HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

Urayama, Kevin Y.; Chokkalingam, Anand P.; Metayer, Catherine; Ma, Xiaomei; Selvin, Steve; Barcellos, Lisa F.; Wiencke, John K.; Taylor, Malcolm; Brennan, Paul; Dahl, Gary V.; Moonsamy, P. V.; Erlich, Henry A.; Trachtenberg, Elizabeth; Buffler, Patricia A.

doi:10.1182/blood-2012-01-404723

Cited by 25 publications

(26 citation statements)

References 47 publications

(63 reference statements)

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“…HLA-DPB1*01∶01 has previously been reported to be underrepresented among UKCCS ALL patients [41] and was recently reported to be associated with an increased risk for ALL in the NCCLS [14]. In addition, our results are suggestive that this haplotype may be overrepresented among T-ALL patients in the UK population (8.39%; P = 0.1).…”

Section: Discussionsupporting

confidence: 60%

Differences in Meiotic Recombination Rates in Childhood Acute Lymphoblastic Leukemia at an MHC Class II Hotspot Close to Disease Associated Haplotypes

et al. 2014

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Childhood Acute Lymphoblastic Leukemia (ALL) is a malignant lymphoid disease of which B-cell precursor- (BCP) and T-cell- (T) ALL are subtypes. The role of alleles encoded by major histocompatibility loci (MHC) have been examined in a number of previous studies and results indicating weak, multi-allele associations between the HLA-DPB1 locus and BCP-ALL suggested a role for immunosusceptibility and possibly infection. Two independent SNP association studies of ALL identified loci approximately 37 kb from one another and flanking a strong meiotic recombination hotspot (DNA3), adjacent to HLA-DOA and centromeric of HLA-DPB1. To determine the relationship between this observation and HLA-DPB1 associations, we constructed high density SNP haplotypes of the 316 kb region from HLA-DMB to COL11A2 in childhood ALL and controls using a UK GWAS data subset and the software PHASE. Of four haplotype blocks identified, predicted haplotypes in Block 1 (centromeric of DNA3) differed significantly between BCP-ALL and controls (P = 0.002) and in Block 4 (including HLA-DPB1) between T-ALL and controls (P = 0.049). Of specific common (>5%) haplotypes in Block 1, two were less frequent in BCP-ALL, and in Block 4 a single haplotype was more frequent in T-ALL, compared to controls. Unexpectedly, we also observed apparent differences in ancestral meiotic recombination rates at DNA3, with BCP-ALL showing increased and T-ALL decreased levels compared to controls. In silico analysis using LDsplit sotware indicated that recombination rates at DNA3 are influenced by flanking loci, including SNPs identified in childhood ALL association studies. The observed differences in rates of meiotic recombination at this hotspot, and potentially others, may be a characteristic of childhood leukemia and contribute to disease susceptibility, alternatively they may reflect interactions between ALL-associated haplotypes in this region.

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Section: Discussionsupporting

confidence: 60%

Differences in Meiotic Recombination Rates in Childhood Acute Lymphoblastic Leukemia at an MHC Class II Hotspot Close to Disease Associated Haplotypes

et al. 2014

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“…The risk allele of this SNP was robustly associated with changes in expression of HLA-DPA1 (increased expression), HLA-DRB1 (increased expression) and HLA-DQA2 (decreased expression) in brain tissues. HLA-DPA1 is an HLA class II α chain paralogue presenting peptides derived from extracellular proteins; 27 this is of particular relevance as impairment of clearance of extracellular debris might increase risk of developing a neurodegenerative condition, 28 including FTD and PD. While HLA-DRB1 has functions similar to HLA-DPA1, HLA-DQA2 belongs to the HLA class II α chain family located in intracellular vesicles: it plays a central role in the peptide loading of MHC class II molecules and releasing the class II-associated invariant chain peptide (CLIP) molecule from the peptide-binding site.…”

Section: Discussionmentioning

confidence: 99%

Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

Ferrari¹,

Wang

Vandrovcová

et al. 2016

J Neurol Neurosurg Psychiatry

107

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Background Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer’s disease (AD) and Parkinson’s disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Methods Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. Results We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3′-UTR=PVRL2, p=2.21×10−12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10−7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Conclusions Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk.

