Takatsuki, Japan
Takatsuki, Japan

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PubMed | Ryougoku East Gate Clinic, National Defense Medical College, Midorigaoka Hospital, University of Tokyo and 2 more.
Type: | Journal: Scientific reports | Year: 2016

Urate transporter 1 (URAT1/SLC22A12), a urate transporter gene, is a causative gene for renal hypouricemia type 1. Among several reported nonsynonymous URAT1 variants, R90H (rs121907896) and W258X (rs121907892) are frequent causative mutations for renal hypouricemia. However, no case-control study has evaluated the relationship between gout and these two variants. Additionally, the effect size of these two variants on serum uric acid (SUA) levels remains to be clarified. Here, 1,993 primary gout patients and 4,902 health examination participants (3,305 males and 1,597 females) were genotyped with R90H and W258X. These URAT1 variants were not observed in any gout cases, while 174 subjects had the URAT1 variant in 2,499 health examination participants, respectively (P=8.310(-46)). Moreover, in 4,902 health examination participants, the URAT1 nonfunctional variants significantly reduce the risk of hyperuricemia (P=6.710(-19); risk ratio=0.036 in males). Males, having 1 or 2 nonfunctional variants of URAT1, show a marked decrease of 2.19 or 5.42mg/dl SUA, respectively. Similarly, females, having 1 or 2 nonfunctional variants, also evidence a decrease of 1.08 or 3.89mg/dl SUA, respectively. We show that URAT1 nonfunctional variants are protective genetic factors for gout/hyperuricemia, and also demonstrated the sex-dependent effect size of these URAT1 variants on SUA (P for interaction=1.510(-12)).

PubMed | University of Otago, National Institute of Genetics, Self Defense Forces Central Hospital, Ryougoku East Gate Clinic and 16 more.
Type: | Journal: Annals of the rheumatic diseases | Year: 2016

A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific.Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study.In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.010Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.

PubMed | National Institute of Genetics, Self Defense Forces Central Hospital, Ryougoku East Gate Clinic, National Defense Medical College and 13 more.
Type: Journal Article | Journal: Annals of the rheumatic diseases | Year: 2016

Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only.A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls.Five gout susceptibility loci were identified at the genome-wide significance level (p<5.010(-8)), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.910(-12); OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.610(-23); OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.410(-9); OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.810(-4)] for urate clearance and r=0.96 [p=5.010(-4)] for urinary urate excretion).Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics.

Ochi Y.,Research Institute for Production Development | Kajita Y.,Nantan General Hospital | Hachiya T.,Midorigaoka Hospital | Arata N.,National Center for Child Health and Development | Hamaoki M.,Yamasa Ltd
Endocrine, Metabolic and Immune Disorders - Drug Targets | Year: 2013

Previously, we reported the conversion phenomenon (CP) of thyroid blocking antibody (TBAb) to thyroid stimulating antibody (TSAb) by induced cAMP production during incubation of TBAb-bound porcine thyroid cells (PTC) with rabbit anti-IgG Ab. In the present experiment we examined the CP by TBAb-positive sera with high TSH binding inhibitor immunoglobulin (TBII) activity in primary hypothyroidism. Two patients with extremely high TBII patients; patient No.1 (35 yo male) with TSH 26.5μU/ml, TSAb negative, TBII 4,600 U/L, TBAb100% and patient No.2 (40 yo female) with TSH 4.5μU/ml, TSAb negative, TBII 1,620 U/L, TBAb 99.8% were examined. Cyclic AMP production was examined by 2nd incubation (3h) of anti-IgG Ab with TBAb-bound PTC that was made by 1st incubation (0.5h) of TBAbpositive serum and PTC. When sera (0.001-0.05 ml) of patient No.1 and No.2 were tested, cAMP production showed 980- 3,700% and 570-3,000% in a dose-dependent manner, respectively. Cyclic AMP production was also observed by anti- IgG fragments Ab [(Fab')2, Fab and light chain]. Cyclic AMP production by anti-F(ab')2 was higher than anti-Fab Ab, and cAMP by anti-κ Ab was significantly higher (>3 fold) than anti-λ Ab. Cyclic AMP production by TBAb-positive sera with high TBII activity (35-270 U/L) showed a correlation with serum TBII activity (R=0.76). The fact that all high TBAb-positive sera show the CP of TBAb to TSAb suggests that TSAb activity may be present in TBAb molecule and TBAb may be the precursor of TSAb. © 2013 Bentham Science Publishers.

