Sheng Hsiang Lin

Genetic association studies of angiogenesis- and vasoconstriction-related genes in women with recurrent pregnancy loss: a systematic review and meta-analysis

BACKGROUND Angiogenesis and an adequate blood supply are critical for several steps in human early pregnancy. Some studies have reported angiogenesis- and vasoconstriction-related genes are associated with recurrent pregnancy loss (RPL), but their sample size was limited. This study was conducted to investigate the genetic association between these angiogenesis- and vasoconstriction-related genes and idiopathic RPL, using meta-analyses. METHODS A systematic review of the published literature from MEDLINE and EMBASE databases was conducted and investigations of an angiogenesis- and vasoconstriction-related gene polymorphism in RPL reported more than three times were selected. Aggregating data from eligible studies were integrated into meta-analyses by means of random effects models. RESULTS Of 185 potentially relevant studies, 18 case-control studies comprising a total of 2397 RPL patients and 1760 controls were included into the meta-analyses. Among these genetic association studies were 4 reports of vascular endothelial growth factor (VEGF) (-1154G>A) polymorphisms, 4 reports of p53 (codon72) and 10 reports of endothelial nitric oxide synthase (eNOS) (B/A, Glu298Asp) with RPL. The integrated results showed that VEGF (-1154G>A), p53 (codon 72) and eNOS (Glu298Asp) polymorphisms were significantly associated with RPL, and their summary odd ratios [95% confidence interval (CI)] were 1.51 (1.13-2.03), 1.84(1.07-3.16) and 1.37 (1.11-1.69), respectively. The summary odd ratio of the eNOS (B/A) polymorphism in RPL was 1.15 (0.94-1.41), and failed to show significance at meta-analysis. CONCLUSIONS Meta-analyses of available data showed significant associations between the VEGF (-1154G>A), p53 (codon72) and eNOS (Glu298Asp) polymorphisms and idiopathic RPL. These angiogenesis- and vasoconstriction-related genes jointly confer higher susceptibility to idiopathic RPL.

Population based study on patients with traumatic brain injury suggests increased risk of dementia

Objective The relationship between traumatic brain injury (TBI) and the risk of dementia remains controversial. This population based study was designed to estimate and compare the risk of dementia in TBI and non-TBI individuals during the 5 year period after TBI. Methods This study was a retrospective cohort study. Data were obtained from the Longitudinal Health Insurance Database 2000. We included 44 925 patients receiving ambulatory or hospital care and 224 625 non-TBI patients; patients were matched for sex, age and year of index use of healthcare. Patients <15 years of age and those admitted to the intensive care unit were excluded. Each individual was studied for 5 years to identify the subsequent development of dementia. Data were analysed by Cox proportional hazard regression. Results During the 5 year follow-up period, 1196 TBI (2.66%) and 224 625 non-TBI patients (1.53%) patients developed dementia. During the 5 year follow-up period, TBI was independently associated with a 1.68 (range 1.57–1.80) times greater risk of dementia after adjusting for sociodemographic characteristics and selected comorbidities. Conclusions The findings of this study suggest an increased risk of dementia among individuals with TBI. We suggest the need for more intensive medical monitoring and health education in individuals with TBI.

More severe sustained attention deficits in nonpsychotic siblings of multiplex schizophrenia families than in those of simplex ones

Sustained attention deficits measured by the Continuous Performance Test (CPT) have been proposed as an endophenotype of schizophrenia. However, little is known about whether sustained attention deficits in first-degree relatives of schizophrenic patients are associated with familial loading for schizophrenia. We examined 107 parents and 84 siblings of simplex schizophrenia families as well as 72 parents and 56 siblings of multiplex schizophrenia families, all nonpsychotic, using the Diagnostic Interview for Genetic Studies and two sessions of the CPT (undegraded and degraded). The effect of perceptual load was assessed using the residual of the regression of the degraded score on the undegraded one. Statistical models that can adjust for familial correlations were used to compare the CPT performance of relatives between the two types of families. Siblings from multiplex families exhibited worse performance on the degraded CPT and less proficiency in processing the perceptual load than those from simplex families. No such difference was observed for the parents on either CPT version. We concluded that sustained attention along with perceptual load processing is more impaired in the siblings of schizophrenic patients with high familial loading and that this finding might be useful for future genetic dissection of schizophrenia.

Sleep apnea and the risk of chronic kidney disease: A nationwide population-based cohort study

STUDY OBJECTIVES Sleep apnea (SA) is characterized by apnea during sleep and is associated with cardiovascular diseases and an increase in all-cause mortality. Chronic kidney disease (CKD) is a global health problem that has placed a substantial burden on healthcare resources. However, the relationship between SA and the incidence of CKD is not clear. This study aimed to determine whether SA is an independent risk factor for the development of CKD. DESIGN Retrospective cohort study. SETTING National Health Insurance Research Database (NHIRD) of Taiwan. PATIENTS OR PARTICIPANTS A total of 4,674 adult patients (age ≥ 30 y) in whom SA was newly diagnosed from 2000 to 2010 were included, together with 23,370 non-SA patients as the comparison group. The two groups were frequency-matched for sex, age, and year of receiving medical service. Each individual was followed until 2011. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS These two groups were monitored and observed for the occurrence of CKD. Patients with SA experienced a 1.94-fold increase (95% confidence interval [CI], 1.52-2.46; P < 0.001) in the incidence of CKD, which was independent of sex, age, and comorbid medical conditions. Additionally, they showed a 2.2-fold increase (95% CI, 1.31-3.69; P < 0.01) in the incidence of end-stage renal disease (ESRD). CONCLUSIONS Patients with sleep apnea are at increased risk for chronic kidney disease and end-stage renal disease compared with the general population. As such, screening renal function and treatment of chronic kidney disease is an important issue in patients with sleep apnea.

Association of polymorphisms/haplotypes of the genes encoding vascular endothelial growth factor and its KDR receptor with recurrent pregnancy loss

BACKGROUND Vascular endothelial growth factor (VEGF) and its kinase insert domain receptor (KDR) play an important role in angiogenesis, and their gene expression patterns also suggest a close relationship with early pregnancy. However, limited information is available regarding the role of the VEGF system, especially its KDR receptor, in recurrent pregnancy loss (RPL). This study was conducted to investigate a genetic association between VEGF and its receptor gene (KDR) with idiopathic RPL. METHODS In this case-control study, 115 women who had experienced at least two consecutive spontaneous miscarriages (n= 62 women with two miscarriages, n= 53 with three or more) and 170 controls were included. A total of 14 tag single-nucleotide polymorphisms (SNPs) of VEGF and KDR were selected from the HapMap Web site and three functional SNPs [rs1570360 (-1154G/A) of VEGF; rs2305948 (V297I) and rs1870377 (Q472H) of the KDR gene] were genotyped using primer extension analysis. We further used multifactor dimensionality reduction analysis to evaluate gene-gene interactions. RESULTS One tag SNP (rs6838752) and the functional SNP (Q472H) of the KDR gene were in complete linkage and showed significant differences between patients and controls (P< 0.05). The frequencies of haplotypes of VEGF (A-T-G haplotype) and KDR (A-C-A-T-G haplotype) showed significant differences in patients versus controls (P< 0.05). All comparisons with controls remained significant when the subgroup of women with three or more miscarriages was analyzed. CONCLUSIONS VEGF and its receptor gene (KDR) are associated with idiopathic RPL. The VEGF/KDR system jointly contributes to recurrent miscarriage in Taiwanese Han women.

Genetic association studies of ACE and PAI-1 genes in women with recurrent pregnancy loss: a systematic review and meta-analysis.

A fine balance between coagulation and fibrinolysis is critical in early pregnancy. Plasminogen activator inhibitor-1 (PAI-1) and angiotensin converting enzyme (ACE) are involved in the fibrinolytic process, and several studies have reported the association between their gene polymorphisms and recurrent pregnancy loss (RPL). This study was conducted to investigate the association between PAI-1 and ACE polymorphisms and idiopathic RPL, using meta-analyses. A systematic review of the published literature from the MEDLINE and EMBASE databases before April 2012 was conducted. Of 209 potentially relevant studies, 22 case-control studies comprising a total of 2,820 RPL patients and 3,009 controls were included. Among these studies were 11 reports of PAI-1 4G/5G and 11 of ACE I/D polymorphisms in patients with RPL. A significant association was found withthe ACE I/D polymorphism [summary odds ratio 1.29 (95% confidence interval 1.02-1.62)] in studies including more than two recurrent abortions. Subgroup analysis did not show significant associations with RPL in Caucasian and non-Caucasian patients. Meta-analyses of PAI-1 4G/5G polymorphism were not found associations with RPL in studies including more than two or three recurrent abortions, and in studies of Caucasian and non-Caucasian patients. In conclusion, meta-analyses showed a significant association between the ACE I/D polymorphism and idiopathic RPL. High clinical heterogeneity existed among studies of PAI-1 4G/5G, and the aggregated data failed to confer higher susceptibility to idiopathic RPL. More well-designed studies with different ethnic populations are required for future integration.

Polymorphisms of endocrine gland-derived vascular endothelial growth factor gene and its receptor genes are associated with recurrent pregnancy loss

BACKGROUND Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) and its receptor genes [prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2)] have been identified in the last decade and their expression is restricted to the steroidogenic glands (ovary, testis, adrenal gland and placenta). Their expression patterns also suggest a close relationship to early pregnancy. However, little information is available regarding the role of EG-VEGF and its receptors (PKR1 and PKR2) in recurrent pregnancy loss (RPL). This study was conducted to investigate the association between polymorphisms of EG-VEGF and its receptor genes (PKR1 and PKR2) and idiopathic RPL. METHODS In this case-control study, 115 women with a history of idiopathic RPL and 170 controls were included. A total of 11 tag single nucleotide polymorphisms (SNPs) selected from EG-VEGF, PKR1 and PKR2 were genotyped. We further used multifactor dimensionality reduction (MDR) analysis to choose a best model and evaluate gene-gene interactions. RESULTS Two tag SNPs of PKR1 (rs4627609, rs6731838) and one tag SNP of PKR2 (rs6053283) were significantly associated with idiopathic RPL (P < 0.05). The frequencies of haplotypes C-G and T-A of PKR1 and haplotype A-G-C-G-G of PKR2 were significantly increased in women with idiopathic RPL (P < 0.05); MDR tests revealed gene-gene interactions between three loci [EG-VEGF (rs7513898), PKR1(rs6731838), PKR2(rs6053283)] based on the association model (P = 0.008). The adjusted odds ratio of high- and low-risk genotype combinations in the three-locus model was 3.94 (95% confidence interval: 2.38-6.52). CONCLUSIONS EG-VEGF receptor (PKR1, PKR2) gene polymorphisms and haplotypes were associated with idiopathic RPL. These three genes (EG-VEGF, PKR1 and PRK2) jointly contribute to RPL in the Taiwanese Han population.

Impaired Flush Response to Niacin Skin Patch Among Schizophrenia Patients and Their Nonpsychotic Relatives: The Effect of Genetic Loading

