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Looking beyond GWAS :
Looking beyond GWAS : allele-specific transcription factor binding drives the association of GALNT2 to HDL-C plasma levels
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- Cavalli, Marco (författare)
- Uppsala universitet,Medicinsk genetik och genomik
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- Pan, Gang (författare)
- Uppsala universitet,Medicinsk genetik och genomik
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- Nord, Helena (författare)
- Uppsala universitet,Medicinsk genetik och genomik
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- Wadelius, Claes (författare)
- Uppsala universitet,Medicinsk genetik och genomik
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(creator_code:org_t)
- 2016-01-27
- 2016
- Engelska.
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Ingår i: Lipids in Health and Disease. - : Springer Science and Business Media LLC. - 1476-511X. ; 15
- Relaterad länk:
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https://uu.diva-port... (primary) (Raw object)
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https://lipidworld.b...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Background: Plasma levels of high-density lipoprotein cholesterol (HDL-C) have been associated to cardiovascular disease. The high heritability of HDL-C plasma levels has been an incentive for several genome wide association studies (GWASs) which identified, among others, variants in the first intron of the GALNT2 gene strongly associated to HDL-C levels. However, the lead GWAS SNP associated to HDL-C levels in this genomic region, rs4846914, is located outside of transcription factor (TF) binding sites defined by chromatin immunoprecipitation followed by DNA sequencing (ChIP-seq) experiments in the ENCODE project and is therefore unlikely to be functional. In this study we apply a bioinformatics approach which rely on the premise that ChIP-seq reads can identify allele specific binding of a TF at cell specific regulatory elements harboring allele specific SNPs (AS-SNPs). EMSA and luciferase assays were used to validate the allele specific binding and to test the enhancer activity of the regulatory element harboring the AS-SNP rs4846913 as well as the neighboring rs2144300 which are in high LD with rs4846914. Findings: Using luciferase assays we found that rs4846913 and the neighboring rs2144300 displayed allele specific enhancer activity. We propose that an inhibitor binds preferentially to the rs4846913-C allele with an inhibitory boost from the synergistic binding of other TFs at the neighboring SNP rs2144300. These events influence the transcription level of GALNT2. Conclusions: The results suggest that rs4846913 and rs2144300 drive the association to HDL-C plasma levels through an inhibitory regulation of GALNT2 rather than the reported lead GWAS SNP rs4846914.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Hälsovetenskap -- Näringslära (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Health Sciences -- Nutrition and Dietetics (hsv//eng)
Nyckelord
- AS-SNPs
- GWAS
- HDL-C
- GALNT2
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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