	.326	0	.26	.179	0.5 [0.13, 1.79]
HLA-DQA101-DQB106	3	(10.71)	4	(14.29)	0		1		.047	0.97 [0.17, 5.74]
HLA-DQA102-DQB102	4	(14.29)	0	(0)	1	.95	0	.113	.231	Inf
HLA-DQA103-DQB103	3	(10.71)	4	(14.29)	0		1		.047	0.97 [0.17, 5.74]
HLA-DQA103-DQB105	0		1	(3.57)	0		0	.492	.09	0 [0, 5.47]
HLA-DQA104-DQB104	1	(3.57)	0	(0)	0		0	.492	.09	Inf
HLA-DQA105-DQB102	8	(28.57)	2	(7.14)	2	.73	0	.0816	.246	4.89 [0.87, 51.4]
HLA-DQA105-DQB103	4	(14.29)	6	(21.43)	0	.109	0	.732	.083	0.63 [0.12, 2.98]
HLA-DQA106-DQB103	0	(0)	1	(3.57)	0		0	.492	.09	0 [0, 5.47]

${}^{\S}$ Adjusted Fisher $P$ -values.

3.1.3 Distribution of HLA-DQA1-DQB1 haplotypes in celiac patients and healthy controls

The HLA-DQA1-DQB1 haplotypes were deter- mined for 14 patients and 14 healthy controls as shown in Table 5. The most frequent haplotype HLA-DQA1*05-DQB1*02 (DQ2) was (28.57%) in patients and (7.14%) in healthy controls ( $p=$ 0.135, OR $=$ 3.81). In the control group, the most frequent haplotype HLA-DQA1*01-DQB1*05 was observed at (35.71%) and this haplotype was observed at (17.86%) in the patient group ( $p=$ 0.728).

4. Discussion

Celiac disease is an autoimmune disorder of the small intestine with a genetic background. In this digestive disorder, the small intestinal mucosa are damaged and cause a disturbance in absorbing materials. If patients diagnosed with celiac disease consume a protein from the gluten group, which exists in some grains such as wheat, barley, and rye, they will experience intolerable symptoms. Apparently, gluten entering the cells of intestinal mucosa will result in a response from the immune system. Inflammatory reaction created will result in villous atrophy and reduction of intestinal enzyme activity. Since a large portion of nutrition absorbed in the intestines is absorbed in the mucosa, destruction of mucosa will result in maladaptation. Most instances of celiac disease are genetic [11]. Among methods of diagnosing this disease are the anti-tissue Transglutaminase (anti-TG2) and auto anti-bodies anti-endomysium (EMA) and biopsy of the small intestine [12]. There is no general agreement on the diagnosis of celiac using non-aggressive tests alone. Recently, the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) has proposed new guidelines that allow the diagnosis of celiac in children in the absence of biopsy of the small intestine in special cases [13].

Table 6
Distribution of HLA-DQ2-DQ8 haplotype in Iranian celiac patients and healthy controls

HlLA-DQ2-DQ8	Patient $n=$ 28	Control $n=$ 28	Chi square ${}^{\text{a}}$	Adj. $P$ -value ${}^{\S}$	Effect size	OR [95% CI for OR]
neg-neg	4 (36.37)	7 (58.34)	0.363	0.267	0.191	0.38 [0.05, 2.36]
neg-pos	1 (9.1)	4 (33.34)	0.678	0.648	0.248	0.429 [0.03, 3.75]
pos-neg	5 (45.46)	1 (8.34)	2.05	0.209	0.36	4.25 [0.57, 53.5]
pos-pos	1 (9.1)	0 (0)	0.002	0.481	0.152	Inf

${}^{\text{a}}$ : Pearson’s Chi-squared test with Yates’ continuity correction. ${}^{\S}$ : Adjusted Fisher exact $P$ -value.

Presently there is no consensus on diagnosing CD without carrying out small bowel biopsy. The last versionof ESPGHAN’s guideline states that patients with apparent clinical symptoms and with highly positive titrationof anti-tTG IgA (10 $\times$ higher than normal) with positive endomysial antibodies (EMA) and with positiveHLA-DQ2 and/or HLA-DQ8 heterodimer can bediagnosed without a biopsy after negotiation with thepatient’s family. However, in patients with low titrationof anti-tTG antibodies and negative EMA test, biopsyis definitely necessary. In patients diagnosed withoutbiopsy, significant relief of symptoms and normalizationin CD antibodies should be closely monitored [8]. With regard to this data, analysis of HLA-DQ2 andHLA-DQ8 haplotypes in celiac disease is essential forthe diagnosis and prevention of misdiagnosis. Althoughsome studies have focused on this issue in theliterature, further studies are necessary.

