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Transient and chronic childhood immune thrombocytopenia are distinctly affected by Fc-γ receptor polymorphisms

David E. Schmidt, Katja M. J. Heitink-Pollé, Annemieke G. Laarhoven, Marrie C. A. Bruin, Barbera Veldhuisen, Sietse Q. Nagelkerke, Taco W. Kuijpers, Leendert Porcelijn, C. Ellen van der Schoot, Gestur Vidarsson and Masja de Haas

Data supplements

Article Figures & Data

Figures

  • Figure 1.

    Meta-analysis for the association of FCGR2/3 variants with susceptibility to childhood ITP. Previous studies analyzing the association of FCGR2/3 with childhood ITP were identified in PubMed and EMBASE by systematic literature search (supplemental Table 1). The study by Bruin et al16 was not included because these patients were also included by Breunis et al.17 Study characteristics are reported in supplemental Table 2. (A) FCGR2C*ORF is significantly associated with susceptibility to childhood ITP. In comparison with FCGR3A*158F/F, FCGR3A*158V/F (B) and FCGR3A*158V/V (C) confer susceptibility to childhood ITP. This genetic variant is in linkage disequilibrium with FCGR2C*ORF, FCGR2A*27Q/W, and the FCGR2B/FCGR2C promoter polymorphism 2B.4. Mantel-Haenszel (MH) estimates of the ORs are given for fixed effect models. *Data were only analyzed from childhood ITP cases included in this study. §Patients with CNV in FCGR3A were excluded, whereas other studies did not supply such data.

  • Figure 2.

    Association of FCGR2/3 variants with prognosis in newly diagnosed childhood ITP. (A) Overview of the human Fc γ receptor gene (FCGR) locus. CNV occurs in regions encompassing multiple genes (CNR). (B) Association of FCGR2C*ORF/STOP with complete recovery rates in patients that were carefully observed (Obs) or treated with IVIg. Complete recovery was defined by the International Working Group criteria as a platelet count of at least 100 × 109/L, which correlates strongly with absence of bleeding symptoms. FCGR2C*ORF enriched for children with favorable response to IVIg and a high rate of spontaneous recovery, and carried a low chance of chronic disease at 12 months’ follow-up. The FCGR2B/FCGR2C promoter variant 2B.4 (C) and FCGR2A*27Q/W SNPs (D), which are in linkage disequilibrium with FCGR2C*ORF, showed similar effects. In particular, FCGR2A*27Q/W did not differentiate as well between course of disease as the other 2 variants. P values are given for a log-rank test, stratified by treatment allocation.

  • Figure 3.

    Effect of a deletion of CNR1 on complete recovery from newly diagnosed childhood ITP. Complete recovery was defined by the International Working Group criteria as a platelet count of at least 100 × 109/L. P values are given for a log-rank test stratified per treatment group.

Tables

  • Table 1.

    Baseline characteristics

    Healthy controls (N = 180)Newly diagnosed ITP (TIKI) (N = 180)Chronic ITP (CINKID) (N = 22)
    Female, n/N (%)133/180 (74)84/180 (47)14/22 (64)
    Caucasian, n/N (%)180/180 (100)123/135 (91)22/22 (100)
    Age at diagnosis, y4.1 (2.6 - 7.7)3.8 (2.1-9.6)
    Preceding infection, n/N (%)96/178 (54)9/16 (56)
    Buchanan ccore >2, n/N (%)72/179 (40)7/22 (32)
    Presenting platelet count, ×109/L6 (3 - 10)15 (10-34)
    • Data are median (interquartile range) unless noted otherwise.

  • Table 2.

    Susceptibility to childhood immune thrombocytopenia

    Healthy controls (N = 180)Newly diagnosed ITP (N = 180)PP (FDR adjusted)OR (95% CI)
    0123401234
    Number of copies
     CNR10 (0)12 (6)155 (86)12 (7)1 (1)0 (0)12 (7)152 (84)16 (9)0 (0).781.0
     CNR20 (0)1 (1)168 (93)11 (6)0 (0)0 (0)0 (0)173 (96)7 (4)0 (0).351.0
     CNR30 (0)0 (0)180 (100)0 (0)0 (0)0 (0)0 (0)180 (100)0 (0)0 (0)NDND
    Alleles
     FCGR2A*27W146 (81)29 (16)5 (3)0 (0)0 (0)127 (71)49 (27)4 (2)0 (0)0 (0).0330.301.94 (1.17-3.29)*
     FCGR2A*131H38 (21)87 (48)55 (31)0 (0)0 (0)39 (22)95 (53)46 (26)0 (0)0 (0).561.0
     FCGR2B*232T143 (79)31 (17)6 (3)0 (0)0 (0)137 (76)40 (22)3 (2)0 (0)0 (0).341.0
     FCGR2C*ORF143 (79)32 (18)5 (3)0 (0)0 (0)122 (68)56 (31)2 (1)0 (0)0 (0).007.081.84 (1.14-2.98)
     FCGR2C*ncORF173 (96)3 (2)4 (2)0 (0)0 (0)170 (94)3 (2)7 (4)0 (0)0 (0).641.0
     FCGR3A*158V79 (44)78 (43)23 (13)0 (0)0 (0)62 (34)85 (47)33 (18)0 (0)0 (0).141.0
     FCGR3B*NA231 (17)79 (44)68 (38)2 (1)0 (0)20 (11)83 (46)77 (43)0 (0)0 (0).171.0
     FCGR3B*SH173 (96)7 (4)0 (0)0 (0)0 (0)172 (96)8 (4)0 (0)0 (0)0 (0)1.01.0
     FCGR2 promoter 2B.4145 (81)31 (17)4 (2)0 (0)0 (0)134 (74)46 (26)0 (0)0 (0)0 (0).020.201.42 (0.87-2.35)
    • Data are n (% of cohort). Number of copies are given for the respective copy number region (CNR). Frequency P value by Fisher's exact test. Bold values denote statistically significant P values. FCGR3B*NA2 and FCGR3B*SH are also described as FCGR3B*02 and FCGR3B*03 according to recent nomenclature.51

    • CI, confidence interval; FDR, adjustment of P values by false discovery rate; ND, not performed; OR, odds ratio.

