Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment

Jaruskova, Monika; Curik, Nikola; Hercog, Rajna; Polivkova, Vaclava; Motlova, Eliska; Benes, Vladimir; Klamova, Hana; Pecherkova, Pavla; Belohlavkova, Petra; Vrbacky, Filip; Machova Polakova, Katerina

doi:10.1186/s13046-017-0523-3

Journal of Experimental & Clinical Cancer Research

Table 1 Regulatory likelihood of the investigated SNPs according to the RegulomeDB database

From: Genotypes of SLC22A4 and SLC22A5 regulatory loci are predictive of the response of chronic myeloid leukemia patients to imatinib treatment

a.
Gene Functional consequence	SNP	Position	Regulome DB score	eQTL (Monocytes)	Histone modification Chromatin state Blood cells	Protein binding K562
SLC22A4 Intron 3	rs156322 A/G	chr5:131653924	1f	SLC22A4 SLC22A5	Quiescent/Low T, B and NK cells from PB Strong transcription Primary neutrophils, monocytes, MNC from PB Weak transcription Primary HSC Genic enhancers K562	NA
SLC22A4 Intron 3	rs272842 C/T	chr5:131656516	1f	SLC22A4 SLC22A5	Quiescent/Low T, B and NK cells from PB Strong transcription Primary neutrophils and monocytes from PB Weak transcription Primary HSC, MNC from PB, K562	NA
SLC22A4 Intron 5	rs272889 C/T	chr5:131665377	1f	SLC22A4 SLC22A5	Quiescent/Low Primary T, B and NK cells from PB Strong transcription MNC from PB Weak transcription T-helper naïve from PB, K562, primary HSC	NA
SLC22A4 Intron 8	rs272872 C/T	chr5:131675863	1f	SLC22A4 SLC22A5	Quiescent/Low primary T, B and NK cells from PB Strong transcription MNC from PB Weak transcription T-helper naïve from PB, K562, primary HSC	NA
SLC22A5 Intron 1	rs2631363 C/T	chr5:131707094	2b	NA	NA	RBBP5, POLR3A
SLC22A5 Intron 1	rs2631362 C/T	chr5:131707292	1f	SLC22A4 SLC22A5	Enhancers MNC and T cells from PB Flanking active TSS K562 Weak transcription MNC from PB, primary HSC	RBBP5
SLC22A5 Intron 1	rs274570 A/G	chr5:131713225	1f	SLC22A4 SLC22A5	Quiescent/Low Primary T cells from PB Weak transcription primary HSC, MNC from PB, K562	NA
SLC22A5 Intron 2	rs274567 A/G	chr5:131714408	1f	SLC22A4 SLC22A5	Quiescent/Low T regulatory and helper cells, primary neutrophils from PB Strong transcription K562, primary T cells from PB, primary HSC G-CSF mobilized female and male Weak transcription primary HSC, primary T, B and NK cells from PB	NA
SLC22A5 Intron 2	rs183898 C/G	chr5:131716901	3a	NA	Quiescent/Low Primary neutrophils from PB, T regulatory and helper cells from PB Weak Transcription B cells, MNC form PB, K562, primary HSC short term culture	NA
SLC22A5 Intron 3	rs274559 C/T	chr5:131720069	1f	SLC22A4 SLC22A5	Quiescent/Low primary neutrophils from PB, T regulatory and helper cells from PB Strong Transcription K562 Weak Transcription primary HSC, primary NK cells from PB, T and B cells from PB, MNC from PB	NA
b.
Gene Functional consequence	SNP	Position	Regulome DB score	Histone modification Chromatin state Blood cells	Protein binding K562	Motif (cell type)	Position-Weight Matrix for TF binding Ref. sequence of SNP
SLC22A4 Promoter	rs460089 C/G	chr5:131629771	2a	NA	POLR2A, PHF8, HMGN3, UBTF, CTCF, ATF3, USF1, MAX, MYC, CBX3, UBTF, ZBTB7A, CCNT2, E2F6, IRF1, BCLAF1, ETS1	MYC:MAX (K562)
SLC22A4 Intron 3	rs270606 C/T	chr5:131650866	3a	NA	HDAC8	STAT5A (NA)
Downstream from SLC22A4 (LOC553103 intron 3)	rs272868 C/G	chr5:131680750	3a	Quiescent/Low Primary T and B cells from PB Strong transcription MNC from PB Weak transcription T-helper naïve from PB, K562, primary HSC	STAT1, STAT2, CEBPB	MEOX2 (NA)
SLC22A5 NC transcript variant, UTR variant 5 prime	rs13180043 C/T	chr5:131705586	2b	NA	POLR2A, PHF8, TAF1, ETS1, IRF1, MYC, UBTF, RBBP5, SAP30, MAX, E2F6, NRF1, HMGN3, KDM5B, E2F1	HIC1 (K562)
SLC22A5 NC transcript variant, UTR variant 5 primes	rs13180295 G/A	chr5:131705587	2b	NA	POLR2A, PHF8, TAF1, ETS1, IRF1, MYC, UBTF, RBBP5, SAP30, MAX, E2F6, NRF1, HMGN3, KDM5B, E2F1	HIC1 (K562)

The table is divided into two sections for clarity. a. Summary of the eQTL, chromatin state in blood cells and protein binding in K562. b. Summary of protein binding in K562, motifs, Position-Weight Matrix (PWM) for transcription factor binding and chromatin state in blood cells. Legend: 1f–likely to affect binding and linked to expression of a gene target (eQTL + TF binding/DNase peak); 2a–likely to affect binding (TF binding + matched TF motif + matched DNase Footprint + DNase peak); 2b–likely to affect binding (TF binding + any motif + DNase Footprint + DNase peak); 3a–less likely to affect binding (TF binding + any motif + DNase peak)

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ISSN: 1756-9966

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