A novel <i><scp>ERAP</scp>2</i> haplotype structure in a <scp>C</scp>hilean population: implications for <scp>ERAP</scp>2 protein expression and preeclampsia risk

Vanhille, Derek L.; Hill, Lilian H.; Hilliard, DaShaunda D.; Lee, Eun D.; Teves, María E.; Srinivas, Sindhu K.; Kusanovic, Juan Pedro; Gomez, Ricardo; Stratikos, Efstratios; Elovitz, Michal A.; Romero, Roberto; Strauss, Jerome F.

doi:10.1002/mgg3.49

Cited by 7 publications

(8 citation statements)

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“…An increased risk for PE in the African American population, but not in the Chilean population, was found. In addition, fetal ERAP2 SNP rs2549782 polymorphism was associated with a higher risk for PE in African American women (53).…”

Section: Discussionmentioning

confidence: 95%

ERAP, KIR, and HLA-C Profile in Recurrent Implantation Failure

Piekarska

Radwan²,

Tarnowska

et al. 2021

Front. Immunol.

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The mother’s uterine immune system is dominated by uterine natural killer (NK) cells during the first trimester of pregnancy. These cells express killer cell immunoglobulin-like receptors (KIRs) of inhibitory or activating function. Invading extravillous trophoblast cells express HLA-C molecules, and both maternal and paternal HLA-C allotypes are presented to KIRs. Endoplasmic reticulum aminopeptidase 1 (ERAP1) and 2 (ERAP2) shape the HLA class I immunopeptidome. The ERAPs remove N-terminal residues from antigenic precursor peptides and generate optimal-length peptides to fit into the HLA class I groove. The inability to form the correct HLA class I complexes with the appropriate peptides may result in a lack of immune response by NK cells. The aim of this study was to investigate the role of ERAP1 and ERAP2 polymorphisms in the context of KIR and HLA-C genes in recurrent implantation failure (RIF). In addition, for the first time, we showed the results of ERAP1 and ERAP2 secretion into the peripheral blood of patients and fertile women. We tested a total of 881 women. Four hundred ninety-six females were patients who, together with their partners, participated in in vitro fertilization (IVF). A group of 385 fertile women constituted the control group. Women positive for KIR genes in the Tel AA region and HLA-C2C2 were more prevalent in the RIF group than in fertile women (p/pcorr. = 0.004/0.012, OR = 2.321). Of the ERAP polymorphisms studied, two of them (rs26653 and rs26618) appear to affect RIF susceptibility in HLA-C2-positive patients. Moreover, fertile women who gave birth in the past secreted significantly more ERAP1 than IVF women and control pregnant women (p < 0.0001 and p = 0.0005, respectively). In the case of ERAP2, the opposite result was observed; i.e., fertile women secreted far less ERAP2 than IVF patients (p = 0.0098). Patients who became pregnant after in vitro fertilization embryo transfer (IVF-ET) released far less ERAP2 than patients who miscarried (p = 0.0032). Receiver operating characteristic (ROC) analyses indicate a value of about 2.9 ng/ml of ERAP2 as a point of differentiation between patients who miscarried and those who gave birth to a healthy child. Our study indicates that both ERAP1 and ERAP2 may be involved in processes related to reproduction.

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Section: Discussionmentioning

confidence: 95%

ERAP, KIR, and HLA-C Profile in Recurrent Implantation Failure

Piekarska

Radwan²,

Tarnowska

et al. 2021

Front. Immunol.

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“…However, the haplotype with this variant contains hundreds of other linked variants with significant population variation and harbors a second conditional ERAP2 eQTL in GTEx v8 LCLs. Moreover, several prior studies have demonstrated associations between ERAP2 expression and cis-variation independently of NMD, although linkage limited the resolution of functional studies ( 33, 45, 49, 50 ). Taken together, these results suggest that ERAP2 is regulated by a complex multi-allelic structure which operates via both gene expression and splicing.…”

Section: Resultsmentioning

confidence: 99%

“…Prior work has shown that a common splice variant at this locus results in nonsense-mediated decay (NMD) and allele-specific expression, which can cause an eQTL signal (48). However, the haplotype with this variant contains hundreds of other linked variants with significant population variation, harbors a second conditional ERAP2 eQTL in GTEx v8 LCLs, and is also regulated by surrounding variation independently of NMD though linkage has limited the resolution of functional studies (34,45,49,50). Notably, all but one of the variants identified in this study had allelic effects in the same direction as the predicted effect of NMD and are linked on the same haplotype.…”

