Dataset Information

HLA-C Level Is Regulated by a Polymorphic Oct1 Binding Site in the HLA-C Promoter Region.

ABSTRACT: Differential HLA-C levels influence several human diseases, but the mechanisms responsible are incompletely characterized. Using a validated prediction algorithm, we imputed HLA-C cell surface levels in 228 individuals from the 1000 Genomes dataset. We tested 68,726 SNPs within the MHC for association with HLA-C level. The HLA-C promoter region variant, rs2395471, 800 bp upstream of the transcription start site, gave the most significant association with HLA-C levels (p = 4.2 × 10-66). This imputed expression quantitative trait locus, termed impeQTL, was also shown to associate with HLA-C expression in a genome-wide association study of 273 donors in which HLA-C mRNA expression levels were determined by quantitative PCR (qPCR) (p = 1.8 × 10-20) and in two cohorts where HLA-C cell surface levels were determined directly by flow cytometry (n = 369 combined, p < 10-15). rs2395471 is located in an Oct1 transcription factor consensus binding site motif where the A allele is predicted to have higher affinity for Oct1 than the G allele. Mobility shift electrophoresis demonstrated that Oct1 binds to both alleles in vitro, but decreased HLA-C promoter activity was observed in a luciferase reporter assay for rs2395471_G relative to rs2395471_A on a fixed promoter background. The rs2395471 variant accounts for up to 36% of the explained variation of HLA-C level. These data strengthen our understanding of HLA-C transcriptional regulation and provide a basis for understanding the potential consequences of manipulating HLA-C levels therapeutically.

SUBMITTER: Vince N

PROVIDER: S-EPMC5142108 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

HLA-C Level Is Regulated by a Polymorphic Oct1 Binding Site in the HLA-C Promoter Region.

Vince Nicolas N Li Hongchuan H Ramsuran Veron V Naranbhai Vivek V Duh Fuh-Mei FM Fairfax Benjamin P BP Saleh Bahara B Knight Julian C JC Anderson Stephen K SK Carrington Mary M

American journal of human genetics 20161103 6

Differential HLA-C levels influence several human diseases, but the mechanisms responsible are incompletely characterized. Using a validated prediction algorithm, we imputed HLA-C cell surface levels in 228 individuals from the 1000 Genomes dataset. We tested 68,726 SNPs within the MHC for association with HLA-C level. The HLA-C promoter region variant, rs2395471, 800 bp upstream of the transcription start site, gave the most significant association with HLA-C levels (p = 4.2 × 10<sup>-66</sup>) ...[more]

PMID: 27817866

Similar Datasets

Project description:BackgroundDNA polymerase β is one of the key enzymes involved in the repair of DNA damage, and its high or low expression is closely related to tumorigenesis. In a previous study on lung cancer, we found three genetic mutations in the promoter region of the Polb gene could be detected in the Han Chinese population. The purpose of this study was to explore the relationship between these mutations and thymic hyperplasia.MethodsGenomic DNA was extracted from 59 thymic hyperplasia patients by the salting out method and used for amplification of the promoter region of the Polb gene. The Polb gene mutation and its frequency were analyzed systematically by comparing them with the deposited wild-type gene sequence in the NCBI database. The three typical mutated sequences in the promoter region of Polb gene, -196G > T, -168C > A and -188_-187insCGCCC, were then amplified and ligated to pGL4.10 vector, so as to get the vectors used for the infection of 293T cells to explore their transcription activities by dual-luciferase reporter system.ResultsTwo types of mutations, -168C>A and-188_-187insCGCCC, were found in a significantly higher percentage in patients with thymic hyperplasia than in normal healthy people after sequencing analysis of 59 patients and 60 healthy controls. These results suggest that the two mutations may be closely related to thymic hyperplasia. in vitro functional experiments showed that-168C>A could significantly increase promoter activity, whereas -188_-187insCGCCC could significantly reduce promoter activity, suggesting that these two mutations may affect the expression level of the Polb gene in cells.ConclusionsTwo types of mutations in the promoter region of the Polb gene, -168C>A and-188_-187insCGCCC, are associated with thymic hyperplasia and may become a new risk factor for this disease.Key pointsSIGNIFICANT FINDINGS OF THE STUDY: Genetic mutations in the Polb gene are reported to be associated with different kinds of cancers. However, their relationship with thymic hyperplasia is still unclear.What this study addsFor the first time, we report that two nucleotide mutations in the promoter region of the Polb gene are closely related with thymic hyperplasia after sequencing 59 patients and 60 healthy controls in the Han Chinese population.

Dataset Information

HLA-C Level Is Regulated by a Polymorphic Oct1 Binding Site in the HLA-C Promoter Region.

Publications

HLA-C Level Is Regulated by a Polymorphic Oct1 Binding Site in the HLA-C Promoter Region.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets