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The amplification and overexpression ofHer2proto-oncogene have been found to be associated with the development and progression of human breast cancer. A polymorphic valine allele at codon 655 of theHer2gene (Her2V655) was suggested by some authors to be a susceptible genetic factor for the development of breast cancer. TheHer2polymorphism at codon 655 was investigated in 304 Korean women including 177 patients with breast cancer. The association betweenHer2genotype andHer2protein overexpression was also examined in breast cancers by immunohistochemistry.Her2V655 was not associated with a significant breast cancer risk (odds ratio (OR), 1.792; 95% confidence interval (CI), 0.459–6.991). The frequency of homozygous or heterozygous valine allele increased in stage 2 patients (OR, 1.67; 95% CI, 0.67–4.19), and patients in stages 3 and 4 (OR, 3.36; 95% CI, 0.85–13.42) compared to patients in stage 0. However, an association between the presence of the valine allele and the overexpression ofHer2protein could not be demonstrated. These results suggest thatHer2polymorphism at codon 655 is not associated with the development of breast cancer in Korean women. However, there is a possibility that the valine allele at codon 655 might be related to increased risk of breast cancer progression. [ABSTRACT FROM AUTHOR]

Objective: Rare disease Background: Hemolytic uremic syndrome (HUS) can be categorized as primary (typical or atypical) or secondary (with a coexisting diseases). Typical HUS usually means shiga-toxin-medicated and thrombotic thrombocytopenic purpura. Secondary HUS is often initiated by coexisting diseases or conditions such as infections, transplantation, cancer, and autoimmune disease. Atypical HUS (aHUS) is usually induced by genetic mutations of one or several complement-regulating genes and associated with dysregulated complement activation. In the era of compliment- inhibiting therapy, early recognition of aHUS is important for patient prognosis. However, complimentinhibiting therapy is not always beneficial in patients with secondary HUS. Case Report: We present a case of a 49-year-old woman with aHUS, which was caused by a novel genetic point mutation of complement factor H gene (p.Gly1110Ala) mimicking secondary HUS with scleroderma. Instead of administering eculizumab treatment for C5 polymorphism, the patient was successfully treated with mycophenolate mofetil. Conclusions: HUS has complex and mixed etiologies and requires genetic testing. Attention should be paid to new point mutations in aHUS. [ABSTRACT FROM AUTHOR]

Folate has essential roles in DNA synthesis, repair and methylation. Folate metabolism-related gene variants may modulate the levels of this vitamin and affect the cancer risk. Thus, whether these polymorphisms play an important role in carcinogenesis, particularly colorectal cancer (CRC) development, has been a subject interest. The present study investigated the association between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS) and the reduced folate carrier 1 (RFC1) genes and CRC risk. Polymorphisms in MTHFR (677C>T and 1298A>C), TS [1494del6 and the TS enhancer region (TSER)] and RFC1 (-43T>C, 80G>A and 696C>T) were characterized using polymerase chain reaction-restriction fragment length polymorphism in 477 CRC cases and 514 controls. Although no polymorphisms were significantly associated with the CRC risk in the overall sample, significant associations between folate metabolism-related polymorphisms and CRC risk were identified in the stratified analyses. The MTHFR 677CT/1298AC and MTHFR 1298AC+CC/TSER 2R3R genotypes in the presence of plasma folate levels ≤4.12 ng/ml were associated with significantly increased CRC risk. In addition, individuals with the MTHFR 677TT/TSER 3R3R or MTHFR 677/TSER 3R3R/TS 1494 0bp6bp+6bp6bp genotypes and diabetes mellitus (DM) were at an increased risk for CRC. Therefore, the data suggest that i) MTHFR polymorphisms combined with low plasma folate levels and ii) polymorphisms in folate metabolism-related genes combined with metabolic syndrome risk factors (hypertension and DM) increase the odds of developing CRC. [ABSTRACT FROM AUTHOR]

Background Polymorphisms in angiogenesis-related genes and metabolic syndrome (MetS) risk factors play important roles in cancer development. Moreover, recent studies have reported associations between a number of 3'-UTR polymorphisms and a variety of cancers. The aim of this study was to investigate the associations of three VEGF 3'-UTR polymorphisms (1451C > T [rs3025040], 1612G > A [rs10434], and 1725G > A [rs3025053]) and MS with colorectal cancer (CRC) susceptibility in Koreans. Methods A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of VEGF polymorphisms was performed by TaqMan allelic discrimination assays. Cancer risks of genetic variations and gene-environment interactions were assessed by adjusted odds ratios (AORs) and 95% confidence intervals (CIs) of multivariate logistic regression analyses. Results VEGF 1451C > T was significantly associated with rectal cancer risk (Dominant model; AOR =1.58; 95% CI =1.09 - 2.28; p =0.015) whereas VEGF 1725G > A correlated with MetS risk (Dominant model; AOR =1.61; 95% CI =1.06 - 2.46; p =0.026). Of the geneenvironment combined effects, the interaction of VEGF 1451C > T and MetS contributed to increased RC risk (AOR =3.15; 95% CI =1.74 - 5.70; p < .001) whereas the combination of VEGF 1725G > A and MetS was involved with elevated CC risk (AOR =2.68; 95% CI =1.30 - 1.55; p =0.008). Conclusions Our results implicate that VEGF 1451C > T and 1725G > A may predispose to CRC susceptibility and the genetic contributions may be varied with the presence of MetS. [ABSTRACT FROM AUTHOR]

