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Germline variants at SOHLH2 influence multiple myeloma risk

Germline variants at SOHLH2 influence multiple myeloma risk

Title: Germline variants at SOHLH2 influence multiple myeloma risk
Author: Duran-Lozano, Laura
Thorleifsson, Gudmar   orcid.org/0000-0003-4623-9087
Lopez de Lapuente Portilla, Aitzkoa
Niroula, Abhishek
Went, Molly
Thodberg, Malte
Pertesi, Maroulio
Ajore, Ram
Cafaro, Caterina
Olason, Pall I.
... 17 more authors Show all authors
Date: 2021-04
Language: English
Scope: 2061774
School: Health Sciences
Department: Office of Division of Diagnostic and Support Services
Faculty of Industrial Engineering, Mechanical Engineering and Computer Science
Series: Blood Cancer Journal; 11(4)
ISSN: 2044-5385
DOI: 10.1038/s41408-021-00468-6
Subject: Hematology; Oncology
URI: https://hdl.handle.net/20.500.11815/4003

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Duran-Lozano , L , Thorleifsson , G , Lopez de Lapuente Portilla , A , Niroula , A , Went , M , Thodberg , M , Pertesi , M , Ajore , R , Cafaro , C , Olason , P I , Stefansdottir , L , Bragi Walters , G , Halldorsson , G H , Turesson , I , Kaiser , M F , Weinhold , N , Abildgaard , N , Andersen , N F , Mellqvist , U H , Waage , A , Juul-Vangsted , A , Thorsteinsdottir , U , Hansson , M , Houlston , R , Rafnar , T , Stefansson , K & Nilsson , B 2021 , ' Germline variants at SOHLH2 influence multiple myeloma risk ' , Blood Cancer Journal , vol. 11 , no. 4 , 76 . https://doi.org/10.1038/s41408-021-00468-6


Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10−14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.


Funding Information: This work was supported by grants from the Knut and Alice Wallenberg Foundation (2012.0193 and 2017.0436), the Swedish Research Council (2017-02023), the Swedish Cancer Society (2017/265), Stiftelsen Borås Forsknings-och Utvecklingsfond mot Cancer, the Nordic Cancer Union (R217-A13329-18-S65), EU-MSCA-COFUND 754299 CanFaster, the Myeloma UK and Cancer Research UK (C1298/A8362), a Jacquelin Forbes-Nixon Fellowship, and Mr. Ralph Stockwell. We thank Ellinor Johnsson and Anna Collin for their assistance. We are indebted to the clinicians and patients who contributed samples. Open access funding provided by Lund University. Publisher Copyright: © 2021, The Author(s).

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