The CIITA genetic polymorphism rs4774*C in combination with the HLA-DRB1*15:01 allele as a putative susceptibility factor to multiple sclerosis in Brazilian females

O polimorfismo rs4774*C no gene CIITA em conjunção com o alelo HLA-DRB1*15:01 é um possível fator de susceptibilidade a esclerose múltipla em mulheres brasileiras

Abstracts

The objective of this study was to investigate the association between the HLA alleles at the DQA1, DQB1 and DRB1 loci, the CIITA genetic polymorphisms -168A/G and +1614G/C, and susceptibility to multiple sclerosis (MS) in a sample from Rio de Janeiro State, Brazil. Furthermore, we wished to determine whether any of these associations might be more significant in women compared with men. DNA samples from 52 relapsing-remitting MS (RRMS) patients and 126 healthy controls matched for sex and age were analyzed. We identified a significant HLA-DRB1*15:01-MS association that was female-specific (Odds Ratio (OR) = 4.78; p = 0.001). Furthermore, we observed that the +1614G/C mutation in combination with the HLA-DRB1*15:01 allele increased susceptibility to MS in females (OR = 4.55; p = 0.01). Together, these findings highlight the polygenic nature of MS.

CIITA gene; HLA; rs4774*C; HLA-DRB1*15:01; multiple sclerosis

O objetivo deste estudo foi investigar a associação entre alelos HLA, loci DQA1, DQB1 e DRB1, polimorfismos -168A/G e +1614G/C no gene CIITA, e suscetibilidade à esclerose múltipla (EM) em uma amostra de Rio de Janeiro, Brasil. Além disso, buscou-se determinar se alguma dessas associações pode ser gênero-dependente. Foram analisadas amostras de DNA de 52 pacientes com EM reincidente-remitente (EMRR) e 126 controles saudáveis ​​pareados por sexo e idade. Foi identificada associação significativa HLA-DRB1*15:01-EMRR, que foi específica para o gênero feminino (Odds Ratio (OR) = 4,78, p = 0,001). Além disso, observou-se que o polimorfismo +1614 G/C, em combinação com o alelo HLA-DRB1*15:01 provoca o aumento da susceptibilidade à EM em pacientes do sexo feminino (OR = 4,55, p = 0,01). Juntos, estes resultados destacam a natureza poligênica da EM.

gene CIITA; HLA; rs4774*C; HLA-DRB1*15:01; esclerose múltipla

Multiple sclerosis is one of the most common causes of chronic neurological disability among young adults in economically productive societies¹. Although MS affects approximately one million people worldwide, it has historically been more common in cold or temperate climates. However, recent reports have suggested that this latitude gradient is disappearing². Among the highly admixed Brazilian population, which is the result of interbreeding between European Caucasians, Africans and Amerindians³, the prevalence of MS is less than 15 cases per 100,000 inhabitants in Sao Paulo City⁴ and about 20,100,000 inhabitants in Rio de Janeiro City⁵.

The genetic components of MS pathogenesis are quite complex⁶, and the human leukocyte antigen (HLA) class II genes (6p21.3) appear to play an important role in determining the risk for MS. For example, the HLA-DRB1*15:01 allele is consistently associated with MS⁶. Studies performed on North American and European populations revealed an association between the HLA-DRB1*15:01, -DQA1*01:02 and -DQB1*06:02 alleles and the development of MS⁷, and these alleles have also been linked to MS in the Brazilian population^8,9,10. In particular, a previous Brazilian study showed that the DRB1*15:01 allele confers ethnicity-dependent MS susceptibility in Caucasian patients, whereas that the DQB1*06:02 allele confers genetic susceptibility regardless of ethnicity⁸. In addition, the HLA-DRB1*15 allelic group has been associated with MS in samples from Brazil⁹ and Portugal^11,12, the European country that originally colonized Brazil.

Studies have also searched for non-MHC genetic risk factors for MS, and CIITA (also called MHC2TA, loci 16p13) polymorphisms have been reported as putative susceptibility factors^13,14. In fact, CIITA is an attractive candidate molecule in studies involving a variety of autoimmune diseases and inflammatory HLA-associated conditions^13,14,15. Furthermore, expression of MHC II is tightly controlled by the class II transactivator, which is a master regulator of both constitutive and inducible MHC II expression¹⁶.

The goal of this study was to investigate the association between a large number of polymorphic alleles and MS in a sample from Rio de Janeiro State, Brazil. In particular, we analyzed 84 polymorphic alleles, including the HLA DQA1, DQB1 and DRB1 loci, as well as the CIITA polymorphisms -168A/G and +1614 G/C. In addition, we searched for gender-related differences in the associations between MS and these polymorphisms.

METHOD

Patients and controls

Peripheral blood samples were taken from 52 relapsing-remitting MS (RRMS) patients [35 females (67.3%); 17 males (32.7%)] who had been diagnosed with MS and were registered with the outpatient clinic of neurology at the University Hospital Clementino Fraga Filho (UFRJ). All the patients fulfill magnetic resonance imaging (MRI) criteria for distribution in space and time¹⁷. Blood samples were also taken from 126 healthy control subjects [85 females (67.46%); 41 males (32.54%)] who had been matched with the MS patient group for ancestry [patient group: 22 Afro-Brazilians (42.30%); 30 non-Afro-Brazilians (57.30%); control group: 52 Afro-Brazilians (41.26%); 74 non Afro-Brazilians (58.74%)], sex and age. Patients were classified according to the criteria laid out by McDonalds et al.¹⁷. The Afro-Brazilians were classified in this ethnic group if they could not identify White ancestry for up to three generations time period. This criteria was accepted in our previous studies ethnicity-dependent⁸.

DNA Typing

DNA was extracted from the blood samples using the organic method, and the HLA-DRB1 (Table 1), HLA-DQB1 (Table 2) and HLA-DQA1 (Table 3) alleles were identified by PCR amplification with sequence-specific primers using the One Lambda (Canoga Park, CA, USA) kit, according to the manufacturer’s recommendations. Sequencing of the single nucleotide polymorphisms (SNPs) +1614G/C (rs4774*C; G500A) and -168A/G (rs3087456) within CIITA was performed using PCR, as described by Patarroyo et al.¹⁸, followed by capillary electrophoresis on the ABI PRISM^® 3500 Genetic Analyzer (Applied Biosystems, Foster City, CA) platform to identify the genetic profiles in the patient and control groups.

Table 1
Frequencies of the HLA-DRB1 polymorphic alleles.

Allele	P	C	p-value	OR	Allele	P	C	p-value	OR
*01:01	6	9	0.5	1.6	*10:01	0	1	0.47	1.1
*01:02	3	4	0.24	1.7	*11:01	3	9	0.32	0.72
*01:03	5	8	0.54	1.43	*11:02	1	9	0.02	0.23
*03:01	5	13	0.37	0.8	*11:03	1	2	0.46	1.1
*03:02	2	4	0.44	1.11	*11:04	1	1	0.57	2.2
*03:05	2	4	0.44	1.11	*12:01	1	2	0.46	1.1
*03:08	0	3	0.24	0.32	*12:02	1	2	0.46	1.1
*03:11	2	3	0.32	1.5	*13:01	3	10	0.26	0.64
*04:01	1	2	0.46	1.1	*13:02	0	3	0.24	0.32
*04:02	2	3	0.32	1.5	*13:03	1	8	0.09	0.26
*04:03	2	3	0.32	1.5	*13:04	0	0	NA	NA
*04:04	0	1	0.47	1.1	*13:05	0	0	NA	NA
*04:05	2	3	0.32	1.5	*13:06	1	3	0.39	0.72
*04:06	0	1	0.47	1.1	*13:09	0	2	0.35	0.54
*04:07	1	3	0.39	1.1	*14:01	1	2	0.46	1.1
*04:08	0	1	0.47	1.1	*14:02	2	4	0.44	1.1
*04:09	2	3	0.32	1.5	*14:05	1	1	0.27	1.1
*04:10	2	4	0.44	1.1	*14:06	1	2	0.46	1.1
*04:11	3	7	0.47	0.95	*15:01	15	13	0.002	3.2
*07:01	3	9	0.32	0.72	*15:02	4	12	0.29	0.72
*08:01	2	8	0.21	0.54	*15:03	8	10	0.09	1.9
*08:03	0	5	0.12	0.21	*16:01	2	6	0.35	0.73
*08:04	0	1	0.47	1.1	*16:02	7	13	0.33	1.2
*08:07	0	3	0.24	0.32	*16:03	5	10	0.41	1.1
*09:01	0	2	0.59	0.43

• P: Allele counts in the patient group; C: Allele counts in the control group.

Table 2
Frequencies of the HLA-DQB1 polymorphic alleles.

