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 societies11 Weber F, Fontaine B, Cournu-Rebeix I, Kroner, A, Knop M, Lutz S et al. IL2RA
and IL7RA genes confer susceptibility for multiple sclerosis in two independent European
populations. Genes Immun. 2008;9(3):259-63.
http://dx.doi.org/10.1038/gene.2008.14
https://doi.org/10.1038/gene.2008.14...
. 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 disappearing22 Alonso, A, Hernán MA. Temporal trends in the incidence of multiple
sclerosis: a systematic review. Neurology. 2008;71(2):129-35.
http://dx.doi.org/10.1212/01.wnl.0000316802.35974.34
https://doi.org/10.1212/01.wnl.000031680...
. Among the highly admixed Brazilian population, which is the result
of interbreeding between European Caucasians, Africans and Amerindians33 Krieger H, Morton NE, Mi MP, Azevêdo ES, Freire-Maia A, Yasuda N. Racial
admixture in north-eastern Brazil. Ann Hum Genet. 1965;29(2):113-25.
http://dx.doi.org/10.1111/j.1469-1809.1965.tb00507.x
https://doi.org/10.1111/j.1469-1809.1965...
, the prevalence of MS is less than 15 cases per 100,000
inhabitants in Sao Paulo City44 Callegaro D, Lolio CA, Radvany J, Tilbery CP, Mendonça RA, Melo ACP.
Prevalence of multiple scllerosis in the city of São Paulo, Brazil, in 1990.
Neuroepidemiology. 1990;11(1):11-4. http://dx.doi.org/10.1159/000110901
https://doi.org/10.1159/000110901...
and about
20,100,000 inhabitants in Rio de Janeiro City55 Lacativa MCS, Naylor R, Cagy M, Alves-Leon SV, Pereira VC, Vasconcelos C et
al. Multiple sclerosis in the city of Rio de Janeiro. Mult Scler.
2012;18(12):1850..
The genetic components of MS pathogenesis are quite complex66 Alcina A, Abad-Grau MM, Fedetz M, Izquierdo G, Lucas M, Fernández O et al.
Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene
in different human populations. PLoS ONE. 2012;7(1):e29819.
http://dx.doi.org/10.1371/journal.pone.0029819
https://doi.org/10.1371/journal.pone.002...
, 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 MS66 Alcina A, Abad-Grau MM, Fedetz M, Izquierdo G, Lucas M, Fernández O et al.
Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene
in different human populations. PLoS ONE. 2012;7(1):e29819.
http://dx.doi.org/10.1371/journal.pone.0029819
https://doi.org/10.1371/journal.pone.002...
. 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 MS77 Dements DA, Ebers GC, Sadovnick AD. Genetics of multiple sclerosis. Lancet
Neurol. 2004;3(2):104-10. http://dx.doi.org/10.1016/S1474-4422(03)00663-X
https://doi.org/10.1016/S1474-4422(03)00...
, and these alleles have
also been linked to MS in the Brazilian population88 Alves-Leon SV, Papais-Alvarenga R, Magalhães M, Alvarenga M, Thuler LC,
Fernández O. Ethnicity-dependent association of HLA DRB1-DQA1-DQB1 alleles in Brazilian
Multiple Sclerosis patients. Acta Neurol Scand. 2007;115(5):306-11.
http://dx.doi.org/10.1111/j.1600-0404.2006.00750.x
https://doi.org/10.1111/j.1600-0404.2006...
,99 Brum DG, Barreira AA, Louzada-Junior P, Mendes-Junior CT, Donadi EA.
Association of the HLA-DRB1*15 allele group and the DRB1*1501 and DRB1*1503 alleles with
multiple sclerosis in White and Mulatto samples from Brazil. J Neuroimmunol.
2007;189(1-2):118-24. http://dx.doi.org/10.1016/j.jneuroim.2007.06.009
https://doi.org/10.1016/j.jneuroim.2007....
,1010 Caballero A, Alvés-León SV, Papais-Alvarenga R, Fernández O, Navarro G,
Alonso A. DQB1*0602 confers genetic susceptibility to multiple sclerosis in
Afro-Brazilians. Tissue Antigens. 1999;54(5):524-6.
http://dx.doi.org/10.1034/j.1399-0039.1999.540511.x
https://doi.org/10.1034/j.1399-0039.1999...
