Dataset Information

Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.

ABSTRACT: Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10(-7)).

SUBMITTER: Stacey SN

PROVIDER: S-EPMC4754045 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Publications

Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.

Stacey Simon N SN Kehr Birte B Gudmundsson Julius J Zink Florian F Jonasdottir Aslaug A Gudjonsson Sigurjon A SA Sigurdsson Asgeir A Halldorsson Bjarni V BV Agnarsson Bjarni A BA Benediktsdottir Kristrun R KR Aben Katja K H KK Vermeulen Sita H SH Cremers Ruben G RG Panadero Angeles A Helfand Brian T BT Cooper Phillip R PR Donovan Jenny L JL Hamdy Freddie C FC Jinga Viorel V Okamoto Ichiro I Jonasson Jon G JG Tryggvadottir Laufey L Johannsdottir Hrefna H Kristinsdottir Anna M AM Masson Gisli G Magnusson Olafur T OT Iordache Paul D PD Helgason Agnar A Helgason Hannes H Sulem Patrick P Gudbjartsson Daniel F DF Kong Augustine A Jonsson Eirikur E Barkardottir Rosa B RB Einarsson Gudmundur V GV Rafnar Thorunn T Thorsteinsdottir Unnur U Mates Ioan N IN Neal David E DE Catalona William J WJ Mayordomo José I JI Kiemeney Lambertus A LA Thorleifsson Gudmar G Stefansson Kari K

Human molecular genetics 20160105 5

Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and pro ...[more]

PMID: 26740556

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Project description:The human genome hosts several active families of transposable elements (TEs), including the Alu, LINE-1, and SVA retrotransposons that are mobilized via reverse transcription of RNA intermediates. We evaluated how insertion polymorphisms generated by human retrotransposon activity may be related to common health and disease phenotypes that have been previously interrogated through genome-wide association studies (GWAS). To address this question, we performed a genome-wide screen for retrotransposon polymorphism disease associations that are linked to TE induced gene regulatory changes. Our screen first identified polymorphic retrotransposon insertions found in linkage disequilibrium (LD) with single nucleotide polymorphisms that were previously associated with common complex diseases by GWAS. We further narrowed this set of candidate disease associated retrotransposon polymorphisms by identifying insertions that are located within tissue-specific enhancer elements. We then performed expression quantitative trait loci analysis on the remaining set of candidates in order to identify polymorphic retrotransposon insertions that are associated with gene expression changes in B-cells of the human immune system. This progressive and stringent screen yielded a list of six retrotransposon insertions as the strongest candidates for TE polymorphisms that lead to disease via enhancer-mediated changes in gene regulation. For example, we found an SVA insertion within a cell-type specific enhancer located in the second intron of the B4GALT1 gene. B4GALT1 encodes a glycosyltransferase that functions in the glycosylation of the Immunoglobulin G (IgG) antibody in such a way as to convert its activity from pro- to anti-inflammatory. The disruption of the B4GALT1 enhancer by the SVA insertion is associated with down-regulation of the gene in B-cells, which would serve to keep the IgG molecule in a pro-inflammatory state. Consistent with this idea, the B4GALT1 enhancer SVA insertion is linked to a genomic region implicated by GWAS in both inflammatory conditions and autoimmune diseases, such as systemic lupus erythematosus and Crohn's disease. We explore this example and the other cases uncovered by our genome-wide screen in an effort to illuminate how retrotransposon insertion polymorphisms can impact human health and disease by causing changes in gene expression.

Dataset Information

Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.

Publications

Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.

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