Disease Markers

Disease Markers / 2015 / Article

Research Article | Open Access

Volume 2015 |Article ID 724935 | 7 pages | https://doi.org/10.1155/2015/724935

Significant Association of HLA-B Alleles and Genotypes in Thai Children with Autism Spectrum Disorders: A Case-Control Study

Academic Editor: Donald H. Chace
Received19 Aug 2015
Revised20 Oct 2015
Accepted27 Oct 2015
Published24 Dec 2015

Abstract

Autism is a severe neurodevelopmental disorder. Many susceptible causative genes have been identified. Most of the previous reports showed the relationship between the Human Leukocyte Antigen (HLA) gene and etiology of autism. In order to identify HLA-B alleles associated with autism in Thai population, we compared the frequency of HLA-B allele in 364 autistic subjects with 952 normal subjects by using a two-stage sequence-specific oligonucleotide probe system (PCR-SSOP) method based on flow-cytometry technology. HLA-13:02 (, OR = 2.229), HLA-38:02 (, OR = 1.628), HLA-44:03 (, OR = 1.645), and HLA-56:01 ( = 1.78 × 10−4, OR = 4.927) alleles were significantly increased in autistic subjects compared with normal subjects. Moreover, we found that the HLA-18:02 (, OR = 0.375) and HLA-46:12 (, OR = 0.147) alleles were negatively associated with autism when compared to normal controls. Both alleles might have a protective role in disease development. In addition, four HLA-B genotypes of autistic patients had statistically significant relationship with control groups, consisting of HLA-39055801 (, OR = 24.697), HLA-27045801 (, OR = 6.872), HLA-35014403 (, OR = 30.269), and HLA-18014402 (P = 0.017, OR = 13.757). This is the first report on HLA-B associated with Thai autism and may serve as a marker for genetic susceptibility to autism in Thai population.

1. Introduction

Autism spectrum disorders (ASD) are neurodevelopmental syndromes characterized by early childhood onset and associated with brain abnormalities [1]. Children with autism have a pattern of behavior deficits in three major domains, namely, social interaction difficulties, verbal and nonverbal communication, and the presence of restricted, repetitive, or stereotypic behaviors or interests. The ASD was classified according to American Psychiatric Association (DSM-IV-TR) 2000 into 5 classes consisting of autistic disorder, Asperger’s syndrome, Rett syndrome, childhood disintegrative disorder (CDD), and pervasive developmental disorders not otherwise specified (PDD-NOS). Clinical features usually have developmental markers of ASD emerging during the first 3 years of life. Prevalence estimates worldwide range from 0.07% to 1.8% [2] and 0.1% in Thailand [3] with a biased male-to-female ratio of 4.2 to 1 [2]. ASD has been incessantly increased so that the understanding of aetiopathogenesis of autism may be important for clinical implementation.

However, the etiology of ASD is still unclear. Genetic, environmental, and immune mechanisms in the nervous system impairments have been proposed [4, 5]. Several immune abnormalities in autistic subjects including the involvement of autoimmune disease and infection have been suggested [68]. Moreover, the dysregulation of the immune response such as partial T cell activation [9] and decreased peripheral lymphocyte numbers [10] as well as cytokine production [11] have been studied. The previous report demonstrated that Human Leukocyte Antigen (HLA) alleles are involved in ASD, especially HLA class I molecules playing a vital role in brain development [1214]. HLA genes are the name for the Major Histocompatibility Complex (MHC) in humans localized on the short arm of chromosome 6 (6p21; about 4 × 106 bp). HLA genes are a high level of polymorphisms composed of class I, II, and III molecules. They are involved in many biological functions such as inflammation, immune response, ligands for immune cell receptors, and complement.

Previous studies demonstrated that HLA-1, 02, 07, 44, 51, DRβ04 (DR4), DR11, DR13, DR14, DRB03, DQB0202, DQB0302, DQB0501, and C4B are associated with ASD [15]. Moreover, in 2002, Torres et al. found that HLA-DR4 was susceptible to autism. In contrast, HLA-DR13 has a protective role toward disease development [16]. In addition, Daniels et al. in 1995 reported that the allelic products of certain genes of the MHC were associated with autism including the null allele of the C4B gene (located in class III region of the MHC), the extended haplotype HLA-DRβ04 (DR4) and HLA-DR13 in class II, and A2 and HLA-44 allele in class I region [17]. The evidence suggests possible associations between HLA alleles and ASD have wide coverage of different ethnicities. Most reports have been noted in Western countries but among Asian populations there is less information. The main aim of this study is to find out the link between HLA-B and ASD in Thai autistic children compared with normal subjects.