Ochi Y.,Research Institute for Production Development | Kajita Y.,Nantan General Hospital | Hachiya T.,Midorigaoka Hospital | Hamaoki M.,Yamasa Ltd.
Medical Hypotheses | Year: 2012

There are doubtful points about the theory that autoimmunity with auto-antibody (Ab) to TSH receptor (R) causes hyperthyroidism in Graves' disease (GD). A main doubtful point is no curative effect of corticosteroid on Graves' hyperthyroidism in spite of curative effect of corticosteroid for all autoimmune diseases. Recently we demonstrated the immunological similarity of TSAb and TBAb-IgG to animal IgGs, except for human (h)IgG, by neutralization and purification of TSAb and TBAb-IgG using (1) heterophilic Ab to animal IgG in GD sera and (2) experimentally generated anti-animal IgG Abs [such as dog (d), bovine (b), porcine (p), and rabbit (rb)]. Furthermore, greater immunological similarity of Fab- and F(ab') 2-portion of TSAb- and TBAb-IgG to bovine Fab, compared to hFab, was demonstrated using goat anti-bovine F(ab') 2 Ab.Existence of b and p TSH-like portions in the LATS-IgG molecule (probably Fab portion) was suggested by a previous report of neutralization of LATS activity by anti-b- or anti-p-TSH Ab. We suggested the existence of a mammalian animal-TSH-like structure, excepting hTSH, in the TSAb-IgG molecule (probably Fab portion), by discovery of anti-mammalian TSH Ab (such as d, b, p, guinea-pig, rat, whale, except h) in sera of GD. Lately, similar TSHR binding of H- and L-chain of human stimulating monoclonal TSHR Ab (M22)-Fab with TSH-α and-β subunit was reported. This evidence suggests that Fab portion of TSAb has a structure like mammalian TSH, but not hTSH.IgG-λ type of d, horse, b, p, goat, ovine is 95% and IgG-κ type is 5%, while human κ and λ chain is 60:40. Previous report that LATS (TSAb)-IgG composed of predominant λ type is supporting evidence that TRAb-IgG has immunological similarity with these animal IgGs compared to hIgG.We speculate that TSAb-IgG may be referred as a mermaid consisted in face (Fab) and trunk-leg (Fc). Face may be a kind of hormone with animal TSH-like structure and trunk-leg has animal IgG-like structure (in spite of no antibody function).There are many reports for co-existence of TSAb and TBAb-IgG in sera of GD. We reported conversion from TBAb (non-thyroid stimulating type IgG) to TSAb by co-incubation of anti-hIgG Ab (containing anti-animal IgG Ab as a cross-reaction) with TBAb-bound porcine thyroid cells. Thus, we suggest that TBAb may be the precursor form of TSAb. © 2012 Elsevier Ltd.

Ochi Y.,Research Institute for Production Development | Kajita Y.,Nantan General Hospital | Hachiya T.,Midorigaoka Hospital | Hamaoki M.,Yamasa Ltd
Endocrine Journal | Year: 2012

Previously we reported neutralization and partial purifcation of TSAb and TBAb activity using heterophilic antibody (Ab) to animal IgG from Graves' disease. Thus, we examined immunological similarity of TSAb and TBAb with animal IgG using experimentally generated anti-animal IgG [dog (d), bovine (b), porcine (p) and rabbit (rb)] Abs. TBII activity of TSAb- and TBAb-positive serum was neutralized by these anti-animal IgG Abs. Applied TSAb- or TBAb-IgG protein (purifed by Protein A) on these anti-animal IgG Abs-bound column was found mainly in the unbound fraction (UF) (>65%) and partially in the bound fraction (BF) (<35%). The TBII and TSAb activity of TSAb-IgG in the BF showed signifcantly higher than the UF. Thus, the ratio of TBII activity (U/L)/mg protein in the BF/UF was high. TBII activity of TBAb-IgG was similarly purifed by this column. We examined immunological characteristics of TSAb- and TBAb-Fab or F(ab') 2 using goat anti-bF(ab') 2 Ab. TBII and TSAb activity of TSAb-Fab or- F(ab') 2 and TBII activity of TBAb-Fab or -F(ab') 2 were neutralized by anti-bF(ab') 2 Ab. Partial purifcation of TSAb- or TBAb-Fab and -F(ab') 2 by anti-bF(ab') 2 Ab-bound column was also possible. Immunological similarity of TSAb- and TBAb-IgG with animal IgG such as d, b, p, rb by anti-animal IgG Ab, and TSAb- or TBAb-Fab and -F(ab') 2 with bFab by anti-bF(ab') 2 Ab were demonstrated. These facts suggest that both Fab and Fc portions of TSAb- and TBAb-IgG molecule have immunological similarity with animal IgG. © The Japan Endocrine Society.

Ochi Y.,Research Institute for Production Development | Kajita Y.,Nantan General Hospital | achiya T.,Midorigaoka Hospital | amaoki M.,Yamasa Ltd
Endocrine Journal | Year: 2012