Allele	P	C	p-value	OR	Allele	P	C	p-value	OR
*02:01	11	33	0.20	1.2	*05:04	2	3	0.32	1.5
*02:03	0	4	0.17	0.62	*06:01	4	6	0.26	1.5
*03:01	7	16	0.47	0.97	*06:02	18	19	0.02	1.8
*03:02	4	17	0.10	0.48	*06:03	8	13	0.22	1.4
*03:03	3	8	0.39	0.82	*06:04	1	4	0.29	0.54
*03:04	2	6	0.35	0.73	*06:05	2	3	0.32	1.5
*03:05	0	1	0.47	1.1	*06:06	0	4	0.17	0.26
*03:07	1	2	0.46	1.1	*06:07	3	5	0.34	1.3
*04:01	6	14	0.46	0.95	*06:08	3	9	0.32	0.72
*04:02	2	5	0.44	0.88	*06:09	0	0	NA	NA
*05:01	13	33	0.23	0.75	*06:10	0	0	NA	NA
*05:02	5	9	0.34	1.2	*06:11	0	2	0.35	0.54
*05:03	9	16	0.27	1.3

• P: Allele counts in the patient group; C: Allele counts in the control group.

Table 3
Frequencies of the HLA-DQA1 polymorphic alleles.

Allele	P	C	p-value	OR
*01:01	11	27	0.38	0.88
*01:02	19	39	0.35	1.1
*01:03	8	19	0.43	0.92
*01:04	5	11	0.48	1.0
*02:01	14	38	0.22	0.75
*03:01	13	36	0.21	0.74
*04:01	8	14	0.27	1.3
*05:01	20	33	0.09	1.5
*05:02	6	14	0.46	0.95
*06:01	0	1	0.47	1.1

• C+: Allele counts in the control group; F%: Relative frequency percentage for P (patients) and C (controls); P+: Allele counts in the patients group.

Statistical analysis

The relative frequencies of the alleles were manually calculated. The p-values and odds ratio (OR) were calculated using the Epi Info, a public-domain software program created by the CDC (Centers for Disease Control and Prevention), and SPSS Statistics software.

Ethics

All patients were duly informed with respect to the use of their clinical and genetic data in accordance with the study protocol, which was approved by the institution’s Internal Review Board. The project was approved by CONEP (National Council for Ethics in Research; #1265) on May 29^th, 2000.

RESULTS

We investigated the association between MS susceptibility and 84 alleles of the polymorphic HLA-Class II genes: 49 from the DRB1 locus, 25 from the DQB1 locus and 10 from the DQA1 locus (Tables 1, 2 and 3). To the best of our knowledge, this is the most comprehensive survey of the association between genetic polymorphisms and MS that has been conducted on a Brazilian population.

We observed that the OR related to MS associated with HLA-DRB1*15:01 was 3.52. In addition, the association between MS and HLA-DRB1*15:01 was only significant in female patients: 31.43% of female patients had the allele (OR = 4.78; p = 0.001), whereas only 23.53% of male patients had the allele (OR = 2.05; p = 0.16) (Table 4).

Table 4
The HLA-DRB1*15:01 allele in males vs. females.

	Patients (n = 52)		Controls (n = 126)
	DRB1*15:01-	DRB1*15:01+	DRB1*15:01-		DRB1*15:01+	OR	p-value
Male	13	4	40		6	2.05	0.16
Female	24	11	73		7	4.78	0.001

We did not find a significant association between the CIITA polymorphism rs3087456 and susceptibility to MS. The data related to the rs4774 CIITA polymorphism are shown in Table 4. We observed that the CIITA polymorphism rs4774 (+1614G/C) in combination with HLA-DRB1*15:01 increased the OR to 2.65 (p = 0.005). Table 5 shows our gender analyses. In particular, females carrying both the rs4774*C and DRB1*15:01 alleles had an OR of 4.55 (p = 0.02).

Table 5
Frequencies of the CIITA genetic polymorphisms rs4774*C and rs4774*C as well as the DRB1*15:01+ allele in the MS patients and healthy controls.

Polymorphism	C+	C-	C (F%)	P+	P-	P (F%)	OR	p-value
rs4774*C (FM)	24	102	19.05	17	35	32.69	2.06	0.02
rs4774*C + DRB1*15:01+ (FM)	4	122	3.17	6	46	11.54	2.65	0.005
rs4774*C + DRB1*15:01+ (F)	3	82	3.53	5	30	14.28	4.55	0.02
rs4774*C + DRB1*15:01+ (M)	2	39	4.87	1	16	5.88	1.21	0.86

• F: Female; M: Male; FM: Female + Male; C+: Controls bearing the allele; C-: Controls without the allele; F%: Relative frequency percentage for P (patients) and C (controls); P+: Patients bearing the allele; P-: Patients without the allele.

