european crystal network workshop

    Polynesian specific gout associated missense variants in lrp2

     

    M. Leask 1, T. Fatima 1, A. Jones 1, M. Cadzow 1, N. Dalbeth 5, L. Stamp 7, J. H. Hindmarsh 6, D. Mount 3, E. Stahl 2, H. Choi 4 and T. Merriman 1

    ¹ Department of Biochemistry, University of Otago, Dunedin, NZ ² Mt Sinai School of Medicine, New York City, NY ³ Renal Division, Brigham and Women's Hospital, Boston, MA 4 Division of Rheumatology, Allergy, and Immunology Massachusetts General Hospital, Harvard Medical School, Boston, M 5 Department of Medicine, University of Auckland, Auckland, New Zealand 6 Ngāti Porou Hauora Charitable Trust, Te Puia Springs, Tairāwhiti, New Zealand 7 Department of Medicine, University of Otago, Christchurch, New Zealand

     

    Background: People of Polynesian (Māori and Pacific) descent are twice as likely to be affected by gout compared to Europeans in New Zealand. We propose that variants specific to Polynesian people within genes previously associated with gout could have large effects in these populations. In European and Asian populations genetic variants within or in close proximity to LRP2 have been associated with serum urate and / or gout. LRP2 (low-density lipoprotein receptor-related protein) is a membrane bound receptor involved in the movement and degradation of many ligands and has been implicated in multiple physiological processes and therefore is a good candidate to investigate for population-specific variants implicated in gout.

    Objectives: This study aimed to identify protein-altering variants specific to Polynesian people within LRP2 and assess whether these variants are associated with gout
    Methods: The exonic region of LRP2 was sequenced from 819 individuals of Polynesian or European ancestry with (n = 427) people with hyperuricaemia or gout in order to identify Polynesian-specific protein-altering variants that associate with gout. A second cohort consisting of 3309 individuals of Polynesian or European ancestry with (n = 1729) and without (n = 1580) gout was used to replicate these results by TaqMan®.

    Results: The exon sequencing identified 81 variants within LRP2, of which 6 protein-altering variants were specific to Polynesian people. Of these, only two variants rs111360923 (p.Tyr658Cys),  and var170115626 (p.Ile808Val) associated with gout (Table 1) within the resequencing cohort, with both variants having protective effects for gout. The gout associations for rs111360923 and var170115626 were confirmed in a meta-analysis within the replication cohort (Table 1).

    Conclusion/significance: Protein-altering variants specific to Polynesian populations within LRP2 protect against gout. However it is not understood how these variants function biologically to affect gout development.

     

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