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ABSTRACT: The risk associated with the serum amyloid A (SAA) 1 gene and developing AA-amyloidosis is still controversial. In familial Mediterranean fever or Caucasoid rheumatoid arthritis (RA), the SAA1.1 allele is a risk factor for the development of AA-amyloidosis. However, individuals with the SAA1.3 allele are susceptible to AA-amyloidosis in the Japanese RA population, but those with the SAA1.1 are not. Previous reports have indicated that the -13T/C single nucleotide polymorphism (SNP) at the 5'-flanking region of SAA1 appears to be a better marker of AA-amyloidosis than the exon-3 based haplotype, i.e., SAA1.1 or SAA1.3, in both Japanese and American Caucasian populations. So far, it is unknown why the -13T SNP increases the amyloidogenicity of the patients. In the present study, a luciferase reporter gene assay showed that the transcriptional activity of the SAA1 having the -13T-containing promoter was significantly higher than activities of those with -13C-containing promoters (Fisher's protected least significance difference test). We suggest that having the -13T SNP in the SAA1 promoter correlates with the amyloidogenicity in part as a result of this increased transcriptional activity.
Amyloid 04/2005; 12(1):26-32. · 2.66 Impact Factor
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Naoko Iwasaki,
Yukio Horikawa,
Takafumi Tsuchiya, Yutaka Kitamura,
Takahiro Nakamura,
Yukio Tanizawa,
Yoshitomo Oka,
Kazuo Hara,
Takashi Kadowaki,
Takuya Awata, [......],
Naohisa Oda,
Li Yu,
Norihiro Yamada,
Makiko Ogata,
Naoyuki Kamatani,
Yasuhiko Iwamoto,
Laura Del Bosque-Plata,
M Geoffrey Hayes,
Nancy J Cox,
Graeme I Bell
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ABSTRACT: Variation in the gene encoding the cysteine protease calpain-10 has been linked and associated with risk of type 2 diabetes. We have examined the effect of three polymorphisms in the calpain-10 gene (SNP-43, Indel-19, and SNP-63) on the development of type 2 diabetes in the Japanese population in a pooled analysis of 927 patients and 929 controls. We observed that SNP-43, Indel-19, and SNP-63 either individually or as a haplotype were not associated with altered risk of type 2 diabetes with the exception of the rare 111/221 haplogenotype (odds ratio (OR) =3.53, P=0.02). However, stratification based on the median age-at-diagnosis in the pooled study population (<50 and > or =50 years) revealed that allele 2 of Indel-19 and the 121 haplotype were associated with reduced risk in patients with later age-at-diagnosis (age-at-diagnosis > or =50 years OR=0.82 and 0.80, respectively; P=0.04 and 0.02). Thus, variation in the calpain-10 gene may affect risk of type 2 diabetes in Japanese, especially in older individuals.
Journal of Human Genetics 01/2005; 50(2):92-8. · 2.57 Impact Factor
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ABSTRACT: The analysis of the haplotype-phenotype relationship has become more and more important. We have developed an algorithm, using individual genotypes at linked loci as well as their quantitative phenotypes, to estimate the parameters of the distribution of the phenotypes for subjects with and without a particular haplotype by an expectation-maximization (EM) algorithm. We assumed that the phenotype for a diplotype configuration follows a normal distribution. The algorithm simultaneously calculates the maximum likelihood (L0max) under the null hypothesis (i.e., nonassociation between the haplotype and phenotype), and the maximum likelihood (Lmax) under the alternative hypothesis (i.e., association between the haplotype and phenotype). Then we tested the association between the haplotype and the phenotype using a test statistic, -2 log(L0max/Lmax). The above algorithm along with some extensions for different modes of inheritance was implemented as a computer program, QTLHAPLO. Simulation studies using single-nucleotide polymorphism (SNP) genotypes have clarified that the estimation was very accurate when the linkage disequilibrium between linked loci was rather high. Empirical power using the simulated data was high enough. We applied QTLHAPLO for the analysis of the real data of the genotypes at the calpain 10 gene obtained from diabetic and control subjects in various laboratories.
Genetics 10/2004; 168(1):525-39. · 4.01 Impact Factor
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Kimie Sai,
Mayumi Saeki,
Yoshiro Saito,
Shogo Ozawa,
Noriko Katori,
Hideto Jinno,
Ryuichi Hasegawa,
Nahoko Kaniwa,
Jun-ichi Sawada,
Kazuo Komamura,
Kazuyuki Ueno,
Shiro Kamakura,
Masafumi Kitakaze, Yutaka Kitamura,
Naoyuki Kamatani,
Hironobu Minami,
Atsushi Ohtsu,
Kuniaki Shirao,
Teruhiko Yoshida,
Nagahiro Saijo
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ABSTRACT: A comprehensive haplotype analysis of UGT1A1 in the Japanese population was conducted, and the effects of these haplotypes were investigated with respect to UGT1A1-related phenotypic parameters in patients with cancer who received irinotecan.