    • * OR given for comparison of 27Q/W vs 27Q/W in association with ITP.

    • OR given for presence of 1 or 2 copies vs absence of the variant in association with ITP.

  • Table 3.

    Linkage disequilibrium among FCGR2A*27W, FCGR2C*ORF, 2B.4, and FCGR3A*158V determines major observed haplotypes

    FCGR2A-27WFCGR2C-ORF, rs759550223FCGR2C-ncORF, rs76277413FCGR2B-2B.4, rs148754834; rs34701572FCGR3A-158VHaplotype frequency
    ControlsCases
    QSTOPWTno 2B.4F0.63900.5580
    QSTOPWTno 2B.4V0.18800.2060
    QSTOPWT2B.4F0.03190.0150
    QSTOPWT2B.4VNA2.2e-07
    QORFWTno 2B.4F5.9e-100.0055
    QORFsplice*no 2B.4V0.01030.0172
    QORFWTno 2B.4V0.00360.0016
    QORFWT2B.4F3.5e-09NA
    QORFWT2B.4V0.01020.0174
    WSTOPWTno 2B.4F0.00360.0015
    WSTOPWTno 2B.4V0.00360.0102
    WSTOPWT2B.4F0.00340.0056
    WSTOPWT2B.4VNA0.0036
    WORFWTno 2B.4FNA0.0042
    WORFWTno 2B.4V0.03170.0544
    WORFWT2B.4V0.07430.0997
    • Data shown for 146 control individuals and 145 patients with newly diagnosed ITP (TIKI) who showed no CNV in CNR1 or CNR2. Bold text indicates the most common haplotypes. Frequencies of haplotypes are derived from posterior probabilities using observed alleles using the haplo.stats package in R. 2B.4 promoter constitutes the observation of a A at position −120 and C at position −386. The 2B.4 haplotype is solely observed as a promoter polymorphism of FCGR2B and SNPs are only indicated for this variant.

    • NA, haplotype not observed.

  • Table 4.

    Variants associated with transient ITP, compared with chronic ITP

    Transient ITP (self-limiting or IVIg-responsive) TIKI (N = 131)Chronic ITP (CINKID & TIKI; N = 43)PP (FDR adjusted)OR (95% CI)
    0123401234
    CNV
     CNR10 (0)4 (3)118 (90)9 (7)0 (0)0 (0)7 (16)33 (77)3 (7)0 (0).011.116.2 (1.8-24.7)*
     CNR20 (0)0 (0)126 (96)5 (4)0 (0)0 (0)1 (2)42 (98)0 (0)0 (0).09.45
     CNR30 (0)0 (0)131 (100)0 (0)0 (0)0 (0)0 (0)43 (100)0 (0)0 (0)NDND
    Alleles
     FCGR2A*27W88 (67)39 (30)4 (3)0 (0)0 (0)37 (86)5 (12)1 (2)0 (0)0 (0).041.373.3 (1.3-10.1)
     FCGR2A*131H27 (21)68 (52)36 (27)0 (0)0 (0)11 (26)18 (42)14 (33)0 (0)0 (0).50.37
     FCGR2B*232T98 (75)30 (23)3 (2)0 (0)0 (0)31 (72)10 (23)2 (5)0 (0)0 (0).721.0
     FCGR2C*ORF81 (62)48 (37)2 (2)0 (0)0 (0)38 (88)5 (12)0 (0)0 (0)0 (0).002.0224.7 (1.9-14.3)
     FCGR2C*ncORF125 (95)3 (2)3 (2)0 (0)0 (0)38 (88)2 (5)3 (7)0 (0)0 (0).19.57
     FCGR3A*158V46 (35)63 (48)22 (17)0 (0)0 (0)13 (30)22 (51)8 (19)0 (0)0 (0).871.0
     FCGR3B*NA211 (8)66 (50)54 (42)0 (0)0 (0)9 (21)18 (42)16 (37)0 (0)0 (0).10.45
     FCGR3B*SH128 (98)3 (2)0 (0)0 (0)0 (0)39 (91)4 (9)0 (0)0 (0)0 (0).06.37
     FCGR2 promoter 2B.492 (70)39 (30)0 (0)0 (0)0 (0)37 (86)6 (14)0 (0)0 (0)0 (0).045.372.6 (1.1-7.3)
    • Data are n (% of cohort). Bold values denote statistically significant P values. Chronic ITP was defined as absence of complete response (platelet count >100 × 109/L) 12 months after diagnosis. Transient ITP was defined as spontaneous recovery or a favorable response to IVIg 3 months after diagnosis. Patients from the TIKI trial with persistent ITP (recovery between 3 and 12 months) were excluded.

    • * OR given for chronic ITP.

    • OR given for comparison of 27Q/W vs 27Q/W in association with transient ITP.

    • OR given for presence of 1 or 2 copies vs absence of the variant in association with transient ITP.