DISCUSSION

Systematic molecular genetic studies have provided important insights into MS susceptibility. In particular, the association between HLA-class II genes and the relative risk for MS has been investigated in several populations^1,6,9, and a link between HLA-DRB1* and MS susceptibility in Brazilian patients has already been reported¹⁹.

In our sample, which was taken from Rio de Janeiro State in Southeast Brazil, HLA-DRB1*15:01 was observed to be a genetic susceptibility factor for MS. However, the significant association between DRB1*15:01 and MS was female-specific (Table 4), consistent with previous reports based on different populations^20,21. Indeed, women are twice as likely as men to develop MS, and this disparity has been increasing for at least 50 years in certain populations². This phenomenon can be partly explained by genetic interactions between polymorphisms in the estrogen receptor (ER)²¹ and Vitamin D receptor (VDR) genes²² and the HLA-DRB1*15:01 allele, which increase the risk for MS²¹. Furthermore, the DRB1*15:01 allele was previously shown to be over-represented within Brazilian patients⁹, and it was associated with both younger age at diagnosis and with being female; however, no association was observed between DRB1*15:01 and disease course²³.

It has been reported that, in general, African-Brazilian patients (e.g., from Rio de Janeiro) possess certain European-derived alleles, such as HLA-DQB1*06:02, but do not possess the DRB1*15:01 allele, which is more common in Brazilian Caucasians, African Americans and Europeans. The HLA-DRB1*15:01-DQB1*06:02 association was already identified as a susceptibility factor for MS in Caucasian Brazilian samples⁸. Unlike previous studies conducted on Brazilian populations^8,24, we did not observe an association between the HLA-DQA1*02:01-03:01 alleles and MS (Table 3). In addition, an association between HLA-DQB1*06:02 and MS in the absence of DRB1*15:01 was not observed in patients of African descent, which also does not agree with previous studies¹⁰. These inconsistent results may be due to differences in the ethnic admixtures of the analyzed population samples.

Although MS is considered to be rare in Brazil, the significant number of affected Brazilians of African descent has drawn the attention of researchers because this ethnic group is rarely affected by MS in other countries²⁵. The fact that such a phenomenon is observed in Brazil could be attributed to the degree of ethnic admixing among the local population¹⁰.

In a recent genome-screening survey, several novel loci were identified that showed significant associations with MS outcome, including IL2RA, IL7RA, CLEC16A, CD58, TNFRSFA1 and IRF8²⁷, the majority of which are located near genes with immune functions or that have been associated with other autoimmune diseases. The CIITA gene is a known regulator of HLA-D expression and is found within the CLEC16A-SOCS1-CIITA gene complex²⁸, a chromosomal region that has been associated with susceptibility to MS^28,29. An association between the rs4774*C missense variant and susceptibility to MS – as well as to other autoimmune diseases, such as lupus erythematous – has been previously described¹³. Bronson et al.¹³, using a European data set of 1,320 MS cases, identified an association between the missense mutation +1614G/C (rs4774) and the HLA-DRB1*15:01 allele as a risk factor for MS in Caucasian European groups¹³. In contrast, earlier studies investigating the association between the +1614G/C mutation and MS did not find a significant association³⁰. We also note that previous studies involving the rs3087456 variant of CIITA presented conflicting results¹³. In a study of a Nordic population, the authors observed significant differences in rs3087456 frequencies between MS patients and the healthy control group³⁰, although another case-control study found no significant differences with respect to this mutation between patients and control groups in Northern Ireland. In addition, Ramagoplan et al.²² failed to identify a relationship between CIITA variants and MS types in a Canadian population. However, in a sample group taken from Rio de Janeiro, Brazil, we found that a combination of the +1614G/C (rs4774) mutation and the HLA-DRB1*15:01 allele increased susceptibility to MS and that the HLA-DRB1*15:01-MS association was stronger in female patients (Table 4). These findings reinforce the multifactorial and polygenic nature of MS.

In conclusion, our results indicated that the HLA-DRB1*15:01 allele was associated with susceptibility to MS in a sample population from Rio de Janeiro, Brazil. Furthermore, this association was more significant in female patients. Therefore, we conclude that the rs4774*C mutation in combination with the HLA-DRB1*15:01 allele increases susceptibility to MS in this population.

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• Support: The authors are grateful to PROAP/CAPES and FINEP for their financial support.

Publication Dates

• Publication in this collection
  Apr 2015

History

• Received
  19 May 2014
• Received
  18 Nov 2014
• Accepted
  09 Dec 2014