2. Materials and Methods

2.1. Subjects

A study was conducted in 1316 Thai individual subjects; 952 subjects were classified as normal control and 364 subjects were diagnosed with autistic spectrum disorder (ASD) according to the 4th edition of the diagnostic and statistical manual of mental disorders criteria (DSM-IV). All autistic subjects were recruited from Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital, Samut Prakan, Thailand. This study received approval from the Ethical Committee of Ramathibodi Hospital. All patients wrote informed consent document before enrolment in the project.

2.2. Genomic DNA Extraction

Blood samples were taken and collected to EDTA tubes. DNA was isolated by using the MagNA Pure automated extraction system (Roche diagnostics, USA) which is based on magnetic-bead technology with a lysis buffer and proteinase K. Nucleic acids are bound to the surface of the magnetic glass particles. Cellular debris was removed by several washing steps and the purified nucleic acids are eluted. From the 1 mL input volume of EDTA-whole blood, 200 μL output volume of extracted genomic DNA product is obtained.

The quality of genomic DNA was assessed by using NanoDrop ND-1000 for measuring the genomic DNA as well as purity with dynamic ranges around 220 to 750 nm. Wavelength at 260 nm is suitable for measuring the genomic DNA and at 280 nm was used to evaluate contaminated protein in the sample. The recommended purified genomic DNA template for this study is 20 ng and the optical density (OD) ratio at 260/280 nm is greater than 1.7. All DNA was aliquoted and stored at −20°C until tested.

2.3. HLA-B Typing

HLA-B genotyping was carried out based on Polymerase Chain Reaction-sequence-specific oligonucleotides (PCR-SSO) by using the Luminex Multiplex Technology, a flow-cytometry method (Luminex IS 100, USA). Briefly, the PCR product was hybridized against a panel of oligonucleotide probes coated on polystyrene microspheres that have sequences complementary to stretches of polymorphism within the target HLA-B alleles. The amplicon-probe complex is visualized using a colorimetric reaction and fluorescence detection technology. Data analysis for the HLA-B assays was performed with software package HLAfusion 2.0.

2.4. Statistical Analysis

The HLA-B allele frequency of the samples was calculated by direct counting and calculated by dividing the total number of occurrences of that allele by the total number of alleles at that locus in the population. The significance of difference in frequencies of HLA-B alleles between autistic subject and control was compared by Chi-square () test or Fisher’s exact test if the number in any cell of the 2 × 2 contingency tables was less than five. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to determine levels of significances. For all tests, a probability () of less than 0.05 was significant.

3. Results

3.1. The Characteristics of Autistic Patients and Normal Subjects

The clinical data of 1316 subjects was shown in Table 1. A mean age of 364 autistic patients was years and was divided into 314 male and 50 female (ratio 6.28 : 1), whereas the mean age of 952 normal subjects was and was classified into 677 male and 285 female (ratio 2.34 : 1).


CharacteristicsAutistic patients
Mean ± SD
Normal subjects
Mean ± SD

Age (years)9.17 ± 4.9945.36 ± 26.15
Gender
 Male314 (86.26%)667 (70.06%)
 Female50 (13.74%)285 (29.93%)

3.2. HLA-B Allele Frequency in Autistic Spectrum Disorders Patients Compared with Normal Subjects

The HLA-B frequencies of 364 autistic patients and 952 normal controls were showed in Table 2. One hundred and thirty-one different HLA-B alleles were identified in this study. In HLA-13:02 (, OR = 2.229), HLA-38:02 (, OR = 1.628), HLA-44:03 (, OR = 1.645), and HLA-56:01 ( = 1.78 × 10−4 OR = 4.927) alleles were found to be significantly associated with autism. Two of the HLA-B alleles were negatively linked to autism: HLA-18:02 (, OR = 0.375) and HLA-46:12 (, OR = 0.147).