The UGT1A1 gene, including the enhancer, the promoter, and all 5 exons and their flanking regions, was sequenced from 195 Japanese subjects. The gene was divided into 2 blocks, and the haplotypes of each block were assigned. The association of these haplotypes with area under the concentration-time curve (AUC) ratios (7-ethyl-10-hydroxycamptothecin glucuronide [SN-38G]/7-ethyl-10-hydroxycamptothecin [SN-38]) and pretreatment levels of serum total bilirubin was investigated in 85 cancer patients who received irinotecan.
Four haplotype groups (*1, *60, *28, and *6) were assigned in block 1, and 2 haplotype groups (*IA and *IB) were in block 2. The majority of the *IB haplotypes in block 2 were linked to either the *1 or the *60 haplotype but not to *28 in block 1. Highly significant associations were obtained between the *28 haplotypes and both a reduced AUC ratio (P =.0014, Jonckheere-Terpstra [JT] test) and an increased total bilirubin level (P =.0007, JT test). Increased total bilirubin levels in the *60 (P =.0048, JT test) and *IB groups (P =.0224, JT test) were also observed. The reduction in the AUC ratio by the *6 group was moderate (P =.0372, JT test) but was remarkable in combination with *60 (*6/*60) or *28 (*6/*28) as compared with the *1 group (*1/*1) (P =.049 and P =.0071, respectively; nonparametric Dunnett test).
This study identified several UGT1A1 haplotypes significantly associated with the reduced AUC ratio (*28 and *6) and with the increased total bilirubin level (*28, *60, and *IB) and suggested that the novel haplotype *IB might be functionally important. These findings will be useful for further pharmacogenetic studies on adverse reactions to irinotecan.
Clinical Pharmacology & Therapeutics 07/2004; 75(6):501-15. · 6.04 Impact Factor
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Hiromi Fukushima-Uesaka,
Yoshiro Saito,
Hidemi Watanabe,
Kisho Shiseki,
Mayumi Saeki,
Takahiro Nakamura,
Kouichi Kurose,
Kimie Sai,
Kazuo Komamura,
Kazuyuki Ueno, [......],
Tomohide Tamura,
Noboru Yamamoto,
Hironobu Minami,
Atsushi Ohtsu,
Teruhiko Yoshida,
Nagahiro Saijo, Yutaka Kitamura,
Naoyuki Kamatani,
Shogo Ozawa,
Jun-ichi Sawada
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ABSTRACT: In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A4 in a Japanese population, the distal enhancer and proximal promoter regions, all exons, and the surrounding introns were sequenced from genomic DNA of 416 Japanese subjects. We found 24 SNPs, including 17 novel ones: two in the distal enhancer, four in the proximal promoter, one in the 5'-untranslated region (UTR), seven in the introns, and three in the 3'-UTR. The most common SNP was c.1026+12G>A (IVS10+12G>A), with a 0.249 frequency. Four non-synonymous SNPs, c.554C>G (p.T185S, CYP3A4(*)16), c.830_831insA (p.E277fsX8, (*)6), c.878T>C (p.L293P, (*)18), and c.1088 C>T (p.T363M, (*)11) were found with frequencies of 0.014, 0.001, 0.028, and 0.002, respectively. No SNP was found in the known nuclear transcriptional factor-binding sites in the enhancer and promoter regions. Using these 24 SNPs, 16 haplotypes were unambiguously identified, and nine haplotypes were inferred by aid of an expectation-maximization-based program. In addition, using data from 186 subjects enabled a close linkage to be found between CYP3A4 and CYP3A5 SNPs, especially among the SNPs at c.1026+12 in CYP3A4 and c.219-237 (IVS3-237, a key SNP site for CYP3A5(*)3), c.865+77 (IVS9+77) and c.1523 in CYP3A5. This result suggested that CYP3A4 and CYP3A5 are within the same gene block. Haplotype analysis between CYP3A4 and CYP3A5 revealed several major haplotype combinations in the CYP3A4-CYP3A5 block. Our findings provide fundamental and useful information for genotyping CYP3A4 (and CYP3A5) in the Japanese, and probably Asian populations.
