To the editor:
Several studies have indicated that platelet recovery occurs in a subgroup of immune thrombocytopenia (ITP) patients after successful Helicobacter pylori (H pylori) eradication.1,2 Interestingly, a higher response rate to H pylori eradication therapy has been reported in Japan and Italy than in the United States and European countries other than Italy,2 suggesting that the efficacy of H pylori eradication is influenced by ethnicity, probably through genetic and environmental factors. In addition, Asahi et al observed that monocytes from H pylori–infected ITP patients demonstrated low levels of inhibitory FcγRIIB and enhanced platelet phagocytosis, both of which were reversed after successful H pylori eradication.3
The FcγRIIB 232I/T (Ile/Thr) polymorphism (rs1050501) has been identified as a genetic factor associated with susceptibility to various autoimmune diseases.4,5 The FcγRIIB 232T cannot inhibit activating receptors because it is not present in lipid rafts, resulting in decreased FcγRIIB-mediated inhibition of macrophage and B-cell responses.6,7
We analyzed the FcγRIIB 232I/T polymorphisms by restriction-fragment-length polymorphism polymerase chain reaction in 206 adult Japanese patients with primary ITP and in 193 healthy controls (supplemental Methods, available on the Blood website). The FcγRIIB 232T carriers were more frequently detected in ITP patients than in healthy controls (P = .003; odds ratio [OR] = 1.87; 95% confidence interval [CI], 1.24-2.82) (Table 1). Our results differed from those described by Breunis et al using 44 adult Dutch patients with ITP and Xu et al using 178 adult Chinese patients with ITP.8,9 This discrepancy might be explained by study design factors including sample size and ethnic differences. Interestingly, the distribution of the FcγRIIB 232T carriers is more common in Asians than in Caucasians.5 This distribution is similar to the regional differences observed for the effect of H pylori eradication therapy in ITP patients.2
FcγRIIB 232I/T polymorphism . | No. (%) . | P, vs healthy controls . | No. (%) . | P, vs healthy controls . | No. (%) . | P, vs healthy controls . | No. (%) . | P . | ||
---|---|---|---|---|---|---|---|---|---|---|
Healthy controls, n = 193 . | Total ITP patients, n = 206 . | H pylori–infected ITP patients, n = 100* . | H pylori–uninfected ITP patients, n = 82* . | H pylori eradication therapy† . | ||||||
Responders, n = 21 . | Nonresponders, n = 21 . | |||||||||
I/I genotype | 134 (69.4) | 113 (54.8) | .01‡ | 51 (51.0) | .01‡ | 47 (57.3) | .2 | 7 (33.3) | 18 (85.7) | .01‡ |
I/T genotype | 56 (29.0) | 84 (40.8) | 44 (44.0) | 33 (40.2) | 12 (57.2) | 3 (14.3) | ||||
T/T genotype | 3 (1.6) | 9 (4.4) | 5 (5.0) | 2 (2.4) | 2 (9.5) | 0 | ||||
Non-T carriers§ | 134 (69.4) | 113 (54.8) | .003 | 51 (51.0) | .002 | 47 (57.3) | .053 | 7 (33.3) | 18 (85.7) | .001 |
T carriers§ | 59 (30.6) | 93 (45.2) | 49 (49.0) | 35 (42.7) | 14 (66.7) | 3 (14.3) |
FcγRIIB 232I/T polymorphism . | No. (%) . | P, vs healthy controls . | No. (%) . | P, vs healthy controls . | No. (%) . | P, vs healthy controls . | No. (%) . | P . | ||
---|---|---|---|---|---|---|---|---|---|---|
Healthy controls, n = 193 . | Total ITP patients, n = 206 . | H pylori–infected ITP patients, n = 100* . | H pylori–uninfected ITP patients, n = 82* . | H pylori eradication therapy† . | ||||||
Responders, n = 21 . | Nonresponders, n = 21 . | |||||||||
I/I genotype | 134 (69.4) | 113 (54.8) | .01‡ | 51 (51.0) | .01‡ | 47 (57.3) | .2 | 7 (33.3) | 18 (85.7) | .01‡ |
I/T genotype | 56 (29.0) | 84 (40.8) | 44 (44.0) | 33 (40.2) | 12 (57.2) | 3 (14.3) | ||||
T/T genotype | 3 (1.6) | 9 (4.4) | 5 (5.0) | 2 (2.4) | 2 (9.5) | 0 | ||||
Non-T carriers§ | 134 (69.4) | 113 (54.8) | .003 | 51 (51.0) | .002 | 47 (57.3) | .053 | 7 (33.3) | 18 (85.7) | .001 |
T carriers§ | 59 (30.6) | 93 (45.2) | 49 (49.0) | 35 (42.7) | 14 (66.7) | 3 (14.3) |
Genotype distributions of the FcγRIIB 232I/T polymorphism in ITP patients and healthy controls, in H pylori–infected and –uninfected ITP patients, and in responders and nonresponders to H pylori eradication therapy. Genotype distributions were tested for statistical significance using the χ-square or Fisher exact test when 1 or more variables was <5.