Background: Polymorphisms in angiogenesis-related genes and metabolic syndrome (MetS) risk factors play important roles in cancer development. Moreover, recent studies have reported associations between a number of 3'-UTR polymorphisms and a variety of cancers. The aim of this study was to investigate the associations of three VEGF 3'-UTR polymorphisms (1451C > T [rs3025040], 1612G > A [rs10434], and 1725G > A [rs3025053]) and MetS with colorectal cancer (CRC) susceptibility in Koreans. Methods: A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of VEGF polymorphisms was performed by TaqMan allelic discrimination assays. Cancer risks of genetic variations and gene-environment interactions were assessed by adjusted odds ratios (AORs) and 95% confidence intervals (CIs) of multivariate logistic regression analyses. Results: VEGF 1451C > T was significantly associated with rectal cancer risk (Dominant model; AOR =1.58; 95% CI = 1.09 - 2.28; p = 0.015) whereas VEGF 1725G > A correlated with MetS risk (Dominant model; AOR =1.61; 95% CI =1.06 - 2.46; p = 0.026). Of the gene-environment combined effects, the interaction of VEGF 1451C > T and MetS contributed to increased rectal cancer risk (AOR = 3.15; 95% CI = 1.74 - 5.70; p < .001) whereas the combination of VEGF 1725G > A and MetS was involved with elevated colon cancer risk (AOR = 2.68; 95% CI = 1.30 - 1.55; p =0.008). Conclusions: Our results implicate that VEGF 1451C > T and 1725G > A may predispose to CRC susceptibility and the genetic contributions may be varied with the presence of MetS. [ABSTRACT FROM AUTHOR]

Hereditary protein S deficiency from a mutation in the PROS1 gene causes a genetic predisposition to develop venous thromboembolic disorders in humans. Recently, the acknowledgment of the clinical significance of large copy number mutations in protein S deficiency has increased. In this study, the authors investigated the genomic architecture of PROS1 in order to understand the microscopic sequence environment leading to large intragenic copy number mutations in the gene. The study subjects were 3 unrelated male patients with hereditary protein S deficiency from a tandem duplication mutation involving exons 5-10 of PROS1. Breakpoint analyses revealed 10-bp microhomology sequences in the intervening sequence (IVS)-4 and IVS-10 at the duplication junction without additional sequence changes, suggesting a single replication-based event as the potential molecular mechanism of rearrangement and founder effect in the mutant alleles. Further analyses on nucleotide sequences flanking the microhomology sequence revealed the presence of a repeat element (LTR-ERV1) and quadruplex-forming G-rich sequences in IVS-4. The results from genotyping multi-allelic short tandem repeats supported founder effect in the identical mutations in the 3 unrelated patients. In conclusion, we identified unique genomic architectures in the intervening sequences of PROS1 that underlie a large intragenic tandem duplication mutation leading to inherited thrombophilia. [ABSTRACT FROM AUTHOR]

Silent brain infarction (SBI) is an asymptomatic cerebrovascular disorder. The aim of the present study was to investigate the association between adrenoceptor-α2 (ADRA2) gene polymorphisms and SBI. A total of 361 patients with SBI and 467 healthy control subjects were examined. The polymerase chain reaction was performed to genotype the ADRA2A 1780G>A, ADRA2B 301-303 insertion/deletion (I/D) and ADRA2C 322-325I/D polymorphisms. The frequency of the ADRA2C 322-325I/D polymorphism was significantly different between patients with SBI and control subjects. When interaction analyses were performed for vascular risk factors, the ADRA2C 322-325ID genotype increased the risk for SBI in the presence of hypertension and elevated plasma homocysteine levels. The ADRA2C 322-325ID genotype and plasma homocysteine levels showed a significant synergistic effect for SBI. In addition, the ADRA2A 1780AA genotype was associated with elevated plasma homocysteine levels. Although further analysis of the association between ADRA2 polymorphisms and clinical risk factors of SBI is required, the present study of a limited set of SBI risk factors with ADRA2 polymorphisms provides the first evidence of the involvement of ADRA2 gene family members in the development of SBI. Further studies using larger and more heterogeneous populations are required to validate the association of ADRA2 polymorphisms with SBI. [ABSTRACT FROM AUTHOR]

