Time course of the changes in right and left ventricle function and associated factors after transcatheter closure of atrial septal defects.

OBJECTIVE: The purpose of this study was to evaluate the changes in right ventricle (RV) and left ventricle (LV) function after transcatheter atrial septal defect (ASD) closure and to assess the influence of the age and the amount of shunt. DESIGN: Retrospective study PATIENTS: Fifty-three adult patients who underwent transcatheter closure were enrolled, then divided into subgroups according to the age (< 40 years vs ≥ 40 years), and the amount of shunt flow (QpQs < 2.5 vs QpQs ≥ 2.5). OUTCOME MEASURES: Two-dimensional tissue Doppler imaging was performed in a four-chamber view at the basal ventricular septum (VS) and tricuspid valve annulus (TVA) before and at 1 month and 6 months after closure. Myocardial velocities, the myocardial performance index (MPI), and isovolumic acceleration (IVA) were assessed. RESULTS: At the TVA, the MPI decreased slightly and then greatly increased at 6 months after closure (P = .002). The IVA improved in all patients (P < .001), and the E'/A' ratio decreased, especially in the old age group (P = .031) and larger shunt group (P = .035). At the VS, S' and the IVA decreased and had not recovered until 6 months in the old age (P = .02) and larger shunt (P = .02). The Qp/Qs showed a significant reverse correlation with a decrease in the E'/A' at the TVA (r = -0.37, P = .008), and age of patient was correlated with a decrease in the IVA at the VS (r = -0.32, P = .019). The age at closure (ß = -0.36, P = .002), the Qp/Qs ratio (ß = -0.45, P = .01), and RV MPI changes (ß = -7.64, P < .001) were found to be associated factors with IVA decrease at the VS. CONCLUSIONS: After ASD closure, RV global function might be impaired. In elderly patients and patients with a large shunt, impairment of LV contractility developed until 6 months after closure. Close long-term observation is required after closure, especially in old-age patients with a large shunt.

Association of human microRNAs miR-22 and miR-491 polymorphisms with panic disorder with or without agoraphobia in a Korean population.

BACKGROUND: The possible involvement of microRNAs (miRNA) in psychiatric disorders has been recently recognized. Several miRNA polymorphisms have been found to be associated with panic disorder (PD) in European populations. However, the association of miRNA polymorphisms on PD has not been reported in Asian populations. We evaluated the effect of miR-22 and miR-491 polymorphisms on susceptibility to PD in a Korean population. METHODS: Genotyping for four polymorphic variants of the primary miRNA (pri-miRNA) regions of miR-22 (rs8076112 and rs6502892) and miR-491 (rs4977831 and rs2039391) was performed using blood samples of 341 Korean patients with PD and 229 healthy control subjects. To evaluate PD phenotypes, the Panic Disorder Severity Scale (PDSS) and Anxiety Sensitivity Inventory-Revised (ASI-R) were administered. RESULTS: Three single-nucleotide polymorphisms (SNPs) were found to be associated with PD: rs8076112 miR-22 and rs4977831 and miR-491 rs2039391. The rs8076112C/rs6502892C haplotypes of miR-22 and rs4977831G/rs2039391G and rs4977831A/rs2039391A haplotypes of miR-491 were significantly overrepresented in patients with PD than in healthy control subjects. In combination analysis, miR-22 rs8076112AC/rs6502892CC and rs8076112CC/rs6502892CC and miR-491 rs4977831AG/rs2039391AA were more frequent in patients with PD. Among the phenotype assessments, ASI-R scores were significantly associated with miR-22 rs6502892 in the subgroup with the agoraphobic phenotype. LIMITATIONS: The results should be considered preliminary due to the relatively small sample size and the selection of only four SNPs. CONCLUSIONS: This is the first report to show possible associations of miR-22 and miR-491 with genetic susceptibility to PD in a Korean population.

Association between folate metabolism-related polymorphisms and colorectal cancer risk.

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.

Genetic variants in 3'-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans.

Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3'-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3'-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3'-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention.

Association of reduced folate carrier-1 (RFC-1) polymorphisms with ischemic stroke and silent brain infarction.

Stroke is the second leading cause of death in the world and in South Korea. Ischemic stroke and silent brain infarction (SBI) are complex, multifactorial diseases influenced by multiple genetic and environmental factors. Moderately elevated plasma homocysteine levels are a major risk factor for vascular diseases, including stroke and SBI. Folate and vitamin B12 are important regulators of homocysteine metabolism. Reduced folate carrier (RFC), a bidirectional anion exchanger, mediates folate delivery to a variety of cells. We selected three known RFC-1 polymorphisms (-43C>T, 80A>G, 696T>C) and investigated their relationship to cerebral infarction in the Korean population. We used the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method to analyze associations between the three RFC-1 polymorphisms, disease status, and folate and homocysteine levels in 584 ischemic stroke patients, 353 SBI patients, and 505 control subjects. The frequencies of the RFC-1 -43TT, 80GG, and 696CC genotypes differed significantly between the stroke and control groups. The RFC-1 80A>G substitution was also associated with small artery occlusion and SBI. In a gene-environment analysis, the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms in the ischemic stroke group had combined effects with all environmental factors. In summary, we found that the RFC-1 -43C>T, 80A>G, and 696T>C polymorphisms may be risk factors for ischemic stroke.

Association study of five functional polymorphisms in matrix metalloproteinase-2, -3, and -9 genes with risk of primary ovarian insufficiency in Korean women.