. 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
ethnicity88 Alves-Leon SV, Papais-Alvarenga R, Magalhães M, Alvarenga M, Thuler LC,
Fernández O. Ethnicity-dependent association of HLA DRB1-DQA1-DQB1 alleles in Brazilian
Multiple Sclerosis patients. Acta Neurol Scand. 2007;115(5):306-11.
http://dx.doi.org/10.1111/j.1600-0404.2006.00750.x
https://doi.org/10.1111/j.1600-0404.2006...
. In addition, the
HLA-DRB1*15 allelic group has been associated with MS in samples from
Brazil99 Brum DG, Barreira AA, Louzada-Junior P, Mendes-Junior CT, Donadi EA.
Association of the HLA-DRB1*15 allele group and the DRB1*1501 and DRB1*1503 alleles with
multiple sclerosis in White and Mulatto samples from Brazil. J Neuroimmunol.
2007;189(1-2):118-24. http://dx.doi.org/10.1016/j.jneuroim.2007.06.009
https://doi.org/10.1016/j.jneuroim.2007....
and Portugal1111 Bettencourt A, Silva AM, Pinho E, Costa P, Silva B, Silva BM. Molecular
genetic studies of multiple sclerosis in the portuguese population. Acta Med Port.
2012;25(4):224-30.,1212 Silva AM, Pereira C, Bettencourt A, Carvalho C, Couto AR, Leite MI et al.
The role of HLA-DRB1 alleles on susceptibility and outcome of a Portuguese Multiple
Sclerosis population. J Neurol Sci. 2007;258(1-2):69-74.
http://dx.doi.org/10.1016/j.jns.2007.02.033
https://doi.org/10.1016/j.jns.2007.02.03...
, 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 factors1313 Bronson PG, Caillier S, Ramsay PP, McCauley JL, Zuvich RL, De Jager PL et
al. CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple
sclerosis. Hum Mol Genet. 2010;19(11):2331-40.
http://dx.doi.org/10.1093/hmg/ddq101
https://doi.org/10.1093/hmg/ddq101...
,1414 Rasmussen HB, Kelly MA, Clausen J. Genetic susceptibility to multiple
sclerosis: detection of polymorphic nucleotides and an intron in the 3’ untranslated
region of the major histocompatibility complex class II transactivator gene. Hum Immunol.
2001;62(4):371-7. http://dx.doi.org/10.1016/S0198-8859(01)00215-4
https://doi.org/10.1016/S0198-8859(01)00...
. In
fact, CIITA is an attractive candidate molecule in studies involving a
variety of autoimmune diseases and inflammatory HLA-associated conditions1313 Bronson PG, Caillier S, Ramsay PP, McCauley JL, Zuvich RL, De Jager PL et
al. CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple
sclerosis. Hum Mol Genet. 2010;19(11):2331-40.
http://dx.doi.org/10.1093/hmg/ddq101
https://doi.org/10.1093/hmg/ddq101...
,1414 Rasmussen HB, Kelly MA, Clausen J. Genetic susceptibility to multiple
sclerosis: detection of polymorphic nucleotides and an intron in the 3’ untranslated
region of the major histocompatibility complex class II transactivator gene. Hum Immunol.
2001;62(4):371-7. http://dx.doi.org/10.1016/S0198-8859(01)00215-4
https://doi.org/10.1016/S0198-8859(01)00...
,1515 Friese MA, Jones EY, Fugger L. MHC II molecules in inflammatory diseases:
interplay of qualities and quantities. Trends Immunol. 2005;26(11):559-61.
http://dx.doi.org/10.1016/j.it.2005.08.011
https://doi.org/10.1016/j.it.2005.08.011...
.
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 expression1616 Mehta NT, Truax AD, Boyd NH, Greer SF. Early epigenetic events regulate the
adaptive immune response gene CIITA. Epigenetics. 2011;6(4):516-25.
http://dx.doi.org/10.4161/epi.6.4.14516
https://doi.org/10.4161/epi.6.4.14516...
.
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 time1717 Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L et al.
Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann
Neurol. 2005;58(6):840-6. http://dx.doi.org/10.1002/ana.20703
https://doi.org/10.1002/ana.20703...
. 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.1717 Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L et al.
Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann
Neurol. 2005;58(6):840-6. http://dx.doi.org/10.1002/ana.20703
https://doi.org/10.1002/ana.20703...
