GENETIC VARIATION AT HBS1L-MYB AND GFI1B-GTF3C5 INFLUENCES WHETHER JAK2 V617F MUTATED MPN PRESENT WITH ET OR PV
(Abstract release date: 05/19/16)
EHA Library. Cross N. 06/11/16; 135262; S506
Prof. Nick Cross
Contributions
Contributions
Abstract
Abstract: S506
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Hall C13
Background
Evidence from epidemiological, familial and genetic studies indicate that common, low penetrance variants present in the general population contribute to the risk of developing MPN and also contribute to the phenotypic pleiotropy observed in these disorders. In a recent genome wide study we found that genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to JAK2-unmutated MPN. Furthermore, focused analysis of these four variants demonstrated that rs9376092 at HBS1L-MYB and the JAK2 46/1 haplotype specifically influence whether JAK2 V617F mutated cases present with PV or ET.
Aims
It is likely that variation at other genetic loci influence disease phenotype in MPN. Our aim was to identify inherited genetic factors on a genome wide basis that influence whether JAK2 V617F positive MPN patients present with PV or ET.
Methods
We undertook a two stage genome-wide association study. At stage 1,556 ET and 556 PV patients with JAK2 V617F were genotyped using Illumina Human OmniExpressExome v1.2 BeadChips. Following standard quality control, allelic chi-square tests were used to compare ET and PV cases. At stage 2, significant SNPs were genotyped in four additional JAK2 V617F-positive ET/PV cohorts from the UK (n=180), Spain (n=664), Italy (n=547) and Germany (n=74). The final effect size and significance of SNPs was determined by a fixed effects meta-analysis. The relationship with disease subtype was determined by comparison of either ET or PV cases against healthy controls (stage 1; WTCCC2 n=5200) and linear regression was used to assess the relationship with JAK2 V617F mutation burden following normalisation using Blom transformation.
Results
After quality control and excluding the p arm of chromosome 9 due to recurrent aUPD in PV and to a lesser extent in ET, 650,386 SNPs were tested in 499 ET and 505 PV cases at stage 1. Using a combination of significance, clustering of significant linked SNPs and functional evidence, 163 SNPs were tested at stage 2. Meta-analysis of ET versus PV cases identified one SNP, rs9399137 43kb upstream of HBS1L and 83kb upstream of MYB, that achieved genome-wide significance (pMETA=2.91x10-9) without heterogeneity between cohorts (Cochran’s Q test, p=0.31). One additional SNP, rs3011271 16kb downstream of GFI1B and 22kb upstream of GTF3C5, with moderate significance for ET versus PV (pMETA=3.00x10-5) and without heterogeneity between cohorts (p=0.18) also reached genome-wide significance (pMETA=2.36x10-8) when compared to V617F mutation level. In comparison with healthy controls, the HBS1L-MYB SNP predisposes to ET (p=2.01x10-6, OR=1.41) while the GFI1B-GTF3C5 SNP predisposes to PV (p=1.66x10-7, OR=1.49). Stratifying PV cases by 9p aUPD, showed that the association with GFI1B-GTF3C5 is restricted to PV cases with 9p aUPD (p=1.95x10-11 in cases with aUPD; p=0.67 in cases without aUPD). We found no evidence that previously reported SNPs at NR3C1 (glucocorticoid receptor), TET2, ATM, SH2B3, ERCC2 or CHEK2 influenced the development or phenotype of JAK2 V617F-mutated MPN.
Conclusion
On a genome wide level (excluding chromosome 9p), we have found that germline variation in the intergenic regions between HBS1L and MYB exerts the strongest influence on JAK2 V617F mutated MPN phenotype. In addition, variation between GFI1B and GTF3C5 predisposes to PV and in particular to cases with high JAK2 V617F mutation burden associated with 9p aUPD. Our findings indicate a complex interplay between somatic and germline genetics in MPN, and provides pointers towards the functional basis of the phenotypic pleiotropy of these disorders.
Session topic: Myeloproliferative neoplasms - Biology
Keyword(s): Essential Thrombocytemia
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Hall C13
Background
Evidence from epidemiological, familial and genetic studies indicate that common, low penetrance variants present in the general population contribute to the risk of developing MPN and also contribute to the phenotypic pleiotropy observed in these disorders. In a recent genome wide study we found that genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to JAK2-unmutated MPN. Furthermore, focused analysis of these four variants demonstrated that rs9376092 at HBS1L-MYB and the JAK2 46/1 haplotype specifically influence whether JAK2 V617F mutated cases present with PV or ET.
Aims
It is likely that variation at other genetic loci influence disease phenotype in MPN. Our aim was to identify inherited genetic factors on a genome wide basis that influence whether JAK2 V617F positive MPN patients present with PV or ET.
