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Alterations in KLRB1 gene expression and a Scandinavian multiple sclerosis association study of the KLRB1 SNP rs4763655.

ABSTRACT: Multiple sclerosis (MS) is a complex autoimmune disease affecting genetically susceptible individuals. A genome-wide association study performed by the International MS Genetics Consortium identified several putative susceptibility genes; among these, the KLRB1 gene is represented by the single-nucleotide polymorphism rs4763655. We could confirm a marginally significant association between rs4763655 and MS (P=0.046, odds ratio=1.06 (1.00-1.13)) in a large Scandinavian case-control study of 5367 MS patients and 4485 controls. The expression of KLRB1 in blood from MS patients was higher compared with healthy controls (P<0.001), and the KLRB1 expression decreased significantly (P<0.001) after interferon (IFN)-? treatment. KLRB1 was expressed in T and natural killer (NK) cells, and expression mainly decreased in NK cells in patients treated with IFN-?. Collectively, our results indicate that KLRB1 gene expression is altered in MS and likely to be involved in the pathogenesis of the disease, whereas rs4763655 in KLRB1 seems to have a minimal role in MS susceptibility.

SUBMITTER: Sondergaard HB

PROVIDER: S-EPMC3190260 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Alterations in KLRB1 gene expression and a Scandinavian multiple sclerosis association study of the KLRB1 SNP rs4763655.

Søndergaard Helle Bach HB Sellebjerg Finn F Hillert Jan J Olsson Tomas T Kockum Ingrid I Lindén Magdalena M Mero Inger-Lise IL Myhr Kjell-Morten KM Celius Elisabeth G EG Harbo Hanne F HF Christensen Jeppe Romme JR Börnsen Lars L Sørensen Per Soelberg PS Oturai Annette Bang AB

European journal of human genetics : EJHG 20110525 10

Multiple sclerosis (MS) is a complex autoimmune disease affecting genetically susceptible individuals. A genome-wide association study performed by the International MS Genetics Consortium identified several putative susceptibility genes; among these, the KLRB1 gene is represented by the single-nucleotide polymorphism rs4763655. We could confirm a marginally significant association between rs4763655 and MS (P=0.046, odds ratio=1.06 (1.00-1.13)) in a large Scandinavian case-control study of 5367 ...[more]

PMID: 21610746

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Project description:BackgroundMultiple Sclerosis (MS) is an autoimmune neurodegenerative disease affecting approximately 3 million people globally. Despite rigorous research on MS, aspects of its development and progression remain unclear. Understanding molecular mechanisms underlying MS is crucial to providing insights into disease pathways, identifying potential biomarkers for early diagnosis, and revealing novel therapeutic targets for improved patient outcomes.MethodsWe utilized publicly available RNA-seq data (GSE138614) from post-mortem white matter tissues of five donors without any neurological disorder and ten MS patient donors. This data was interrogated for differential gene expression, alternative splicing and single nucleotide variants as well as for functional enrichments in the resulting datasets.ResultsA comparison of non-MS white matter (WM) to MS samples yielded differentially expressed genes involved in adaptive immune response, cell communication, and developmental processes. Genes with expression changes positively correlated with tissue inflammation were enriched in the immune system and receptor interaction pathways. Negatively correlated genes were enriched in neurogenesis, nervous system development, and metabolic pathways. Alternatively spliced transcripts between WM and MS lesions included genes that play roles in neurogenesis, myelination, and oligodendrocyte differentiation, such as brain enriched myelin associated protein (BCAS1), discs large MAGUK scaffold protein 1 (DLG1), KH domain containing RNA binding (QKI), and myelin basic protein (MBP). Our approach to comparing normal appearing WM (NAWM) and active lesion (AL) from one donor and NAWM and chronic active (CA) tissues from two donors, showed that different IgH and IgK gene subfamilies were differentially expressed. We also identified pathways involved in white matter injury repair and remyelination in these tissues. Differentially spliced genes between these lesions were involved in axon and dendrite structure stability. We also identified exon skipping events and spontaneous single nucleotide polymorphisms in membrane associated ring-CH-type finger 1 (MARCHF1), UDP glycosyltransferase 8 (UGT8), and other genes important in autoimmunity and neurodegeneration.ConclusionOverall, we identified unique genes, pathways, and novel splicing events affecting disease progression that can be further investigated as potential novel drug targets for MS treatment.

Dataset Information

Alterations in KLRB1 gene expression and a Scandinavian multiple sclerosis association study of the KLRB1 SNP rs4763655.

Publications

Alterations in KLRB1 gene expression and a Scandinavian multiple sclerosis association study of the KLRB1 SNP rs4763655.

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