. 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-dependent88 Alves-Leon SV, Papais-Alvarenga R, Magalhães M, Alvarenga M, Thuler LC,
Fernández O. Ethnicity-dependent association of HLA DRB1-DQA1-DQB1 alleles in Brazilian
Multiple Sclerosis patients. Acta Neurol Scand. 2007;115(5):306-11.
http://dx.doi.org/10.1111/j.1600-0404.2006.00750.x
https://doi.org/10.1111/j.1600-0404.2006...
.
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.1818 Patarroyo JC, Stuve O, Piskurich JF, Hauser, SL, Oksenberg JR, Zamvil SS.
Single nucleotide polymorphisms in MHC2TA, the gene encoding the MHC class II
transactivator (CIITA). Genes Immun. 2002;3(1):34-7.
http://dx.doi.org/10.1038/sj.gene.6363808
https://doi.org/10.1038/sj.gene.6363808...
, 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.
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 29th, 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).
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).
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 populations11 Weber F, Fontaine B, Cournu-Rebeix I, Kroner, A, Knop M, Lutz S et al. IL2RA
and IL7RA genes confer susceptibility for multiple sclerosis in two independent European
populations. Genes Immun. 2008;9(3):259-63.
http://dx.doi.org/10.1038/gene.2008.14
https://doi.org/10.1038/gene.2008.14...
,66 Alcina A, Abad-Grau MM, Fedetz M, Izquierdo G, Lucas M, Fernández O et al.
Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene
in different human populations. PLoS ONE. 2012;7(1):e29819.
http://dx.doi.org/10.1371/journal.pone.0029819
https://doi.org/10.1371/journal.pone.002...
,99 Brum DG, Barreira AA, Louzada-Junior P, Mendes-Junior CT, Donadi EA.
Association of the HLA-DRB1*15 allele group and the DRB1*1501 and DRB1*1503 alleles with
multiple sclerosis in White and Mulatto samples from Brazil. J Neuroimmunol.
2007;189(1-2):118-24. http://dx.doi.org/10.1016/j.jneuroim.2007.06.009
https://doi.org/10.1016/j.jneuroim.2007....
, and
a link between HLA-DRB1* and MS susceptibility in Brazilian patients has
already been reported1919 Kaimen-Maciel DR, Reiche EM, Borelli SD, Morimoto HK, Melo FC, Lopes J et
al. HLA-DRB1* allele-associated genetic susceptibility and protection against multiple
sclerosis in Brazilian patients. Mol Med Rep. 2009;2:993-8.
http://dx.doi.org/10.3892/mmr_00000204
https://doi.org/10.3892/mmr_00000204...
.
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 populations2020 Irizar H, Muñoz-Culla M, Zuriarrain O, Goyenechea E, Castillo-Triviño T,
Prada A et al. HLA-DRB1*15:01 and multiple sclerosis: a female association? Mult Scler.
2012;18(5):569-77. http://dx.doi.org/10.1177/1352458511426813
https://doi.org/10.1177/1352458511426813...
,2121 Kikuchi S, Fukazawa T, Niino M, Yabe I, Miyagishi R, Hamada T et al.
Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients:
interaction with HLA-DRB1*1501 and disease modulation. J Neuroimmunol.
2002;128(1-2):77-81. http://dx.doi.org/10.1016/S0165-5728(02)00140-6
https://doi.org/10.1016/S0165-5728(02)00...
.
Indeed, women are twice as likely as men to develop MS, and this disparity has been
increasing for at least 50 years in certain populations22 Alonso, A, Hernán MA. Temporal trends in the incidence of multiple
sclerosis: a systematic review. Neurology. 2008;71(2):129-35.
http://dx.doi.org/10.1212/01.wnl.0000316802.35974.34
https://doi.org/10.1212/01.wnl.000031680...
. This phenomenon can be partly explained by genetic interactions
between polymorphisms in the estrogen receptor (ER)2121 Kikuchi S, Fukazawa T, Niino M, Yabe I, Miyagishi R, Hamada T et al.
Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients:
interaction with HLA-DRB1*1501 and disease modulation. J Neuroimmunol.
2002;128(1-2):77-81. http://dx.doi.org/10.1016/S0165-5728(02)00140-6
https://doi.org/10.1016/S0165-5728(02)00...
and Vitamin D receptor
(VDR) genes2222 Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton SM, Dyment DA
et al. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501
is regulated by vitamin D. PLoS Genet. 2009;5(2):e1000369.
http://dx.doi.org/10.1371/journal.pgen.1000369
https://doi.org/10.1371/journal.pgen.100...
and the
HLA-DRB1*15:01 allele, which increase the risk for MS2121 Kikuchi S, Fukazawa T, Niino M, Yabe I, Miyagishi R, Hamada T et al.
