World Distribution of HLA Alleles and Implications for Disease

Bodmer, Julia G.

doi:10.1002/9780470514887.ch13

Cited by 14 publications

(10 citation statements)

References 20 publications

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“…This is especially an issue with studies of HLA alleles, which even among European populations can be highly variable in frequency. 18 Using GWA SNP data has allowed us to minimize this potential problem as formal statistical analysis provided no significant evidence that population substructure is a confounding factor in our study. Survivorship is a potential source of bias if a variant influences prognosis as seen in the study of some cancers.…”

Section: Discussionmentioning

confidence: 98%

MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia

Hosking

Leslie

Dilthey

et al. 2011

Blood

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A role for specific human leukocyte antigen (HLA) variants in the etiology of childhood acute lymphoblastic leukemia (ALL) has been extensively studied over the last 30 years, but no unambiguous association has been identified. To comprehensively study the relationship between genetic variation within the 4.5 Mb major histocompatibility complex genomic region and precursor B-cell (BCP) ALL risk, we analyzed 1075 observed and 8176 imputed single nucleotide polymorphisms and their related haplotypes in 824 BCP-ALL cases and 4737 controls. Using these genotypes we also imputed both common and rare alleles at class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) HLA loci. Overall, we found no statistically significant association between variants and BCP-ALL risk. We conclude that major histocompatibility complex-defined variation in immune-mediated response is unlikely to be a major risk factor for BCP-ALL. (Blood. 2011;117(5):1633-1640)

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Section: Discussionmentioning

confidence: 98%

MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia

Hosking

Leslie

Dilthey

et al. 2011

Blood

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“…MHC genes are amongst the most polymorphic genes in higher vertebrates, indeed over 1500 human alleles have been characterised [5]. The allele HLA-A*0201 is one of the most frequent class I alleles in many populations [6]. It is expressed in 50% of Caucasians [7] and it has been demonstrated to play a critical role in antigen presentation of viral and tumour antigens [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Towards the chemometric dissection of peptide – HLA-A*0201 binding affinity: comparison of local and global QSAR models

Doytchinova

Walshe

Borrow

et al. 2005

J Comput Aided Mol Des

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The affinities of 177 nonameric peptides binding to the HLA-A*0201 molecule were measured using a FACS-based MHC stabilisation assay and analysed using chemometrics. Their structures were described by global and local descriptors, QSAR models were derived by genetic algorithm, stepwise regression and PLS. The global molecular descriptors included molecular connectivity chi indices, kappa shape indices, E-state indices, molecular properties like molecular weight and log P, and three-dimensional descriptors like polarizability, surface area and volume. The local descriptors were of two types. The first used a binary string to indicate the presence of each amino acid type at each position of the peptide. The second was also position-dependent but used five z-scales to describe the main physicochemical properties of the amino acids forming the peptides. The models were developed using a representative training set of 131 peptides and validated using an independent test set of 46 peptides. It was found that the global descriptors could not explain the variance in the training set nor predict the affinities of the test set accurately. Both types of local descriptors gave QSAR models with better explained variance and predictive ability. The results suggest that, in their interactions with the MHC molecule, the peptide acts as a complicated ensemble of multiple amino acids mutually potentiating each other.

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“…HLA-A3 is a common class I allele in humans expressed in up to 25% of people of European descent (63), and several HLA-A3-restricted HIV-1 epitopes have been identified. These include 2 overlapping Gag epitopes, only 1 of which is consistently immunodominant (18,19,(64)(65)(66).…”

Section: Introductionmentioning

confidence: 99%

Portable flanking sequences modulate CTL epitope processing

Gall¹,

Stamegna²,

Walker³

2007

J. Clin. Invest.

150

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Peptide presentation is critical for immune recognition of pathogen-infected cells by CD8 + T lymphocytes.Although a limited number of immunodominant peptide epitopes are consistently observed in diseases such as HIV-1 infection, the relationship between immunodominance and antigen processing in humans is largely unknown. Here, we have demonstrated that endogenous processing and presentation of a human immunodominant HIV-1 epitope is more efficient than that of a subdominant epitope. Furthermore, we have shown that the regions flanking the immunodominant epitope constitute a portable motif that increases the production and antigenicity of otherwise subdominant epitopes. We used a novel in vitro degradation assay involving cytosolic extracts as well as endogenous intracellular processing assays to examine 2 well-characterized HIV-1 Gag overlapping epitopes presented by the same HLA class I allele, one of which is consistently immunodominant and the other subdominant in infected persons. The kinetics and products of degradation of HIV-1 Gag favored the production of peptides encompassing the immunodominant epitope and destruction of the subdominant one. Notably, cytosolic digestion experiments revealed flanking residues proximal to the immunodominant epitope that increased the production and antigenicity of otherwise subdominant epitopes. Furthermore, specific point mutations in these portable flanking sequences modulated the production and antigenicity of epitopes. Such portable epitope processing determinants provide what we believe is a novel approach to optimizing CTL responses elicited by vaccine vectors.

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World Distribution of HLA Alleles and Implications for Disease

Cited by 14 publications

References 20 publications

MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia

MHC variation and risk of childhood B-cell precursor acute lymphoblastic leukemia

Towards the chemometric dissection of peptide – HLA-A*0201 binding affinity: comparison of local and global QSAR models

Portable flanking sequences modulate CTL epitope processing

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