Human Mutation 01/2004; 23(1):100. · 5.69 Impact Factor
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Kimie Sai,
Nahoko Kaniwa,
Masaya Itoda,
Yoshiro Saito,
Ryuichi Hasegawa,
Kazuo Komamura,
Kazuyuki Ueno,
Shiro Kamakura,
Masafumi Kitakaze,
Kuniaki Shirao,
Hironobu Minami,
Atsushi Ohtsu,
Teruhiko Yoshida,
Nagahiro Saijo, Yutaka Kitamura,
Naoyuki Kamatani,
Shogo Ozawa,
Jun-Ichi Sawada
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ABSTRACT: We performed comprehensive haplotyping of ABCB1/MDR1 gene blocks using 49 genetic polymorphisms, including seven novel ones, obtained from 145 Japanese subjects. The ABCB1/MDR1 gene was divided into four blocks (Blocks -1, 1, 2, and 3) based on linkage disequilibrium analysis of polymorphisms. Using an expectation-maximization based program, 1, 2, 8, and 3 haplotype groups (3, 12, 32, and 18 haplotypes) were identified in Blocks -1, 1, 2, and 3, respectively. Within Block 2, haplotype groups *1, *2, *4, *6, and *8 reported by Kim and colleagues (Clin Pharmacol Ther 2001; 70:189-199) were found, and additional three groups (*9 to *11) were newly defined. We analyzed the association of haplotypes with the renal clearance of irinotecan and its metabolites in 49 Japanese cancer patients given irinotecan intravenously. There was a significant association of the *2 haplotype in Block 2, which includes 1236C>T, 2677G>T and 3435C>T, with a reduced renal clearance of those compounds. Moreover, tendencies of reduced and increased renal clearance were also observed with *1f in Block 2 and *1b in Block 3, respectively. These findings suggest that the P-glycoprotein encoded by ABCB1/MDR1 in the proximal tubules plays a substantial role in renal exclusion of drugs and, moreover, that block-haplotyping is valuable for pharmacogenetic studies.
Pharmacogenetics 12/2003; 13(12):741-57.
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Mayumi Saeki,
Yoshiro Saito,
Takahiro Nakamura,
Norie Murayama,
Su-Ryang Kim,
Shogo Ozawa,
Kazuo Komamura,
Kazuyuki Ueno,
Shiro Kamakura,
Toshiharu Nakajima,
Hirohisa Saito, Yutaka Kitamura,
Naoyuki Kamatani,
Jun-ichi Sawada
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ABSTRACT: In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A5 in a Japanese population, we sequenced the proximal promoter region, all exons, and the surrounding intronic regions using genomic DNA from 187 Japanese subjects. Thirteen SNPs, including seven novel ones: 13108T>C, 16025A>G, 16903A>G, 16993C>G, 27448C>A, 29782A>G, and 31551T>C (A of the translational start codon of GenBank Accession # NG_000004.2 is numbered 1 according to the CYP Allele Nomenclature), were identified. The most common SNP was 6986A>G (key SNP for CYP3A5*3), with a 0.759 frequency. Two novel SNPs, 29782A>G (I456V) and 31551T>C (I488T), as well as 12952T>C (*5 marker) were found, but these alterations were always associated with the *3A marker SNPs, 6986A>G and 31611C>T. Using these 13 SNPs, haplotype analysis was performed and five novel *1 haplotypes (subtypes) (*1e to *1i) and six novel *3 haplotypes (subtypes) (*3d to *3i) were identified. Our findings suggest that CYP3A5*3 is the major defective allele and that other functional exonic SNPs are rare in the Japanese.
Human Mutation 07/2003; 21(6):653. · 5.69 Impact Factor
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ABSTRACT: N-acetyltransferase 2 (NAT2) is a key enzyme for the acetylation of sulfasalazine (SSZ). We examine whether there was a correlation between diplotype configurations (combinations of 2 haplotypes for a subject) at the NAT2 gene and the adverse effects of SSZ used for the treatment of rheumatoid arthritis (RA).
The findings from 144 patients with RA who had been treated with SSZ were collected from our outpatient department and used for a retrospective study. Haplotype analysis was performed by the maximum-likelihood estimation based on the EM algorithm using the obtained polymorphism data.
Sixteen patients (11.1%) had experienced adverse effects from SSZ, the most common being allergic reactions including rash and fever. The slow acetylators who had no NAT2*4 haplotype had experienced adverse effects more frequently (62.5%) than the fast acetylators who had at least one NAT2*4 haplotype (8.1%) (p < 0.001, OR 7.73, 95% CI 3.54-16.86). In 25% of the slow acetylators, the adverse effects were so severe that they were hospitalized.