HLA-B
alleles
Number of individuals (%) OR (95% CI) value
ASD
Allele frequencies (%)
Control
Allele frequencies (%)

B07:023 (0.41)19 (1.00)0.411 (0.121–1.391)0.153
B07:0519 (2.61)30 (1.58)1.674 (0.936–2.993)0.082
B07:090 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B07:130 (0.00)3 (0.16)0.373 (0.019–7.228)0.514
B07:140 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B07:180 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B08:014 (0.55)11 (0.58)0.951 (0.302–2.996)0.931
B08:020 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B08:031 (0.14)1 (0.05)2.618 (0.164–41.906)0.496
B08:120 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B08:330 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B13:0140 (5.49)146 (7.67)0.700 (0.488–1.004)0.527
B13:0216 (2.20)19 (1.00)2.229 (1.140–4.359)0.019
B13:030 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B13:090 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B13:280 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B13:390 (0.00)2 (0.11)0.522 (0.025–10.893)0.675
B14:022 (0.27)0 (0.00)13.107 (0.629–273.362)0.097
B14:130 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B15:0112 (1.65)23 (1.21)1.371 (0.678–2.769)0.379
B15:0255 (7.55)160 (8.40)0.891 (0.648–1.226)0.477
B15:031 (0.14)0 (0.00)7.854 (0.319–193.017)0.207
B15:041 (0.14)5 (0.26)0.522 (0.061–4.479)0.554
B15:060 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B15:071 (0.14)3 (0.16)0.872 (0.091–8.393)0.905
B15:110 (0.00)7 (0.37)0.174 (0.010–3.044)0.231
B15:123 (0.41)7 (0.37)1.121 (0.289–4.348)0.868
B15:132 (0.27)13 (0.68)0.401 (0.090–1.780)0.229
B15:171 (0.14)10 (0.53)0.261 (0.034–2.039)0.200
B15:183 (0.41)4 (0.21)1.965 (0.439–8.804)0.377
B15:202 (0.27)0 (0.00)13.107 (0.629–273.362)0.097
B15:214 (0.55)6 (0.32)1.748 (0.492–6.211)0.388
B15:220 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B15:2511 (1.51)27 (1.42)1.067 (0.526–2.161)0.858
B15:272 (0.27)2 (0.11)2.619 (0.368–18.634)0.336
B15:310 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B15:321 (0.14)8 (0.42)0.326 (0.041–2.601)0.291
B15:353 (0.41)22 (1.16)0.354 (0.106–1.186)0.092
B15:880 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B18:0124 (3.30)58 (3.05)1.085 (0.669–1.759)0.741
B18:027 (0.96)48 (2.52)0.375 (0.169–0.836)0.016
B18:090 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B18:180 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B27:031 (0.14)5 (0.26)0.522 (0.061–4.479)0.554
B27:0413 (1.79)37 (1.94)0.917 (0.485–1.736)0.791
B27:0612 (1.65)15 (0.79)2.111 (0.983–4.531)0.055
B27:070 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B27:610 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B27:860 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B35:0114 (1.92)36 (1.89)1.017 (0.546–1.898)0.957
B35:021 (0.14)2 (0.11)1.308 (0.118–14.449)0.826
B35:036 (0.82)21 (1.10)0.745 (0.299–1.854)0.527
B35:059 (1.24)39 (2.05)0.599 (0.288–1.242)0.168
B35:081 (0.14)0 (0.00)7.854 (0.319–193.017)0.207
B35:110 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B35:580 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B36:682 (0.27)0 (0.00)13.107 (0.629–273.362)0.097
B37:014 (0.55)9 (0.47)1.163 (0.357–3.789)0.802
B38:015 (0.69)4 (0.21)3.285 (0.879–12.267)0.077
B38:0227 (3.71)44 (2.31)1.628 (1.001–2.649)0.049
B38:130 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B38:170 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B38:200 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B38:220 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B38:230 (0.00)4 (0.21)0.289 (0.016–5.391)0.406