The role of HLA-DQ genotyping has been proven in celiac disease. The majority of celiac patients have haplotype HLA-DQ2 (HLA-DQA1*05- DQB1*02) and/or HLA-DQ8 HLA-DQA1*03- (DQB1*03*02) [14, 6, 7]. HLA-DQ2/DQ8 genotype testing is done with high sensitivity, but does not have high specialty. This is because these alleles are positive for approximately 40% of the general public [15]. However, in extensive screening, the outbreak of celiac is reported at about 1% [16]. Therefore, most researchers are interested in determining the HLA-DQ2/DQ8 allele at its highly negative prediction value, as it is confirmed by the results of the study by Pena-Quintana et al. [17, 18, 19]. Other research studies have also supported this claim that the diagnosis of celiac only based on histology has not always been reliable and HLA-DQ typing for verifying the diagnosis in negative cases of HLA-DQ2-DQ8 is of significance [20]. A limited number of studies also exist in Iran on the HLA of celiac patients. In those studies, the DQ2-DQ8 haplotype has also been introduced as the most important haplotype among celiac patients in Iran [21, 22, 23]. In the current study, alleles and HLA-DQA1 genotypes for 14 patients and 14 healthy controls with similar age and gender, and alleles and HLA-DQB1 genotypes for 40 celiac patients and 40 healthy controls have been determined. The results obtained from this study indicate that the most frequent allele and genotype observed for the HLA-DQA1 locus in patients were the HLA-DQA1*05 allele and HLA-DQA1*01/05 genotype, respectively. Even though their frequency with the healthy controls was not statistically significant, results from studies carried out on other populations indicate that this genotype is introduced as a predisposing factor of the disease in patients. In a study carried out by Murad et al. [24] on Celiac children in Syria, the frequency of DQB1*02:01 specifically increased in patients compared to healthy controls (77.6% to 58.6%, $P=$ 0.00). In addition, the frequency of the DQB1*03:02 allele increased in patients compared to the healthy controls, while $P$ value was at the borderline (10.2% to 8.6%, $P=$ 0.09) [24].

In the study by Zamani et al., the DQB1*02 and DQB1*03:02 alleles and HLA-DQB1*02:01/03:02 genotype were specifically related to the increased risk of celiac patients [21]. In the current study, HLA-DQB1*02 and HLA-DQB1*03 alleles had higher frequency among patients as compared to the healthy controls (an overall of 65%).

In a study by Basturk et al. [25] on celiac patients in Turkey, the prevalence of haplotypes HLA-DQ2 and HLA-DQ8 were investigated. In 67% of the patients, HLA-DQ2 was positive, in 25% HLA-DQ8 was positive and in 76% of the cases both haplotypes were positive, even though 24% of the patients in both haplotypes had negative results [25]. In the current study, 57.14% of the patients had positive HLA-DQ2; however, determining the HLA-DQ8 haplotype was not possible since determining the type of HLA requires using low-resolution methods. Also, determining the percentage of patients that were negative for both haplotypes was not possible. This is while 28.57% of the patients had decisively negative results for both haplotypes and 57.14% of the healthy controls had decisively negative results for both haplotypes (Table 6).

In a study by Rostami-Nejad et al. on celiac patients in Iran, the prevalence of the HLA-DQ8 haplotype was reported as 25.4% in patients [23], the rate of which is similar to Turkish and Indian populations of North America, Mexicans and specific racial groups in South Africa [26].

Results obtained from analyses done in the review of literature indicate that the HLA-DQ haplotype is similar in celiac patients of various populations.

Surprisingly, in contrast to the low prevalence of HLA-DQ8 in the CD population reported in the literature (0.6% in Cameroon, 2% in Italy, 2.3% in Hungary, 4.2% in the United States, 6.4% in Finland and 7.6% in Japan) [12, 26], we found a higher prevalence (25.4%) of this genotype in the Iranian CD population.

Results obtained from our study also confirm this fact and increase its reliability as a screening test in individuals at high risk of this disease. However, due to the high frequency of this allele in the general population, it cannot be used as an adequate screening test.

This study also faces some limitations. Among these limitations is the inability to do high resolution HLA-DQB1 genotyping in which case the HLA-DQ8 haplotype cannot be definitely determined (HLA-DQA1*03-DQB1*03:02). The HLA-DQB1*03 allele might be HLA-DQB1*03:01 and/or HLA-DQB1*03: 02 in which case if it is HLA-DQB1*03:02, it will have a predisposing role and if it is HLA-DQB1*03:01 it will have a protective role. Also, in this study information related to serology and biopsy tests have not been given.

5. Conclusion

At the present time, the use of HLA-DQ2/DQ8 tested alone has restrictions in the diagnosis of CD. It is better that it not be used in the screening procedure for CD in the general population since it may result in misinterpretation and misdiagnosis. Therefore, it should be noted that this haplotype be considered with a high suspicion of existing CD. These results may have an important impact on clinical practice, especially when developing personalized programs focused on subclinical CD in risk groups and in defining the timing of serological screening depending on the HLA-DQ genotype.

Footnotes

Acknowledgments

The current study was supported by a grant from Shahid Beheshti University of Medical Sciences.

Conflict of interest

The authors declare they have no conflict of interest.

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Association between HLA alleles and risk of celiac disease in Iranian patients

Abstract

Keywords

1. Introduction

2. Material and methods

2.1 Patients and controls

2.2 HLA-DQA1 and DQB1 genotyping

2.3 Statistical analysis

3. Results

3.1 Distribution of DQA1 and DQB1 alleles between the patient and healthy controls

Table 1 Distribution of HLA-DQA1 alleles in Iranian celiac patients and healthy controls

3.1.2 Distribution of HLA-DQB1 genotype in patients and healthy controls

Table 3 Distribution of HLA-DQA1 genotypes in Iranian celiac patients and healthy controls

4. Discussion

Table 6 Distribution of HLA-DQ2-DQ8 haplotype in Iranian celiac patients and healthy controls

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Distribution of HLA-DQA1 alleles in Iranian celiac patients and healthy controls

Table 3
Distribution of HLA-DQA1 genotypes in Iranian celiac patients and healthy controls

Table 6
Distribution of HLA-DQ2-DQ8 haplotype in Iranian celiac patients and healthy controls