Background: The alpha2-adrenergic receptor (α2-AR) mediates physiological responses to endogenous catecholamine, and genetic variants of α2-AR may predispose to clinical vascular diseases. We evaluated whether common genetic variants of each three subtype of alpha2-adrenergic receptor (ADRA2A, ADRA2B, and ADRA2C) were associated with ischemic stroke. Methods: A total of 616 patients with ischemic stroke and 512 controls were genotyped for the ADRA2A 1780G>A, ADRA2B 301-303 I/D, and ADRA2C 322-325 I/D polymorphisms. Logistic regression analyses, adjusting for multiple comparisons, were used to determine the association between the minor allele of each of three ADRA2 genes and the risk of ischemic stroke and pathophysiological subtypes. Results: The ADRA2B 301-303 D allele was more prevalent in the stroke group, compared to controls (DD vs. II, OR: 1.78, 95% CI: 1.18-2.69; recessive, OR: 1.55, 95% CI: 1.06-2.26). A subgroup analysis revealed that this association was found only in the small vessel diseases (SVD) type (DD vs. II, OR: 1.92, 95% CI: 1.11-3.33). The ADRA2A and ADRA2C polymorphisms did not contribute to an increased risk of ischemic stroke or any pathophysiological subtype. Conclusions: The ADRA2B 301-303 D allele confers an increased risk of overall ischemic stroke and SVD subtype. [ABSTRACT FROM AUTHOR]

Background and Purpose: The aims of this study were to evaluate the role of tumor necrosis factor-α (TNF-α) polymorphisms in patients susceptible to ischemic stroke and silent brain infarction (SBI), and to determine the relationship between TNF-α polymorphisms and plasma total homocysteine (tHcy) levels. Methods: We studied 237 patients with ischemic stroke, 257 patients with SBIs, and 216 control subjects. For control subjects, we selected healthy individuals matched for gender and age from those individuals who came to our hospital for health examinations. The TNF-α-308G→A and -238G→A genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method. Results: The frequency of the TNF-α-308G→A polymorphism was significantly different between the patients with ischemic stroke and the control group (GG vs. GA+AA; adjusted odds ratio, AOR, 0.50; 95% CI 0.255-0.989). By subgroup analysis, when tHcy levels were stratified into high (>10.80 μmol/l), moderate (8.21-10.80 μmol/l), and low levels (<8.21 μmol/l), the frequency of the TNF-α-308GA+AA genotype in the highest tertile group was higher than in the lowest tertile group (AOR 2.46; 95% CI 1.063-5.699). However, the relationship between SBI susceptibility and polymorphisms of TNF-αwas not established. The tHcy levels were significantly and inversely correlated with folate levels in the TNF-α-308GG and TNF-α-238GG genotypes in the ischemic stroke, SBI, and control groups (p< 0.05). Conclusions: Our results suggest that the TNF-α-308G→A polymorphism is responsible for susceptibility to ischemic stroke and is associated with high tHcy levels in Koreans. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This study was performed to identify whether cytogenetics, International Prognostic Scoring System (IPSS), or World Health Organization Classification-Based Prognostic Scoring System are predictive of the efficacy of azacitidine in patients with myelodysplastic syndrome (MDS). We retrospectively reviewed the clinical records of 113 patients with MDS treated with azacitidine. The “response alternating disease natural history,” “cytogenetic response,” and “hematologic improvement” were assessed by serial bone marrow biopsy, cytogenetic study, and hemogram analyses. The complete and partial remission rates were 17.6% and 3.9% in 51 evaluable patients. There were no significant differences in response rate in the different cytogenetic/IPSS/WPSS groups. The overall hematologic response (HR) rate was 49.6%, and the HR rate was significantly greater in patients classed as “very high” risk according to the WPSS compared with other patient groups. The 1-year overall survival (OS) rate was higher among patients with HR compared with those without HR (80.9% vs 63.3%, p = 0.046), and the 1-year OS rate among patients classed as being at high risk by each criteria was similar to that of patients classed as being at low risk. The hazard ratio of death among patients with HR compared with those without HR was 0.17 (95% CI 0.04–0.69) for high + very high risk group based on WPSS. Patients in the WPSS high-risk group had an increased HR rate compared with other patient groups, and the achievement of HR was associated with a significant increase in OS. Azacitidine showed similar efficacy in all patient groups, even in patients with poor cytogenetics and in high-risk groups. [ABSTRACT FROM AUTHOR]