Genotyping the NAT2 gene followed by estimation of diplotype configuration before administration of SSZ is likely to reduce the frequency of adverse effects in Japanese patients with RA.
The Journal of Rheumatology 01/2003; 29(12):2492-9. · 3.69 Impact Factor
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ABSTRACT: Matrix metalloproteinase (MMP)-1 and MMP-3 genes are associated with tumor cell invasion and metastasis with their promoter polymorphisms influencing the level of transcription. Our study explored the association of these polymorphisms with colorectal cancer risk in a Japanese population. DNA was extracted from peripheral blood of 101 patients with colorectal cancer and 127 age- and gender-matched healthy volunteers. Genotyping was carried out using PCR-RFLP and direct sequencing. In the MMP-1 gene polymorphism, the frequency of the 2G/2G genotype that is associated with higher enzyme activity was significantly increased in colorectal cancer patients when compared to controls (p = 0.0067; OR = 2.077; 95% CI = 1.221-3.534). With regard to the MMP-3 polymorphism, unexpectedly, the frequency of the 6A/6A genotype causing lower enzyme activity was significantly increased in patients (p = 0.0129; OR = 2.110; 95% CI = 1.165-3.822). Because the loci for the 2 MMP genes are closely linked, we examined linkage disequilibrium between the 2 loci using expectation-maximization algorithm. We found that the 2 loci were in linkage disequilibrium and that 2G-6A haplotype was significantly increased in patients compared to controls (p = 0.0010; OR = 1.949; 95% CI = 1.305-2.911). Our present data suggest that the MMP-1 and MMP-3 promoter polymorphisms may be associated with a colorectal cancer susceptibility in Japanese.
International Journal of Cancer 01/2003; 102(5):526-9. · 5.44 Impact Factor
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ABSTRACT: To analyze the frequencies of haplotypes of single-nucleotide polymorphisms (SNPs) of the IL1A gene (at -889, +4729, and +4845) in patients with systemic sclerosis (SSc) and in healthy control subjects, and to determine whether the IL1A gene haplotype is associated with SSc susceptibility or disease severity.
We studied 60 patients with SSc (34 with diffuse cutaneous SSc and 26 with limited cutaneous SSc) and 70 healthy control subjects. Polymorphisms of the IL1A gene were genotyped by direct sequencing using the ABI Prism 377 Sequence Detection System. The LDSupport program, which was recently developed in our laboratory, was used to estimate the haplotype frequencies of SNPs in the study population.
We confirmed the presence of 2 SNPs at positions -889 (C/T) and +4845 (G/T) of the IL1A gene, as previously reported. We also identified a novel SNP at position +4729 (T/C). Six haplotypes, CTG (49.7%), TCT (14.7%), CCT (20.3%), TTG (13.2%), CCG (1.4%), and TTT (0.7%), were found in the healthy controls. In contrast, only 2 haplotypes, CTG (95%) and TCT (5%), were detected in the SSc patients. Notably, the CTG haplotype was present at a significantly higher frequency in the SSc patients than in the healthy controls (P < 0.0001). We also examined the relationship between the CTG/CTG diplotype frequencies and interstitial lung disease (ILD), a major complication of SSc, as an indicator of disease severity. All SSc patients with ILD had the CTG/CTG diplotype, whereas the frequency of this diplotype was only 67% in patients without ILD.
Our observations suggest that the CTG haplotype of the IL1A gene may be an important marker for the susceptibility to, and the severity of, SSc.
Arthritis & Rheumatism 01/2003; 48(1):186-92. · 7.87 Impact Factor
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ABSTRACT: 5,10-Methylenetetrahydrofolate reductase (MTHFR), a key enzyme involved in folate metabolism, has two common polymorphisms that affect enzyme activity. The objective of this study was to examine whether there was a correlation between the genotype or haplotype of the MTHFR gene and the efficacy or toxicity of methotrexate (MTX) in the treatment of rheumatoid arthritis. MTX-treated rheumatoid arthritis patients (n = 106) were selected from outpatient clinics and used for a retrospective study to examine the correlation between genotypes or haplotypes concerning polymorphisms of the MTHFR gene, and the efficacy or toxicity of MTX. Estimation of the haplotype frequencies was performed by maximum likelihood estimation based on expectation maximization algorithm. Single locus analysis examining each locus separately showed that patients with 1298C were receiving significantly lower doses of MTX compared to patients without [P < 0.05, relative risk (RR) = 2.18, 95% confidence interval (CI) 1.17-4.06], while a higher rate of overall MTX toxicity was observed in patients with 677T than those without (P < 0.05, RR = 1.25, 95% CI 1.05-1.49). An estimation of haplotype frequencies showed that there was no 677T-1298C haplotype in the population. Posterior distribution of the diplotype configuration for each individual was concentrated on a single configuration. Patients with the 677C-1298C haplotype were receiving lower doses of MTX than those without (P < 0.05, RR = 2.14, 95% CI 1.13-4.07), while subjects with 677T-1298A had a higher frequency of side-effects from MTX (P < 0.05, RR = 1.42, 95% CI 1.11-1.82). Both single locus and haplotype analyses suggest that polymorphisms within the MTHFR gene are associated with both the efficacy and toxicity of MTX in rheumatoid arthritis patients. Pharmacokinetic studies are necessary to prove the association.