B39:017 (0.96)11 (0.58)1.412 (0.561–3.554)0.463
B39:030 (0.00)3 (0.16)0.373 (0.019–7.228)0.514
B39:051 (0.14)2 (0.11)1.308 (0.118–14.449)0.826
B39:096 (0.82)13 (0.68)1.209 (0.458–3.192)0.702
B39:151 (0.14)13 (0.68)0.200 (0.026–1.532)0.121
B39:241 (0.14)6 (0.32)0.435 (0.052–3.621)0.441
B40:0172 (9.89)155 (8.14)1.239 (0.923–1.661)0.153
B40:0210 (1.37)24 (1.26)1.091 (0.519–2.293)0.818
B40:030 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B40:045 (0.69)4 (0.21)3.285 (0.879–12.267)0.077
B40:063 (0.41)11 (0.58)0.712 (0.198–2.559)0.603
B40:090 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B40:100 (0.00)6 (0.32)0.200 (0.011–3.563)0.274
B40:230 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B40:590 (0.00)2 (0.11)0.522 (0.025–10.893)0.675
B41:010 (0.00)2 (0.11)0.522 (0.025–10.893)0.675
B41:100 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B44:010 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B44:026 (0.82)11 (0.58)1.430 (0.527–3.881)0.482
B44:0340 (5.49)65 (3.41)1.645 (1.099–2.463)0.016
B44:430 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B44:541 (0.14)0 (0.00)7.854 (0.319–193.017)0.207
B46:0186 (11.81)209 (10.98)1.086 (0.832–1.419)0.543
B46:122 (0.27)35 (1.84)0.147 (0.035–0.613)0.008
B46:161 (0.14)0 (0.00)7.854 (0.319–193.017)0.207
B48:013 (0.41)7 (0.37)1.121 (0.289–4.348)0.868
B48:031 (0.14)5 (0.26)0.522 (0.061–4.479)0.554
B48:210 (0.00)3 (0.16)0.373 (0.019–7.228)0.514
B50:011 (0.14)2 (0.11)1.308 (0.118–14.449)0.826
B51:0124 (3.30)68 (3.57)0.921 (0.573–1.478)0.732
B51:026 (0.82)20 (1.05)0.783 (0.313–1.957)0.600
B51:041 (0.14)6 (0.32)0.435 (0.052–3.621)0.441
B51:060 (0.00)3 (0.16)0.373 (0.019–7.228)0.514
B51:071 (0.14)0 (0.00)7.854 (0.319–193.017)0.207
B51:430 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B51:450 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B52:0110 (1.37)48 (2.52)0.538 (0.271–1.070)0.077
B52:071 (0.14)0 (0.00)7.854 (0.319–193.017)0.207
B52:111 (0.14)1 (0.05)2.618 (0.164–41.906)0.496
B52:250 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B53:170 (0.00)3 (0.16)0.373 (0.019–7.228)0.514
B54:0114 (1.92)26 (1.37)1.416 (0.735–2.728)0.298
B54:040 (0.00)2 (0.11)0.522 (0.025–10.893)0.675
B54:140 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B54:161 (0.14)0 (0.00)7.854 (0.319–193.017)0.207
B55:011 (0.14)9 (0.47)0.289 (0.037–2.290)0.240
B55:028 (1.10)26 (1.37)0.803 (0.362–1.781)0.588
B55:040 (0.00)2 (0.11)0.522 (0.025–10.893)0.675
B55:100 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B55:131 (0.14)0 (0.00)7.854 (0.319–193.017)0.207
B55:230 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B55:320 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B55:440 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B56:0113 (1.79)7 (0.37)4.927 (1.958–12.399)1.78 ×
B56:020 (0.00)4 (0.21)0.289 (0.016–5.391)0.406
B56:030 (0.00)2 (0.11)0.522 (0.025–10.893)0.675
B56:040 (0.00)6 (0.32)0.200 (0.011–3.563)0.274
B56:120 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B56:162 (0.27)1 (0.05)5.242 (0.474–57.905)0.176
B57:0116 (2.20)24 (1.26)1.760 (0.929–3.333)0.083
B57:211 (0.14)2 (0.11)1.308 (0.118–14.449)0.826
B58:0165 (8.93)163 (8.56)1.047 (0.775–1.415)0.764
B58:341 (0.14)0 (0.00)7.854 (0.319–193.017)0.207
B58:420 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B67:010 (0.00)1 (0.05)0.871 (0.035–21.406)0.933
B73:011 (0.14)0 (0.00)7.854 (0.319–193.017)0.207