Of 182 patients with ITP evaluated for H pylori infection status, 100 were confirmed positive for H pylori infection based on a positive urea breath test and/or serum anti–H pylori antibodies measured by an enzyme-linked immunosorbent assay kit.
Forty-two H pylori–infected ITP patients were administered amoxicillin (750 mg twice daily), clarithromycin (400 mg twice daily), and lansoprazole (30 mg twice daily) for 7 days. Twenty-one ITP patients were responders, defined as having a platelet count higher than 50 × 109/L and doubling of the baseline level at 24 weeks after initiation of the eradication regimen.
The corrected P (Pcorr) values were calculated by multiplying the observed P value by the number of comparisons made. Pcorr = .03.
We compared the distribution of FcγRIIB 232I/T polymorphisms between H pylori–infected ITP patients and healthy controls or H pylori–uninfected ITP patients and healthy controls (Table 1). The frequency of the FcγRIIB 232T carriers was significantly higher in H pylori–infected ITP patients than in healthy controls (49.0% vs 30.6%; P = .002; OR = 2.18; 95% CI, 1.33-3.59). H pylori infection plays a role in ITP pathogenesis by altering the FcγR balance of monocytes in favor of activating FcγR, through downregulation of inhibitory FcγRIIB.3 Furthermore, our data suggest that the functionally impaired FcγRIIB 232T carriers may contribute to disease pathogenesis in a subgroup of H pylori–infected ITP patients.
We further evaluated associations between FcγRIIB 232I/T polymorphisms and therapeutic response rates to H pylori eradication in ITP patients (Table 1). ITP patients who were FcγRIIB 232T carriers contained significantly higher frequencies of responders than did noncarriers (66.7% vs 14.3%; P = .001; OR = 12.0; 95% CI, 2.62-54.99). Thus, more efficient eradication therapy in 232T carriers may improve H pylori infection-related immunoregulatory systems, such as activating and inhibiting FcγR balance,3 thereby interrupting phagocytosis and antigen presentation.
In summary, our data suggest that FcγRIIB 232I/T polymorphisms may play an important role in susceptibility to H pylori–infected ITP and in platelet responses after H pylori eradication in ITP patients.
The online version of this article contains a data supplement.
Authorship
Acknowledgments: We thank Dr Toshio Okazaki for helpful discussions.
This work was supported by research grants from the Yokohama Foundation for Advancement of Medical Science 2011, the Kanagawa Nanbyou Study Foundation 2010, a Kitasato University Research Grant for Young Researchers 2011, the Kitasato University School of Allied Health Sciences (Grant-in-Aid for Research Project, No. 2011-1053), and the Kitasato University Graduate School of Medical Sciences (Integrative Research Program 2011).
Contribution: T.S., A.S., N.A., Y.O., and T.N. performed experiments; T.S., K.M., A.S., and M.K. analyzed the data; T.S., K.M., T.A., S.M., Y.K., Y.I., M.H., and M.K. collected patients and healthy control samples; K.M., Y.I., M.H., and M.K. collected the clinical data; S.T. contributed essential tools; M.K. helped revise the paper; and T.S. designed the research and wrote the paper.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Takashi Satoh, Division of Hematology, Kitasato University School of Allied Health Sciences, 1-15-1 Kitasato, Minami-ku, Sagamihara 252-0373, Japan; e-mail: [email protected].
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