Section: Experimental Fine-mapping Of Complex Trait Associationsmentioning

confidence: 99%

Multiple Causal Variants Underlie Genetic Associations in Humans

DeGorter

Gloudemans

Greenwald

et al. 2021

Preprint

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The majority of associations between genetic variation and human traits and diseases are non-coding and in strong linkage disequilibrium (LD) with surrounding genetic variation. In these cases, a single causal variant is often assumed to underlie the association, however no systematic assessment of the number of causal variants has been performed. In this study, we applied a massively parallel reporter assay (MPRA) in lymphoblastoid cells to functionally evaluate 49,256 allelic pairs, representing 30,893 genetic variants in high, local linkage disequilibrium for 744 independent cis-expression quantitative trait loci (eQTL) and assessed each for colocalization across 114 traits. We identified 3,536 allele-independent regulatory regions containing 907 allele-specific regulatory variants, and found that 17.3% of eQTL contained more than one significant allelic effect. We show that detected regulatory variants are highly and specifically enriched for activating chromatin structures and allelic transcription factor binding, for which ETS-domain family members are a large driver. Integration of MPRA profiles with eQTL/complex trait colocalizations identified causal variant sets for associations with blood cell measurements, Multiple Sclerosis, Irritable Bowel Disease, and Crohns Disease. These results demonstrate that a sizable number of association signals are manifest through multiple, tightly-linked causal variants requiring high-throughput functional assays for fine-mapping.

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“…However, association studies of this SNP are rare. Previous studies have found that ERAP2 haplotypes containing rs2287988 affect ERAP2 splicing and expression [50,51]. Thus, additional association studies in different populations are necessary to investigate the role of this polymorphism during the initiation and development of cervical cancer.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in endoplasmic reticulum aminopeptidase genes are associated with cervical cancer risk in a Chinese Han population

Zhang

et al. 2020

BMC Cancer

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Background Antigen-processing machinery molecules play crucial roles in infectious diseases and cancers. Studies have shown that polymorphisms in endoplasmic reticulum aminopeptidase (ERAP) genes can influence the enzymatic activity of ERAP proteins and are associated with the risk of diseases. In the current study, we evaluated the influence of ERAP gene (ERAP1 and ERAP2) polymorphisms on susceptibility to cervical intraepithelial neoplasia (CIN) and cervical cancer. Methods Six single nucleotide polymorphisms (SNPs) in ERAP1 and 5 SNPs in ERAP2 were selected and genotyped in 556 CIN patients, 1072 cervical cancer patients, and 1262 healthy control individuals. Candidate SNPs were genotyped using SNaPshot assay. And the association of these SNPs with CIN and cervical cancer was analysed. Results The results showed that allelic and genotypic frequencies of rs26653 in ERAP1 were significantly different between cervical cancer and control groups (P = 0.001 and 0.004). The allelic frequencies of rs27044 in ERAP1 and rs2287988 in ERAP2 were significantly different between control and cervical cancer groups (P = 0.003 and 0.004). Inheritance model analysis showed that genotypes of rs27044, rs26618, rs26653 and rs2287988 SNPs may be associated with the risk of cervical cancer (P = 0.003, 0.004, 0.001 and 0.002). Additionally, haplotype analysis results showed that the ERAP1 haplotype, rs27044C-rs30187T-rs26618T-rs26653G-rs3734016C, was associated with a lower risk of cervical cancer (P = 0.001). The ERAP2 haplotypes rs2549782G- rs2548538A-rs2248374A-rs2287988G-rs1056893T (P = 0.009 and 0.006) and rs2549782T-rs2548538T-rs2248374G-rs2287988A-rs1056893T (P = 0.003 and 0.009) might be associated with cervical cancer and the development from CIN to cervical cancer. Conclusion Our results indicated that rs27044, rs26618 and rs26653 in ERAP1 and rs2287988 in ERAP2 influenced susceptibility to cervical cancer.

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A novel ERAP2 haplotype structure in a Chilean population: implications for ERAP2 protein expression and preeclampsia risk

Cited by 7 publications

References 0 publications

ERAP, KIR, and HLA-C Profile in Recurrent Implantation Failure

ERAP, KIR, and HLA-C Profile in Recurrent Implantation Failure

Multiple Causal Variants Underlie Genetic Associations in Humans

Polymorphisms in endoplasmic reticulum aminopeptidase genes are associated with cervical cancer risk in a Chinese Han population

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