Methods
We undertook a two stage genome-wide association study. At stage 1,556 ET and 556 PV patients with JAK2 V617F were genotyped using Illumina Human OmniExpressExome v1.2 BeadChips. Following standard quality control, allelic chi-square tests were used to compare ET and PV cases. At stage 2, significant SNPs were genotyped in four additional JAK2 V617F-positive ET/PV cohorts from the UK (n=180), Spain (n=664), Italy (n=547) and Germany (n=74). The final effect size and significance of SNPs was determined by a fixed effects meta-analysis. The relationship with disease subtype was determined by comparison of either ET or PV cases against healthy controls (stage 1; WTCCC2 n=5200) and linear regression was used to assess the relationship with JAK2 V617F mutation burden following normalisation using Blom transformation.
Results
After quality control and excluding the p arm of chromosome 9 due to recurrent aUPD in PV and to a lesser extent in ET, 650,386 SNPs were tested in 499 ET and 505 PV cases at stage 1. Using a combination of significance, clustering of significant linked SNPs and functional evidence, 163 SNPs were tested at stage 2. Meta-analysis of ET versus PV cases identified one SNP, rs9399137 43kb upstream of HBS1L and 83kb upstream of MYB, that achieved genome-wide significance (pMETA=2.91x10-9) without heterogeneity between cohorts (Cochran’s Q test, p=0.31). One additional SNP, rs3011271 16kb downstream of GFI1B and 22kb upstream of GTF3C5, with moderate significance for ET versus PV (pMETA=3.00x10-5) and without heterogeneity between cohorts (p=0.18) also reached genome-wide significance (pMETA=2.36x10-8) when compared to V617F mutation level. In comparison with healthy controls, the HBS1L-MYB SNP predisposes to ET (p=2.01x10-6, OR=1.41) while the GFI1B-GTF3C5 SNP predisposes to PV (p=1.66x10-7, OR=1.49). Stratifying PV cases by 9p aUPD, showed that the association with GFI1B-GTF3C5 is restricted to PV cases with 9p aUPD (p=1.95x10-11 in cases with aUPD; p=0.67 in cases without aUPD). We found no evidence that previously reported SNPs at NR3C1 (glucocorticoid receptor), TET2, ATM, SH2B3, ERCC2 or CHEK2 influenced the development or phenotype of JAK2 V617F-mutated MPN.
Conclusion
On a genome wide level (excluding chromosome 9p), we have found that germline variation in the intergenic regions between HBS1L and MYB exerts the strongest influence on JAK2 V617F mutated MPN phenotype. In addition, variation between GFI1B and GTF3C5 predisposes to PV and in particular to cases with high JAK2 V617F mutation burden associated with 9p aUPD. Our findings indicate a complex interplay between somatic and germline genetics in MPN, and provides pointers towards the functional basis of the phenotypic pleiotropy of these disorders.
Session topic: Myeloproliferative neoplasms - Biology
Keyword(s): Essential Thrombocytemia
Abstract: S506
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Hall C13
Background
Evidence from epidemiological, familial and genetic studies indicate that common, low penetrance variants present in the general population contribute to the risk of developing MPN and also contribute to the phenotypic pleiotropy observed in these disorders. In a recent genome wide study we found that genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to JAK2-unmutated MPN. Furthermore, focused analysis of these four variants demonstrated that rs9376092 at HBS1L-MYB and the JAK2 46/1 haplotype specifically influence whether JAK2 V617F mutated cases present with PV or ET.
Aims
It is likely that variation at other genetic loci influence disease phenotype in MPN. Our aim was to identify inherited genetic factors on a genome wide basis that influence whether JAK2 V617F positive MPN patients present with PV or ET.
Methods
We undertook a two stage genome-wide association study. At stage 1,556 ET and 556 PV patients with JAK2 V617F were genotyped using Illumina Human OmniExpressExome v1.2 BeadChips. Following standard quality control, allelic chi-square tests were used to compare ET and PV cases. At stage 2, significant SNPs were genotyped in four additional JAK2 V617F-positive ET/PV cohorts from the UK (n=180), Spain (n=664), Italy (n=547) and Germany (n=74). The final effect size and significance of SNPs was determined by a fixed effects meta-analysis. The relationship with disease subtype was determined by comparison of either ET or PV cases against healthy controls (stage 1; WTCCC2 n=5200) and linear regression was used to assess the relationship with JAK2 V617F mutation burden following normalisation using Blom transformation.
Results
After quality control and excluding the p arm of chromosome 9 due to recurrent aUPD in PV and to a lesser extent in ET, 650,386 SNPs were tested in 499 ET and 505 PV cases at stage 1. Using a combination of significance, clustering of significant linked SNPs and functional evidence, 163 SNPs were tested at stage 2. Meta-analysis of ET versus PV cases identified one SNP, rs9399137 43kb upstream of HBS1L and 83kb upstream of MYB, that achieved genome-wide significance (pMETA=2.91x10-9) without heterogeneity between cohorts (Cochran’s Q test, p=0.31). One additional SNP, rs3011271 16kb downstream of GFI1B and 22kb upstream of GTF3C5, with moderate significance for ET versus PV (pMETA=3.00x10-5) and without heterogeneity between cohorts (p=0.18) also reached genome-wide significance (pMETA=2.36x10-8) when compared to V617F mutation level. In comparison with healthy controls, the HBS1L-MYB SNP predisposes to ET (p=2.01x10-6, OR=1.41) while the GFI1B-GTF3C5 SNP predisposes to PV (p=1.66x10-7, OR=1.49). Stratifying PV cases by 9p aUPD, showed that the association with GFI1B-GTF3C5 is restricted to PV cases with 9p aUPD (p=1.95x10-11 in cases with aUPD; p=0.67 in cases without aUPD). We found no evidence that previously reported SNPs at NR3C1 (glucocorticoid receptor), TET2, ATM, SH2B3, ERCC2 or CHEK2 influenced the development or phenotype of JAK2 V617F-mutated MPN.