Chi-square test.
OR: odds ratio; 95% CI: confidence interval. The bold font in table refers to significant association of alleles.
3.3. HLA-B Genotype Frequencies in Autistic Children and Normal Subjects

There were 442 different HLA-B genotypes in the 1316 subjects. Four HLA-B genotypes of autistic patients had statistically significant relationship with control groups (Table 3) which are composed of HLA-18014402 (, OR = 13.757), HLA-27045801 (, OR = 6.872), HLA-35014403 (, OR = 30.269), and HLA-39055801 (, OR = 24.697).


GenotypesASD
(%)
Control
(%)
OR (95% CI) value

1801/44025 (1.38)1 (0.10)13.757 (1.602–118.158)0.017
B2704/58015 (1.38)2 (0.20)6.872 (1.327–35.577)0.022
B3501/44035 (1.38)0 (0.00)30.269 (1.669–548.816)0.021
B3905/58014 (1.10)0 (0.00)24.697 (1.326–459.879)0.032

Chi-square test. OR: odds ratio; 95% CI: confidence interval.

4. Discussion

Although the causes and mechanisms of ASD were unclear, the genetic and environment factors were believed to play an important role in the pathophysiology of the ASD. It was clear that no single genetic locus was the sole cause of this disorder. Recently, the genome-wide association studies revealed a number of rare mutations. Many of these genes encode proteins integral to formation, refinement, maintenance, function, and/or plasticity of synapses in the CNS; others encode proteins traditionally thought to play roles exclusively in the immune system, including MHC genes [18]. The interruption in MHC expression in the developing brain caused by mutations and/or immune deregulation may contribute to the altered brain connectivity and function characteristic of autism [4, 5, 19]. In addition, increased levels of cytokines in the plasma were found to be linked with greater impairments in characteristic ASD behavioral domains including social interaction and communication, as well as associated features such as aberrant behaviors [11].

Moreover, the A2-B44 and A2-B51 haplotypes were two times more frequent in autistic subjects [16]. In Egypt autistic children study found that autistic children had significant higher frequency of HLA-DRB11 allele and lower frequency of HLA-DRB03 allele than healthy-matched-children control (). Acquisition of HLA-DRB11 and absence of HLA-DRB03 had significant risk of association with autism and HLA-DRB11 had a significant risk for association with a family history of autoimmunity in autistic children [20]. Moreover, Chien et al. 2012 suggested that HLA-DRB1 gene might be associated with autism in Han Chinese and found that DR4, DR11, and DR14 had a different effect on intelligence and neuropsychology tests among autistic children [21].

In our study, the findings obtained have shown that HLA-13:02, HLA-38:02, HLA-44:03, and HLA-56:01 alleles were significantly associated with autism. This data was similar to the previous study by Torres et al. which reported a higher prevalence of HLA-44 and HLA-51 among ASD children than controls [13]. Contradictory, the previous finding of Al-Hakbany et al. reported a higher prevalence of HLA-07 and HLA-51 among ASD children than controls [15]. In addition, we found that the HLA-18:02 and HLA-46:12 alleles were significantly higher among controls than autistic subjects which demonstrated that these alleles might play a protective role toward disease development. We found that only HLA-44:03 alleles in autistic patients showed a significant difference in HLA-B genotype when compared with normal group. It might be the influence on gene-gene interaction that would result in autism development. The finding of small possibility of HLA-B genotype is a limitation of this study. As the result of HLA-B genotype, there are quite a small number of HLA-B genotypes in control. Either small sample size or family members should be included in further study for proving that those genotypes are associated in autistic patients.

With the different results in HLA-B publication, most of genetic studies unavoidably increase the attention to the ethnic variation. This finding might serve as genetic markers for susceptibility to ASD in Thailand and reveals a cover-up of genetic effect on autism. However, the interaction between HLA and different infectious agents or environmental allergen across geographical regions remains of interest for clarification ASD etiology.

5. Conclusions

Our studies suggest that HLA-13:02 (, OR = 2.229), HLA-38:02 (, OR = 1.628), HLA-44:03 (, OR = 1.645), and HLA-56:01 ( = 1.78 × 10−4 OR = 4.927) alleles were significantly increased in autistic subjects compared with normal subjects. These alleles may have a consequence on ASD development. However, the understanding of how HLA-B alleles have an impact on autism still needs more investigation.

Conflict of Interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the paper.

Acknowledgments

This study was supported by grants of the (1) Pharmacogenomics for Autistic Child Project, Khoon Poom Foundation, The Project in Her Royal Highness Princess Ubonratana Rajakanya Siriwatana Bhanawadee, (2) Office of National Research Council of Thailand, (3) Faculty of Medicine Ramathibodi Hospital, and (4) Mahidol University. The authors thank all the staff in Yuwaprasart Waithayopathum Child and Adolescent Psychiatric Hospital and all the children and adolescents with ASD who participated in the study.

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Copyright © 2015 Apichaya Puangpetch et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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