Page 213 - 2021_09-Haematologica-web

Letters to the Editor
Chinese β-thalassemia anemia population, a favorable genetic environment for the selection of otherwise ery- throcytosis-causing mutations.11 Several erythropoietic transcription factors have been shown to be prevented from binding to the mutant locus, resulting in lowered Myb gene activation and increased HbF synthesis.12 A link to increased Epo levels, suggesting secondary (Epo- dependent) rather than primary (Epo-independent) ery- throcytosis, has not been made in these original reports. GWAS performed in a UK Biobank cohort and a Japanese population showed significant associations between the HBS1L-MYB locus and RBC-related phenotypes.13,14 Together with our direct replication of the association with circulating Epo levels in a Swiss cohort, these results further confirm the implication of this locus in erythro- poiesis, maybe both upstream as well as downstream of Epo. However, it is currently not known whether the HBS1L-MYB locus also contributes to the heritable genetic determinants triggering Epo levels.
A gene score and a pathway analysis, run with the PASCAL algorithm based on our GWAS results, failed to show any significant pathway after applying multiple testing corrections.
For a candidate-based approach, we selected 33 genes known to influence EPO gene expression. The associa- tion gene scores from PASCAL could be retrieved from 30 of these 33 genes. Bonferroni correction applied to the number of genes observed led to a significance threshold of 1.67x10-3. The OS9 gene was significantly associated with a gene score association P-value of 1.47x10-3 (Online Supplementary Table S3). OS-9 is known to interact with both HIF-1α and HIF prolyl-4-hydroxylases, promoting HIF-1α degradation. Interestingly, a OS9 gene variant has previously been reported to be associated with erythro- cytosis in a single patient.15
The top SNP of the MAP2K5-SKOR1-PIAS1 locus (rs413451) was subjected to a phenome-wide association study (PHEWAS) using the MR-Base database of the UK Biobank cohort. SNP rs413451 was most significantly associated with BMI-related phenotypes. Interestingly, Hb concentration (P=6.35x10-6), reticulocyte count (P=7.28x10-6), hematocrit (P=1.16x10-4), reticulocyte frac- tion of RBC (P=2.04x10-4) and RBC count (P= 2.23x10-4) were also highly associated with rs413451. Circulatory Epo levels were not available in the UK Biobank. However, the GWAS Atlas database showed a preponderance of BMI-related phenotypes for most sig- nificant studies in the database of published GWAS.
In summary, our study revealed the heritability of cir- culating Epo levels, validated a previously published association with the HBS1L-MYB locus, and identified an association with the MAP2K5-SKOR1-PIAS1 locus. From the list of candidate Epo-regulatory genes, OS9 showed the highest association with circulating Epo levels. However, the two latter associations require replication, and the functional implication of all three loci in Epo reg- ulation needs to be further investigated. Regarding the idiopathic nature of the majority of erythrocytosis cases, we suggest that especially in patients with high Epo lev- els, indicative of secondary erythrocytosis, these loci should be considered for further investigation.
Tanguy Corre,1,2,3 Belen Ponte,4 Edward Pivin,1 Menno Pruijm,5 Daniel Ackermann,6 Georg Ehret,7 Katharina Spanaus,8 Murielle Bochud,1,2
and Roland H. Wenger2,9
1Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne; 2National Center of Competence in Research
“Kidney.CH”, Zurich; 3Department of Computational Biology, University of Lausanne, Lausanne; 4Nephrology Service, Department Medicine, Geneva University Hospital, Geneva; 5Nephrology Service, University Hospital of Lausanne and University of Lausanne, Lausanne; 6Department of Nephrology and Hypertension, Inselspital, Bern and University Hospital, University of Bern, Bern; 7Cardiology, Department of Medicine, Geneva University Hospital, Geneva; 8Institute of Clinical Chemistry, University Hospital of Zurich, Zurich and 9Institute of Physiology, University of Zurich, Zurich, Switzerland
Correspondence:
ROLAND H. WENGER - roland.wenger@access.uzh.ch doi:10.3324/haematol.2021.278389
Received: January 17, 2021.
Accepted: February 26, 2021.
Pre-published: April 8, 2021.
Disclosures: no conflicts of interest to disclose.
Contributions: BP, MP, DA, and GE provided materials; KS meas- ured the samples; TC, EP and MB performed data analysis; TC, MB and RHW wrote the manuscript; MB and RHW supervised the study.
Acknowledgments: we wish to thank P. Spielmann for expert technical help.
Funding: this project was supported by the NCCR "Kidney.CH".
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