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“…Previous studies have shown a relationship between HLA polymorphisms and susceptibility to certain hematologic malignancies such as chronic lymphocytic leukemia, multiple myeloma, and acute lymphoblastic leukemia. [9][10][11] However, there is little information about the relationship between HLA polymorphisms and susceptibility to developing B-NHL or their outcomes. [12][13][14][15][16] Focusing on diffuse large B-cell lymphoma (DLBCL), some associations between HLA specificities and this B-NHL subtype have been described, as well as with other genetic polymorphisms.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, we describe for the first time the role of HLA polymorphisms in the prognosis of DLBCL patients receiving rituximabbased regimens as first-line treatment. Our results show that the presence of the HLA-DRB1*01 and the absence of HLA-C*03 polymorphism are associated with susceptibility to DLBCL, while the HLA-B44 supertype, especially the presence of HLA-B*18 and HLA-B*44 polymorphisms, have an independent influence on survival.The HLA system has been related to susceptibility to several hematologic and nonhematologic diseases, [9][10][11]36 including a variety of HLA polymorphisms associated with B-NHL development and outcome. [12][13][14][15][16] However, this feature has not been extensively studied specifically in DLBCL, although some data suggest an association between HLA subtypes and disease susceptibility (ie, a higher incidence of HLA-DRB1*04:01 allele in this lymphoma subgroup).…”

mentioning

confidence: 99%

HLA specificities are related to development and prognosis of diffuse large B-cell lymphoma

Alcoceba

Sebastián

Marı́n

et al. 2013

Blood

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Key Points• DLBCL patients carrying the HLA-B44 supertype have a worse progression-free and overall survival after R-CHOP-like treatment.• The HLA-DRB1*01 allele increases the risk of DLBCL development.Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n 5 64, 26%) or with (n 5 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs 19.5%, P 5 .0008, Pc 5 .0104) and a lower frequency of HLA-C*03 (6.4% vs 17.9%, P < .0005, Pc 5 .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P 5 .019) and 5-year overall (71% vs 92%, P 5 .001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect. (Blood. 2013;122(8):1448-1454 IntroductionSeveral genetic polymorphisms have been associated with susceptibility or prognosis in various B-cell non-Hodgkin lymphoma (B-NHL) subtypes.1,2 In recent years, genome-wide association studies have identified 6p21.3 as a risk region for susceptibility of different lymphomas, such as follicular lymphoma [3][4][5] or Hodgkin lymphoma. 6,7 The HLA system, located in this region, plays a key role in antitumor immune responses and lymphoma-cell apoptosis 8 and so may be essential for neoplasia control. Previous studies have shown a relationship between HLA polymorphisms and susceptibility to certain hematologic malignancies such as chronic lymphocytic leukemia, multiple myeloma, and acute lymphoblastic leukemia.9-11 However, there is little information about the relationship between HLA polymorphisms and susceptibility to developing B-NHL or their outcomes.12-16 Focusing on diffuse large B-cell lymphoma (DLBCL), some associations between HLA specificities and this B-NHL subtype have been described, as well as with other genetic polymorphisms. Shorter progression-free survival (PFS) and overall survival (OS) have been observed in DLBCL patients lacking the HLA-DR2 or carrying TNF -308A.13 In addition, OS is shorter in those patients carrying the C*07-B*08-LTA1 252G -TNF -308A haplotype 14 or the HLA-C*07:01. 16 However, these studies considered patients treated before...

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HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

Cited by 25 publications

References 47 publications

Differences in Meiotic Recombination Rates in Childhood Acute Lymphoblastic Leukemia at an MHC Class II Hotspot Close to Disease Associated Haplotypes

Differences in Meiotic Recombination Rates in Childhood Acute Lymphoblastic Leukemia at an MHC Class II Hotspot Close to Disease Associated Haplotypes

Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases

HLA specificities are related to development and prognosis of diffuse large B-cell lymphoma

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