We previously reported familial aggregation in flush response to niacin skin patch among schizophrenia patients and their nonpsychotic relatives. However, little is known about whether this abnormal skin response is associated with genetic loading for schizophrenia. This study compared the niacin flush response in subjects from families with only one member affected with schizophrenia (simplex families) with those from families having a sib-pair with schizophrenia (multiplex families). Subjects were patients with schizophrenia and their nonpsychotic first-degree relatives from simplex families (176 probands, 260 parents, and 80 siblings) and multiplex families (311 probands, 180 parents, and 52 siblings) as well as 94 healthy controls. Niacin patches of 3 concentrations (0.001M, 0.01M, and 0.1M) were applied to forearm skin, and the flush response was rated at 5, 10, and 15 minutes, respectively, with a 4-point scale. More attenuated flush response to topical niacin was shown in schizophrenia probands and their relatives from multiplex families than in their counterparts from simplex families, and the differentiation was better revealed using 0.1M concentration of niacin than 0.01M or 0.001M. For the highest concentration of 0.1M and the longest time lag of 15 minutes, a subgroup of probands (23%), parents (27%), and siblings (19%) still exhibited nonflush response. Flush response to niacin skin patch is more impaired in schizophrenia patients and their relatives from families with higher genetic loading for schizophrenia, and this finding has implications for future genetic dissection of schizophrenia.

Association of sex hormone receptor gene polymorphisms with recurrent pregnancy loss: a systematic review and meta-analysis

OBJECTIVE To investigate the genetic association between estrogen and progesterone receptor polymorphisms (ER, PR) and skewed X chromosome inactivation (XCI) and idiopathic recurrent pregnancy loss (RPL). DESIGN A systematic review and meta-analysis using electronic database (MEDLINE and EMBASE) up to April 2011. SETTING 24 eligible studies from 14 countries. PATIENT(S) 2,750 RPL patients and 3,123 controls were included. INTERVENTION(S) Meta-analyses by means of random-effects models. MAIN OUTCOME MEASUREMENT(S) Common polymorphisms of ER and PR and skewed XCI. RESULT(S) Of 221 potentially relevant studies, 24 case-control studies were included: 6 reports of PR polymorphisms (PROGINS), 6 reports of ER-α (3 each of rs2234693 [PvuII], rs9340799 [XbaI], and B domain) and 12 reports of skewed XCI. The integrated result showed that women with skewed XCI (>90%) had a higher risk for RPL (the summary OR [95% CI]: 2.43 [1.34-4.43]), and the subgroup analysis of those studies that included more than three consecutive miscarriages (5 studies), also showed a significant association with RPL (2.52 [1.16-5.44]). Among studies of PR (PROGINS) and ER (PuvII, XbaI, B domain) polymorphisms in RPL, the summary ORs were 1.46 (0.56-3.79), 0.90 (0.47-1.75), 0.83 (0.53-1.29), and 1.07 (0.43-2.63), respectively. CONCLUSION(S) Meta-analyses of the available data showed a significant association between skewed XCI and idiopathic RPL. More data on the associations between ER and PR polymorphisms and RPL would be helpful to elucidate their roles in RPL.

Overexpression of the RNA-binding proteins Lin28B and IGF2BP3 (IMP3) is associated with chemoresistance and poor disease outcome in ovarian cancer

Background:RNA-binding proteins have an important role in messenger RNA (mRNA) regulation during tumour development and carcinogenesis. In the present study, we examined the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; hereafter refered to as IMPs) and Lin28 family expressions in epithelial ovarian carcinoma (EOC) patients and correlated their expression levels with the response to chemotherapy, hCTR1 expression and patient survival.Methods:Patients clinical information, real-time RT-PCR, immunohistochemistry, western blot, Transwell migration invasion assays, and cytotoxicity assays were used.Results:From 140 EOC patients, high expression of IMP3 or Lin28B was associated with poor survival, and women diagnosed at advanced stages with elevated IMP3 and Lin28B were at higher risk of developing chemoresistance. High IMP3 levels combined with high Lin28B levels significantly correlated with the poorest 5-year survival rates. Knockdown of IMP3 or Lin28B decreased cell proliferation, migration, and invasion, and increased the platinum sensitivity, but not taxol sensitivity, of ovarian cancer cells through increased expression of hCTR1, a copper transporter involved in platinum uptake. High expression of hCTR1 correlated with low expression of IMP3/Lin28B and better progression-free survival in advanced-stage EOC patients.Conclusion:Testing for a combination of elevated IMP3 and Lin28B levels could further facilitate the identification of a patient subgroup with the worst prognosis.