There are several reports that sera from Graves' patients contain heterophilic antibody (Ab) to animal IgG such as human anti-mouse antibody (HAMA). We examined the binding of TSAb and TBAb with heterophilic Ab. The binding of animal IgG with patient's IgG was examined by the inhibition of animal IgG on the binding of labeled bovine (b) IgG with patient's IgG. The binding to labeled bIgG was detected in the serum of 5 patients (2.7%) among 185 patients with Graves' disease. The binding of the labeled bIgG with patient's IgG was inhibited by animal serum or the crude IgG (45% ammonium sulfate fraction of serum) (such as dog, horse, bovine, porcine, goat, ovine, rabbit, guinea-pig, rat, mouse) except human, monkey and chick. This heterophilic Ab which had cross-reaction with mammalian IgG (except human, monkey) was used as human anti-animal IgG Ab. TBII and TSAb activity of TSAb-positive serum, and TBII activity of TBAb-positive serum were neutralized by incubation with this Ab-bound column. Partial purifcation of TSAb- or TBAb-IgG from Protein A-purifed TSAb- or TBAb-IgG was possible using this Ab-bound column. TBII and TSAb activity of TSAb-IgG and TBII activity of TBAb-IgG were neutralized by incubation with rabbit anti-human (h) IgG Ab (having cross-reaction with animal IgG). Further purification of Protein A-purifed TSAb-IgG or TBAb-IgG by rabbit anti-hIgG Ab-bound column was impossible. The binding of TSAb and TBAb with heterophlic Ab means that TSAb-and TBAb-specifc IgG have immunological similarity with mammalian species IgG compared to human IgG. © The Japan Endocrine Society.

Shimizu T.,Midorigaoka Hospital | Kitada H.,Midorigaoka Hospital | Umeyama M.,Nippon Chemiphar Co. | Hori H.,Midorigaoka Hospital | Takasaki N.,Midorigaoka Hospital
Journal of Urology | Year: 2013

Purpose: We clarified whether the clinical profiles of patients with a history of urolithiasis (stone formers) truly reflect those of patients who currently have renal stones (stone carriers). Materials and Methods: We evaluated 463 patients with gout using helical computerized tomography, urolithiasis history and relevant clinical parameters. Results: Nephrolithiasis was observed in 157 of the 463 patients (34%) on helical computerized tomography but only 75 (16%) had a urolithiasis history. Of the 157 stone carriers 107 (68%) did not have a urolithiasis history. In those 157 patients serum urate and serum creatinine were higher than in the 306 nonstone carriers (p = 0.017), and the estimated glomerular filtration rate and urinary pH were lower (p = 0.0096 and 0.0249, respectively). However, there was no significant difference in laboratory findings between the 75 stone formers and 388 nonstone formers. Serum urate and creatinine were higher, and the estimated glomerular filtration rate and urine pH in bilateral stone carriers were lower than in unilateral stone carriers. According to HU density attenuation values on computerized tomography, an estimated third of the calculi that complicated 31 recent gout cases was uric acid. Conclusions: The concept of stone formers may lead to underestimating the prevalence of urolithiasis. Our analysis of stone carriers showed that a higher stone burden is associated with greater renal derangement, as determined by serum urate and creatinine, the estimated glomerular filtration rate and urine pH. To accurately clarify the correlation of gout and urolithiasis, it is advantageous to select stone carriers as subjects of study. © 2013 American Urological Association Education and Research, Inc.

Ochi Y.,Research Institute for Production Development | Hachiya T.,Midorigaoka Hospital | Arata N.,National Center for Child Health and Development
Endocrine, Metabolic and Immune Disorders - Drug Targets | Year: 2015

We reported a conversion assay in which thyroid blocking antibody (TBAb) functions as a thyroid stimulating antibody (TSAb). TBAb-bound porcine thyroid cells (PTC) were made by incubating TBAb(+) serum and PTC for 1 hour. When these TBAb-bound PTC were incubated 4 h with rabbit anti-human (h) IgG antibody (Ab), cAMP production was high, but when incubated with normal rabbit serum (NRS) cAMP production was low. TBAb-Mnoclonal Ab (MoAb) (KI-70) showed similar conversion. However, when TSAb-MoAb(M22) was assayed, anti-hIgG Ab-produced cAMP was lower than NRS-produced cAMP. When a mixture of M22 and KI-70 was assayed, antihIgG Ab-produced cAMP was higher than NRS. Thus, it is possible to determine existence of TBAb in TSAb(+)serum when anti-IgG Ab-produced cAMP is higher than NRS-produced cAMP. In this assay TBAb activity in TSAb(+)serum was scored as positive, gray zone and negative when the difference [anti-hIgG Ab-produced cAMP(%)―NRS-produced cAMP(%)] was >100%, 50-100% and <±50%, respectively. In TSAb(+)sera of Graves’ patients with no treatment or antithyroid therapy, positive TBAb was 9% (3/33)and 6.9% (5/72), and gray zone was 18% (6/33) and 25% (18/72), respectively. A low prevelance of TBAb and low TBAb activity (<200% as cAMP) was found in these Graves’ patients. A radioisotope treated Graves’ patient showed existence of both TSAb and TBAb at 5 months (NRS, 800% cAMP and anti-IgGAb,1,350% cAMP), and highly positive TBAb (NRS, 180% cAMP and anti-hIgG Ab, 3,200% cAMP) at 30 months. This conversion assay is useful principally for TBAb determination but it is also useful for TBAb determination in TSAb(+)serum. © 2015 Bentham Science Publishers.

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