Variants in ELL2 Influencing Immunoglobulin Levels Associate with Multiple Myeloma

Overview

Journal Nat Commun

Specialty Biology

Date 2015 May 27

PMID 26007630

Citations 52

Authors

Bhairavi Swaminathan

Gudmar Thorleifsson

Magnus Joud

Mina Ali

Ellinor Johnsson

Ram Ajore

Patrick Sulem

Britt-Marie Halvarsson

Gudmundur Eyjolfsson

Vilhelmina Haraldsdottir

Christina Hultman

Erik Ingelsson

Sigurdur Y Kristinsson

Anna K Kahler

Stig Lenhoff

Gisli Masson

Ulf-Henrik Mellqvist

Robert Mansson

Sven Nelander

Isleifur Olafsson

Olof Sigurdardottir

Hlif Steingrimsdottir

Annette Vangsted

Ulla Vogel

Anders Waage

Hareth Nahi

Daniel F Gudbjartsson

Thorunn Rafnar

Ingemar Turesson

Urban Gullberg

Kari Stefansson

Markus Hansson

Unnur Thorsteinsdottir

Bjorn Nilsson

Affiliations

Soon will be listed here.

Abstract

Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 × 10(-10)). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells. We find that the MM risk allele harbours a Thr298Ala missense variant in an ELL2 domain required for transcription elongation. Consistent with a hypomorphic effect, we find that the MM risk allele also associates with reduced levels of immunoglobulin A (IgA) and G (IgG) in healthy subjects (P=8.6 × 10(-9) and P=6.4 × 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024).

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References

Shell S, Martincic K, Tran J, Milcarek C . Increased phosphorylation of the carboxyl-terminal domain of RNA polymerase II and loading of polyadenylation and cotranscriptional factors contribute to regulation of the ig heavy chain mRNA in plasma cells. J Immunol. 2007; 179(11):7663-73. DOI: 10.4049/jimmunol.179.11.7663. View

Emilsson V, Thorleifsson G, Zhang B, Leonardson A, Zink F, Zhu J . Genetics of gene expression and its effect on disease. Nature. 2008; 452(7186):423-8. DOI: 10.1038/nature06758. View

Lynch H, Ferrara K, Barlogie B, Coleman E, Lynch J, Weisenburger D . Familial myeloma. N Engl J Med. 2008; 359(2):152-7. PMC: 2775509. DOI: 10.1056/NEJMoa0708704. View

Kong A, Masson G, Frigge M, Gylfason A, Zusmanovich P, Thorleifsson G . Detection of sharing by descent, long-range phasing and haplotype imputation. Nat Genet. 2009; 40(9):1068-75. PMC: 4540081. DOI: 10.1038/ng.216. View

Landgren O, Kyle R, Pfeiffer R, Katzmann J, Caporaso N, Hayes R . Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009; 113(22):5412-7. PMC: 2689042. DOI: 10.1182/blood-2008-12-194241. View

Landgren O, Kristinsson S, Goldin L, Caporaso N, Blimark C, Mellqvist U . Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood. 2009; 114(4):791-5. PMC: 2716021. DOI: 10.1182/blood-2008-12-191676. View

Kristinsson S, Bjorkholm M, Goldin L, Blimark C, Mellqvist U, Wahlin A . Patterns of hematologic malignancies and solid tumors among 37,838 first-degree relatives of 13,896 patients with multiple myeloma in Sweden. Int J Cancer. 2009; 125(9):2147-50. PMC: 2737604. DOI: 10.1002/ijc.24514. View

Martincic K, Alkan S, Cheatle A, Borghesi L, Milcarek C . Transcription elongation factor ELL2 directs immunoglobulin secretion in plasma cells by stimulating altered RNA processing. Nat Immunol. 2009; 10(10):1102-9. PMC: 2771556. DOI: 10.1038/ni.1786. View

Kristinsson S, Bjorkholm M, Andersson T, Eloranta S, Dickman P, Goldin L . Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance: a population-based study. Haematologica. 2009; 94(12):1714-20. PMC: 2791946. DOI: 10.3324/haematol.2009.010066. View

10.

Kong A, Steinthorsdottir V, Masson G, Thorleifsson G, Sulem P, Besenbacher S . Parental origin of sequence variants associated with complex diseases. Nature. 2009; 462(7275):868-74. PMC: 3746295. DOI: 10.1038/nature08625. View

11.

McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F . Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics. 2010; 26(16):2069-70. PMC: 2916720. DOI: 10.1093/bioinformatics/btq330. View

12.

Willer C, Li Y, Abecasis G . METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010; 26(17):2190-1. PMC: 2922887. DOI: 10.1093/bioinformatics/btq340. View

13.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A . The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-303. PMC: 2928508. DOI: 10.1101/gr.107524.110. View

14.

Gudbjartsson D, Helgason H, Gudjonsson S, Zink F, Oddson A, Gylfason A . Large-scale whole-genome sequencing of the Icelandic population. Nat Genet. 2015; 47(5):435-44. DOI: 10.1038/ng.3247. View

15.

Devlin B, Roeder K . Genomic control for association studies. Biometrics. 2001; 55(4):997-1004. DOI: 10.1111/j.0006-341x.1999.00997.x. View

16.

Lynch H, Sanger W, Pirruccello S, Weisenburger D . Familial multiple myeloma: a family study and review of the literature. J Natl Cancer Inst. 2001; 93(19):1479-83. DOI: 10.1093/jnci/93.19.1479. View

17.

Gretarsdottir S, Thorleifsson G, Reynisdottir S, Manolescu A, Jonsdottir S, Jonsdottir T . The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat Genet. 2003; 35(2):131-8. DOI: 10.1038/ng1245. View

18.

Shilatifard A, Duan D, Haque D, Florence C, Schubach W, Conaway J . ELL2, a new member of an ELL family of RNA polymerase II elongation factors. Proc Natl Acad Sci U S A. 1997; 94(8):3639-43. PMC: 20493. DOI: 10.1073/pnas.94.8.3639. View

19.

Kyle R, Therneau T, Rajkumar S, Larson D, Plevak M, Offord J . Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006; 354(13):1362-9. DOI: 10.1056/NEJMoa054494. View

20.

Altieri A, Chen B, Lorenzo Bermejo J, Castro F, Hemminki K . Familial risks and temporal incidence trends of multiple myeloma. Eur J Cancer. 2006; 42(11):1661-70. DOI: 10.1016/j.ejca.2005.11.033. View