HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis

Hensiek, Anke; Sawcer, Stephen; Feakes, Robert; Deans, J.; Mander, Adrian P.; Åkesson, Eva; Roxburgh, Richard; Coraddu, Francesca; Smith, Sheila I.; Compston, D. A. S.

doi:10.1136/jnnp.72.2.184

Cited by 151 publications

(120 citation statements)

References 39 publications

(24 reference statements)

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“…This phenomenon can be partly explained by genetic interactions between polymorphisms in the estrogen receptor (ER) 21 and Vitamin D receptor (VDR) genes 22 and the HLA-DRB1*15:01 allele, which increase the risk for MS 21 . Furthermore, the DRB1*15:01 allele was previously shown to be over-represented within Brazilian patients 9 , 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 course 23 .…”

Section: Discussionmentioning

confidence: 84%

The CIITA genetic polymorphism rs4774C in combination with the HLA-DRB115:01 allele as a putative susceptibility factor to multiple sclerosis in Brazilian females

Paradela

Alves-Leon

Figueiredo

et al. 2015

Arq. Neuro-Psiquiatr.

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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.

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Section: Discussionmentioning

confidence: 84%

The CIITA genetic polymorphism rs4774C in combination with the HLA-DRB115:01 allele as a putative susceptibility factor to multiple sclerosis in Brazilian females

Paradela

Alves-Leon

Figueiredo

et al. 2015

Arq. Neuro-Psiquiatr.

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“…We did not have serum samples from our cases and controls to examine associations with serum levels in childhood ALL. It is still unclear why there may be a sex effect in HLA complex associations, but in light of similar findings in other diseases (Meyer et al 2001;Fisher et al 2002;Hensiek et al 2002;Tian et al 2006), this aspect of the association we are reporting here warrants further study. In two rat models, HSP70 has a higher expression level in males in response to a viral infection (Klein et al 2004) or following acute tail-shock stress (Nickerson et al 2006) in lymphoid organs.…”

Section: Discussionmentioning

confidence: 84%

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

Ucisik-Akkaya

Davis

Gorodezky

et al. 2010

Cell Stress and Chaperones

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Three heat shock protein 70 (HSP70) genes, HSPA1L, HSPA1A, and HSPA1B, are located within the human leukocyte antigen (HLA) class III region. HSPs act as stress signals and regulate natural killer cell response to cancer. HSP70 gene polymorphisms show disease associations partly due to their linkage disequilibrium with HLA alleles. To systematically evaluate their associations with childhood acute lymphoblastic leukemia (ALL), we examined the three functional single nucleotide polymorphisms (SNPs) rs2227956 (T493M) in HSPA1L, rs1043618 in HSPA1A 5′UTR, and rs1061581 (Q351Q) in HSPA1B by TaqMan assays or polymerase chain reaction-restriction fragment length polymorphism in 114 ALL cases and 414 controls from Wales (UK), in 100 Mexican Mestizo ALL cases and 253 controls belonging to the same ethnic group, and in a panel of 82 HLA-typed reference cell line samples. Homozygosity for HSPA1B rs1061581 minor allele G was associated with protection (odds ratio (OR)=0.37, 95% confidence interval (CI)=0.16-0.78; P=0.007) with genedosage effect (additive model) reaching significance (P= 0.0001) in the Welsh case-control group. This association was replicated in the second case-control group from Mexico (OR (recessive model)=0.49, 95% CI=0.24-0.96; P=0.03), and the pooled analysis yielded a strong association (Mantel-Haenszel OR=0.43, 95% CI=0.27-0.69, P= 0.0004). The association was stronger in males in each group and in the pooled analysis. A three-SNP haplotype including the major allele A of rs1061581 showed a highly significant increase in Welsh cases compared with respective controls (6.7% vs 1.8%; P=0.0003) due to the difference between male cases and controls. The protective allele of rs1061581 occurred more frequently on the HLA-DRB3 haplotypes (especially DRB1*03) in the cell line panel, but the HSPA1B association was independent from the HLA-DRB4 association previously detected in the same case-control group from Wales (adjusted P=0.001). Given the cancer promoting roles played by HSPs intracellularly as well as roles in immune surveillance when expressed on the cell surface and the known correlations between expression levels and the HSP polymorphisms, these results are likely to indicate a primary association and warrant detailed assessment in childhood ALL development.

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“…The most consistent effect of HLA on MS phenotype is for the HLA-DRB1*15:01 allele on the age of onset. Several studies showed that this allele decreases the age of onset and does so in a dosedependent manner (Celius et al, 2000;Masterman et al, 2000;Hensiek et al, 2002;Smestad et al, 2007;Cree et al, 2009;Sawcer et al, 2011). HLA-DRB1*15:01 may also contribute to the radiographic burden of disease on T2-weighted brain magnetic resonance imaging (MRI) and impact cognitive performance (Okuda et al, 2009).…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Multiple sclerosis genetics

Cree

2014

Handbook of Clinical Neurology

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HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis

Cited by 151 publications

References 39 publications

The CIITA genetic polymorphism rs4774C in combination with the HLA-DRB115:01 allele as a putative susceptibility factor to multiple sclerosis in Brazilian females

The CIITA genetic polymorphism rs4774C in combination with the HLA-DRB115:01 allele as a putative susceptibility factor to multiple sclerosis in Brazilian females

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

Multiple sclerosis genetics

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HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis

Cited by 151 publications

References 39 publications

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

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

HLA complex-linked heat shock protein genes and childhood acute lymphoblastic leukemia susceptibility

Multiple sclerosis genetics

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Product

Resources

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The CIITA genetic polymorphism rs4774C in combination with the HLA-DRB115:01 allele as a putative susceptibility factor to multiple sclerosis in Brazilian females

The CIITA genetic polymorphism rs4774C in combination with the HLA-DRB115:01 allele as a putative susceptibility factor to multiple sclerosis in Brazilian females