Estrogen receptor gene polymorphism and multiple sclerosis in Japanese patients:
interaction with HLA-DRB1*1501 and disease modulation. J Neuroimmunol.
2002;128(1-2):77-81. http://dx.doi.org/10.1016/S0165-5728(02)00140-6
https://doi.org/10.1016/S0165-5728(02)00...
. Furthermore, the
DRB1*15:01 allele was previously shown to be over-represented within
Brazilian patients99 Brum DG, Barreira AA, Louzada-Junior P, Mendes-Junior CT, Donadi EA.
Association of the HLA-DRB1*15 allele group and the DRB1*1501 and DRB1*1503 alleles with
multiple sclerosis in White and Mulatto samples from Brazil. J Neuroimmunol.
2007;189(1-2):118-24. http://dx.doi.org/10.1016/j.jneuroim.2007.06.009
https://doi.org/10.1016/j.jneuroim.2007....
, 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 course2323 Hensiek AE, Sawcer SJ, Feakes R, Deans J, Mander A, Akesson E et al. HLA-DR
15 is associated with female sex and younger age at diagnosis in multiple sclerosis. J
Neurol Neurosurg Psychiatry. 2002;72(2):184-7.
http://dx.doi.org/10.1136/jnnp.72.2.184
https://doi.org/10.1136/jnnp.72.2.184...
.
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
samples88 Alves-Leon SV, Papais-Alvarenga R, Magalhães M, Alvarenga M, Thuler LC,
Fernández O. Ethnicity-dependent association of HLA DRB1-DQA1-DQB1 alleles in Brazilian
Multiple Sclerosis patients. Acta Neurol Scand. 2007;115(5):306-11.
http://dx.doi.org/10.1111/j.1600-0404.2006.00750.x
https://doi.org/10.1111/j.1600-0404.2006...
. Unlike previous studies
conducted on Brazilian populations88 Alves-Leon SV, Papais-Alvarenga R, Magalhães M, Alvarenga M, Thuler LC,
Fernández O. Ethnicity-dependent association of HLA DRB1-DQA1-DQB1 alleles in Brazilian
Multiple Sclerosis patients. Acta Neurol Scand. 2007;115(5):306-11.
http://dx.doi.org/10.1111/j.1600-0404.2006.00750.x
https://doi.org/10.1111/j.1600-0404.2006...
,2424 Santos CCC. Analysis of HLA DQ, DP, DR alleles associated with multiple
sclerosis susceptibility in a population f,rom Rio City [dissertation]. Arq
Neuropsiquiatr. 2002;60(4):1051.
http://dx.doi.org/10.1590/S0004-282X2002000600037
https://doi.org/10.1590/S0004-282X200200...
, 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
studies1010 Caballero A, Alvés-León SV, Papais-Alvarenga R, Fernández O, Navarro G,
Alonso A. DQB1*0602 confers genetic susceptibility to multiple sclerosis in
Afro-Brazilians. Tissue Antigens. 1999;54(5):524-6.
http://dx.doi.org/10.1034/j.1399-0039.1999.540511.x
https://doi.org/10.1034/j.1399-0039.1999...
. 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 countries2525 Cree BA, Reich DE, Khan O, De Jager PL, Nakashima I, Takahashi T et al.
Modification of multiple sclerosis phenotypes by African ancestry at HLA. Arch Neurol.
2009;66(2):226-33. http://dx.doi.org/10.1001/archneurol.2008.541
https://doi.org/10.1001/archneurol.2008....
. The fact that such a phenomenon is observed in Brazil could be
attributed to the degree of ethnic admixing among the local population1010 Caballero A, Alvés-León SV, Papais-Alvarenga R, Fernández O, Navarro G,
Alonso A. DQB1*0602 confers genetic susceptibility to multiple sclerosis in
Afro-Brazilians. Tissue Antigens. 1999;54(5):524-6.
http://dx.doi.org/10.1034/j.1399-0039.1999.540511.x
https://doi.org/10.1034/j.1399-0039.1999...
.
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 IRF82727 Kemppinen AK, Kaprio J, Palotie A, Saarela J. Systematic review of
genome-wide expression studies in multiple sclerosis. BMJ Open. 2011;18;1(1):e000053.
http://dx.doi.org/10.1136/bmjopen-2011-000053
https://doi.org/10.1136/bmjopen-2011-000...