OBJECTIVE: Primary ovarian insufficiency (POI) is diagnosed clinically by increased follicle-stimulating hormone (FSH) levels and estradiol (E2) deficiency. A previous report suggests a possible association matrix metalloproteinase (MMP) and estrogen signaling pathway; however, there are no reports of MMP genetic associations with POI. STUDY DESIGN: Blood samples were collected from 374 karyotypically normal study participants consisting of 138 patients with POI (46, XX; mean age ± standard deviation [SD], 31.7 ± 3.51 years) and 236 control subjects (46, XX; 32.2 ± 3.50 years). Five functional polymorphisms in MMP-2 (-1575G>A [rs243866] and -1306C>T [rs243865]), MMP-3 (-1612 5A/6A [rs3025058]), and MMP-9 (-1562C>T [rs3918242] and 2678G>A [rs17576]) genes were genotyped using polymerase chain reaction-restriction fragment length polymorphism assays in a cohort of 236 controls and 138 POIs. RESULTS: MMP-2 -1306CT+TT was associated with POI occurrence. Moreover, relatively lower serum estradiol levels were detected in healthy women with the MMP-2 -1575GA+AA/MMP-2 -1306CT+TT and MMP-2 -1306CT+TT/MMP-9 2678GG combination genotypes. CONCLUSIONS: MMP-2 -1306C>T polymorphism may contribute to an increased POI prevalence in Korean women. Further studies are needed to confirm the genetic associations in other ethnic populations.

Interplay between 3'-UTR polymorphisms in the vascular endothelial growth factor (VEGF) gene and metabolic syndrome in determining the risk of colorectal cancer in Koreans.

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.

Interleukin-1beta -511T>C genetic variant contributes to recurrent pregnancy loss risk and peripheral natural killer cell proportion.

OBJECTIVE: To identify whether interleukin gene polymorphisms are risk factors for idiopathic recurrent pregnancy loss (RPL) in Korean women. DESIGN: Case-control study. SETTING: Hospital-based study. PATIENT(S): A cohort of 385 idiopathic RPL patients and 232 controls with Korean ethnicity. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Genotyping was assessed with a polymerase chain reaction-restriction fragment length polymorphism assay. We examined polymorphisms in three interleukin (IL) genes: IL-1ß, IL-4, and IL-10. RESULT(S): The IL-1ß -511T>C polymorphism was associated with RPL (-511TT vs. -511CC: adjusted odds ratio 1.826; 95% confidence interval 1.130-2.953). Allelic gene-gene interaction analysis revealed that the T/B2/G (IL-1ß/IL-4/IL-10) allele combination was only detected in the RPL group (adjusted odds ratio 20.046; 95% confidence interval 1.188-338.204). The proportion of peripheral natural killer cells was higher in patients with the IL-1ß -511C allele compared with the -511T allele. CONCLUSION(S): According to these results, IL-1ß -511T>C may be a predisposing factor to RPL susceptibility. However, the mechanism underlying the function of IL-1ß -511T>C in RPL remains to be determined, and further studies are needed to improve understanding of the roles of IL-1ß -511T>C, using a larger and more heterogeneous cohort.

Association between common genetic variants of α2A-, α2B- and α2C-adrenoceptors and the risk of silent brain infarction.

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.

Association of polymorphisms in microRNA machinery genes (DROSHA, DICER1, RAN, and XPO5) with risk of idiopathic primary ovarian insufficiency in Korean women.

OBJECTIVE: The aim of our study was to investigate whether polymorphisms in microRNA machinery genes are associated with the risk of primary ovarian insufficiency (POI). METHODS: We genotyped 136 POI patients and 236 controls among Korean women for nine single nucleotide polymorphisms (SNPs; DROSHA rs6877842 and rs10719; DICER1 rs13078 and rs3742330; RAN rs14035; and XPO5 rs34324334, rs2257082, rs11544382, and rs11077) by polymerase chain reaction-restriction fragment length polymorphism analysis. Differences in genotype frequencies between patients and controls were compared, and odds ratios (ORs) and 95% CIs were determined as measures of the strength of the association between genotype and POI. RESULTS: Of the nine SNPs, XPO5 rs34324334 and rs11544382 were monomorphic and were not analyzed further. The XPO5 rs2257082 CT and CT + TT variant genotypes were more frequent in patients (OR, 2.097; 95% CI, 1.207-3.645) than in controls (OR, 2.030; 95% CI, 1.196-3.445). The combined frequencies of XPO5 rs2257082 CT + TT and rs11077 AC + CC genotypes were higher in patients than in controls (OR, 2.526; 95% CI, 1.088-5.865). An association of POI risk with other polymorphisms was not found. A haplotype-based analysis of seven polymorphisms of the microRNA machinery genes for gene-gene interactions suggests that ***ACTA, ***GCCA, ***G*C*, *T*ATTA, and ***ACT* haplotypes (asterisk indicates SNP locus not included; DROSHA rs6877842 and rs10719, DICER1 rs13078 and rs3742330, RAN rs14035, and XPO5 rs2257082 and rs11077 polymorphisms) are associated with higher POI prevalence, and that ***GCTA, ***ACCA, *C*ATTA, and *C*ATT* haplotypes are associated with lower POI prevalence. CONCLUSIONS: Our data demonstrate that the XPO5 rs2257082 T variant allele occurs more frequently in POI patients than in controls, suggesting that this allele may be associated with increased POI risk.