Conclusion
On a genome wide level (excluding chromosome 9p), we have found that germline variation in the intergenic regions between HBS1L and MYB exerts the strongest influence on JAK2 V617F mutated MPN phenotype. In addition, variation between GFI1B and GTF3C5 predisposes to PV and in particular to cases with high JAK2 V617F mutation burden associated with 9p aUPD. Our findings indicate a complex interplay between somatic and germline genetics in MPN, and provides pointers towards the functional basis of the phenotypic pleiotropy of these disorders.
Session topic: Myeloproliferative neoplasms - Biology
Keyword(s): Essential Thrombocytemia
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:00 - 16:15
Location: Hall C13
Background
Evidence from epidemiological, familial and genetic studies indicate that common, low penetrance variants present in the general population contribute to the risk of developing MPN and also contribute to the phenotypic pleiotropy observed in these disorders. In a recent genome wide study we found that genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to JAK2-unmutated MPN. Furthermore, focused analysis of these four variants demonstrated that rs9376092 at HBS1L-MYB and the JAK2 46/1 haplotype specifically influence whether JAK2 V617F mutated cases present with PV or ET.
Aims
It is likely that variation at other genetic loci influence disease phenotype in MPN. Our aim was to identify inherited genetic factors on a genome wide basis that influence whether JAK2 V617F positive MPN patients present with PV or ET.
Methods
We undertook a two stage genome-wide association study. At stage 1,556 ET and 556 PV patients with JAK2 V617F were genotyped using Illumina Human OmniExpressExome v1.2 BeadChips. Following standard quality control, allelic chi-square tests were used to compare ET and PV cases. At stage 2, significant SNPs were genotyped in four additional JAK2 V617F-positive ET/PV cohorts from the UK (n=180), Spain (n=664), Italy (n=547) and Germany (n=74). The final effect size and significance of SNPs was determined by a fixed effects meta-analysis. The relationship with disease subtype was determined by comparison of either ET or PV cases against healthy controls (stage 1; WTCCC2 n=5200) and linear regression was used to assess the relationship with JAK2 V617F mutation burden following normalisation using Blom transformation.
Results
After quality control and excluding the p arm of chromosome 9 due to recurrent aUPD in PV and to a lesser extent in ET, 650,386 SNPs were tested in 499 ET and 505 PV cases at stage 1. Using a combination of significance, clustering of significant linked SNPs and functional evidence, 163 SNPs were tested at stage 2. Meta-analysis of ET versus PV cases identified one SNP, rs9399137 43kb upstream of HBS1L and 83kb upstream of MYB, that achieved genome-wide significance (pMETA=2.91x10-9) without heterogeneity between cohorts (Cochran’s Q test, p=0.31). One additional SNP, rs3011271 16kb downstream of GFI1B and 22kb upstream of GTF3C5, with moderate significance for ET versus PV (pMETA=3.00x10-5) and without heterogeneity between cohorts (p=0.18) also reached genome-wide significance (pMETA=2.36x10-8) when compared to V617F mutation level. In comparison with healthy controls, the HBS1L-MYB SNP predisposes to ET (p=2.01x10-6, OR=1.41) while the GFI1B-GTF3C5 SNP predisposes to PV (p=1.66x10-7, OR=1.49). Stratifying PV cases by 9p aUPD, showed that the association with GFI1B-GTF3C5 is restricted to PV cases with 9p aUPD (p=1.95x10-11 in cases with aUPD; p=0.67 in cases without aUPD). We found no evidence that previously reported SNPs at NR3C1 (glucocorticoid receptor), TET2, ATM, SH2B3, ERCC2 or CHEK2 influenced the development or phenotype of JAK2 V617F-mutated MPN.
Conclusion
On a genome wide level (excluding chromosome 9p), we have found that germline variation in the intergenic regions between HBS1L and MYB exerts the strongest influence on JAK2 V617F mutated MPN phenotype. In addition, variation between GFI1B and GTF3C5 predisposes to PV and in particular to cases with high JAK2 V617F mutation burden associated with 9p aUPD. Our findings indicate a complex interplay between somatic and germline genetics in MPN, and provides pointers towards the functional basis of the phenotypic pleiotropy of these disorders.
Session topic: Myeloproliferative neoplasms - Biology
Keyword(s): Essential Thrombocytemia
{{ help_message }}
{{filter}}