, 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 complex2828 Zuvich RL, Bush WS, McCauley JL, Beecham AH, De Jager PL, Ivinson, AJ et al.
Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis
susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex. Hum
Mol Genet. 2011;20(17):3517-24. http://dx.doi.org/10.1093/hmg/ddr250
https://doi.org/10.1093/hmg/ddr250...
, a chromosomal region that has been associated with susceptibility
to MS2828 Zuvich RL, Bush WS, McCauley JL, Beecham AH, De Jager PL, Ivinson, AJ et al.
Interrogating the complex role of chromosome 16p13.13 in multiple sclerosis
susceptibility: independent genetic signals in the CIITA-CLEC16A-SOCS1 gene complex. Hum
Mol Genet. 2011;20(17):3517-24. http://dx.doi.org/10.1093/hmg/ddr250
https://doi.org/10.1093/hmg/ddr250...
,2929 Haines JL, Pericak-Vance MA. Genetics of multiple sclerosis [Theofilopoulos
AN, editor. Genes and genetics of autoimmunity]. Curr Dir Autoimmun. 1999;1:273-88.
http://dx.doi.org/10.1159/000060491
https://doi.org/10.1159/000060491...
. 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 described1313 Bronson PG, Caillier S, Ramsay PP, McCauley JL, Zuvich RL, De Jager PL et
al. CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple
sclerosis. Hum Mol Genet. 2010;19(11):2331-40.
http://dx.doi.org/10.1093/hmg/ddq101
https://doi.org/10.1093/hmg/ddq101...
. Bronson
et al.1313 Bronson PG, Caillier S, Ramsay PP, McCauley JL, Zuvich RL, De Jager PL et
al. CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple
sclerosis. Hum Mol Genet. 2010;19(11):2331-40.
http://dx.doi.org/10.1093/hmg/ddq101
https://doi.org/10.1093/hmg/ddq101...
, 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
groups1313 Bronson PG, Caillier S, Ramsay PP, McCauley JL, Zuvich RL, De Jager PL et
al. CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple
sclerosis. Hum Mol Genet. 2010;19(11):2331-40.
http://dx.doi.org/10.1093/hmg/ddq101
https://doi.org/10.1093/hmg/ddq101...
. In contrast, earlier studies
investigating the association between the +1614G/C mutation and MS did not find a
significant association3030 Swanberg M, Lidman O, Padyukov L, Eriksson P, Akesson E, Jagodic M et al.
MHC2TA is associated with differential MHC molecule expression and susceptibility to
rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat Genet.
2005;37(5):486-94. http://dx.doi.org/10.1038/ng1544
https://doi.org/10.1038/ng1544...
. We also note
that previous studies involving the rs3087456 variant of CIITA presented
conflicting results1313 Bronson PG, Caillier S, Ramsay PP, McCauley JL, Zuvich RL, De Jager PL et
al. CIITA variation in the presence of HLA-DRB1*1501 increases risk for multiple
sclerosis. Hum Mol Genet. 2010;19(11):2331-40.
http://dx.doi.org/10.1093/hmg/ddq101
https://doi.org/10.1093/hmg/ddq101...
. In a study of a
Nordic population, the authors observed significant differences in rs3087456 frequencies
between MS patients and the healthy control group3030 Swanberg M, Lidman O, Padyukov L, Eriksson P, Akesson E, Jagodic M et al.
MHC2TA is associated with differential MHC molecule expression and susceptibility to
rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat Genet.
2005;37(5):486-94. http://dx.doi.org/10.1038/ng1544
https://doi.org/10.1038/ng1544...
, 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.2222 Ramagopalan SV, Maugeri NJ, Handunnetthi L, Lincoln MR, Orton SM, Dyment DA
et al. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501
is regulated by vitamin D. PLoS Genet. 2009;5(2):e1000369.
http://dx.doi.org/10.1371/journal.pgen.1000369
https://doi.org/10.1371/journal.pgen.100...
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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» https://doi.org/10.1159/000060491 -
30Swanberg M, Lidman O, Padyukov L, Eriksson P, Akesson E, Jagodic M et al. MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat Genet. 2005;37(5):486-94. http://dx.doi.org/10.1038/ng1544
» https://doi.org/10.1038/ng1544
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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