Pharmacogenetics 04/2002; 12(3):183-90.
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Japanese Journal of Clinical Immunology 03/2002; 25(1):105-9.
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ABSTRACT: Some patients with Graves' disease who select surgical therapy so they can discontinue antithyroid medication require lifelong levo-thyroxin (l-T4) replacement therapy because of irreversible postoperative hypothyroidism. The aim of this study was to enable the replacement of absent thyroid hormone through autotransplanted thyroid tissue that had been cryopreserved since the initial thyroid operation, and to release these patients from lifelong l-T4 administration.
At the time of subtotal thyroidectomy for Graves' disease, the surgical specimen was partially cryopreserved at -196 degrees C until it was used for autotransplantation. After obtaining sufficient informed consent, four patients with postoperative hypothyroidism underwent autotransplantation of cryopreserved thyroid tissues. These patients required 50 to 150 microg/day of l-T4 at 1.8, 3.4, 3.5, and 2.8 years after operation. For the transplantation, 2.5 to 3.5 g of cryopreserved thyroid tissue was autotransplanted into the forearm muscle of each patient.
In three of the patients, l-T4 administration could be discontinued and the clinical symptoms of hypothyroidism disappeared because of an improved serum thyroid-stimulating hormone level. Pathologic and immunohistochemical examinations of the thawed cryopreserved tissue demonstrated well-preserved thyroid structure and thyroglobulin-positive follicular cells and colloids, suggesting that the transplanted material was functional. In addition, 123I scintiscanning in patients 1 and 2 indicated an accumulation of radioactive iodine at the transplantation sites. One patient, who was able to discontinue l-T4 administration for 6 months, subsequently required l-T4 again because of recurrent hypothyroidism.
Despite a few remaining uncertainties that must be resolved before this procedure is optimized, autotransplantation of cryopreserved thyroid tissue promises to be a useful therapeutic procedure for treating permanent postoperative hypothyroidism in patients with Graves' disease.
Journal of the American College of Surgeons 02/2002; 194(1):14-22. · 4.55 Impact Factor
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Kazuo Shimizu,
Mitsuji Nagahama, Yutaka Kitamura,
Koei Chin,
Wataru Kitagawa,
Tetsuo Shibuya,
Takashi Mimura,
Osamu Ozaki,
Kiminori Sugino,
Kunihiko Ito,
Shigeo Tanaka
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ABSTRACT: Twenty-two cases of partial or wholly composed clear-cell thyroid tumors were reviewed to differentiate between a primary nodule and metastatic clear-cell renal carcinoma in the thyroid. Pathological reevaluation of HE-stained specimens, immunohistochemical observation using anti-thyroglobulin (TG) antibody, and periodic acid-Schiff (PAS) staining were performed. The pathological characteristics in metastases from the kidney have a greater tendency to demonstrate a strikingly clear cytoplasm with small nuclei, rich vascularization, and a trabecular arrangement of tumor cells than do primary thyroid cases. The immunohistochemical TG staining in conjunction with PAS staining for the recognition of follicular colloid could provide much more reliable information of primary cases compared to that using TG staining alone. Clinically, in primary cases, the female: male ratio is substantially higher while the mean age is lower than in metastatic cases reflecting differentiated thyroid carcinoma. In conclusion, immunohistochemical staining for TG with PAS staining for the recognition of follicular colloid proved to be the most sensitive method for identifying primary clear cell thyroid tumors. In addition, a careful assessment of past and/or present kidney disorders to rule out metastatic renal cell carcinoma is advisable. Age, gender, and physiological findings are also informative when differentiating between them.
Surgery Today 11/1995; 25(12):1015-1022. · 1.22 Impact Factor
