Endothelial Nitric Oxide Synthase (eNOS) gene polymorphisms in spontaneously aborted embryos

Endothelium-derived nitric oxide (NO) is synthesized from L-arginine by endothelial nitric oxide synthase (eNOS) encoded by the eNOS gene on chromosome 7. The effects of the eNOS polymorphisms with the risk of spontaneous pregnancy losses are conflicting. In this study, we investigated the association of the eNOS genotypes with spontaneously aborted embryos in Koreans. Case-control studies were performed to evaluate the association between endothelial nitric oxide synthase (eNOS) gene polymorphisms and spontaneously aborted embryos. Ninety-nine spontaneously aborted fetuses at <20 weeks of gestational age and 103 child controls and 282 adult controls. Genotype frequency of three eNOS gene polymorphisms, ?786T>C, VNTR in intron 4 (4a4b), and 894G>T in spontaneously aborted embryos was surveyed. The frequencies of ?786TC and CC genotypes in aborted embryos were significantly higher than in both child and adult controls. The frequencies of 4a4a homozygote of VNTR polymorphism in intron 4 and TT homozygote of 894G>T polymorphisms were also higher in aborted embryos than in adult controls. Haploptype analysis suggested that ?786T>C polymorphism was a possible risk factor for spontaneously aborted embryos. eNOS gene polymorphisms, ?786T>C, VNTR in intron 4 (4a4b), and 894G>T, are associated with the risk of spontaneously aborted fetuses.     

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.     

Polymorphisms of folate metabolism-related genes and survival of patients with colorectal cancer in the Korean population

Background

5-Fluorouracil (5-FU) is a cornerstone of chemotherapy for colorectal cancer (CRC), and the major targets of 5-FU are thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), and reduced folate carrier 1 (RFC1). We hypothesized that polymorphisms in the genes encoding these proteins would be associated with CRC patient survival.

Patients and methods

We genotyped the following polymorphisms in 372 CRC patients: TS enhancer region (TSER), TS 1494del6, MTHFR 677C > T and 1298A > C, and RFC1 − 43T > C, 80G > A, and 696C > T. Using Kaplan–Meier curves, log-rank tests, and Cox proportional hazard models, we evaluated associations between these polymorphisms and overall survival (OS).

Results

The combined TS 1494 0bp6bp + 6bp6bp genotype was associated with reduced OS compared to the TS 1494 0bp0bp genotype. Among rectal cancer patients, the RFC1 − 43CC and 80AA genotypes were associated with favorable OS.

Conclusions

Our data suggest that TS and RFC1 polymorphisms are associated with CRC prognosis in Korean patients. Further studies are needed to verify these findings.     

Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation

BACKGROUND: The reduced folate carrier (RFC1) is a ubiquitously expressed integral membrane protein that mediates delivery of 5‐methyltetrahydrofolate into mammalian cells. In this study, embryonic/fetal development is characterized in an RFC1 knockout mouse model in which pregnant dams receive different levels of folate supplementation. METHODS: RFC1^+/? males were mated to RFC1^+/? females, and pregnant dams were treated with vehicle (control) or folic acid (25 or 50 mg/kg) by daily subcutaneous injection (0.1 mL/10 g bwt), beginning on E0.5 and continuing throughout gestation until the time of sacrifice. RESULTS: Without maternal folate supplementation, RFC1 nullizygous embryos die shortly postimplantation. Supplementation of pregnant dams with 25 mg/kg/day folic acid prolongs survival of mutant embryos until E9.5–E10.5, but they are developmentally delayed relative to wild‐type littermates, display a marked absence of erythropoiesis, severe neural tube and limb bud defects, and failure of chorioallantoic fusion. Fgfr2 protein levels are significantly reduced or absent in the extraembryonic membranes of RFC1 nullizygous embryos. Maternal folate supplementation with 50 mg/kg/day results in survival of 22% of RFC1 mutants to E18.5, but they develop with multiple malformations of the eyelids, lungs, heart, and skin. CONCLUSIONS: High doses of daily maternal folate supplementation during embryonic/fetal development are necessary for early postimplantation embryonic viability of RFC1 nullizygous embryos, and play a critical role in chorioallantoic fusion, erythropoiesis, and proper development of the neural tube, limbs, lungs, heart, and skin. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia

The objectives of this study were to identify tissue-specific differentially methylated regions (T-DMR’s) in the folate transport genes in placental tissue compared with leukocytes, and from placental tissues obtained from normal infants or with neural tube defects (NTDs). Using pyrosequencing, we developed methylation assays for the CpG islands (CGIs) and the CGI shore regions of the folate receptor α (FOLR1), proton-coupled folate transporter (PCFT) and reduced folate carrier 1 (RFC1) genes. The T-DMRs differed in location for each gene and the difference in methylation ranged between 2 and 54%. A higher T-DMR methylated fraction was associated with a lower mRNA level of the FOLR1 and RFC1 genes. Methylation fractions differed according to RFC1 80G > A genotype in the NTD cases and in leukocytes from subjects with high total plasma homocysteine (tHcy). There were no differences in methylated fraction of folate transporter genes between NTD cases and controls. We suggest that T-DMRs participate in the regulation of expression of the FOLR1 and RFC1 genes, that the RFC1 80G > A polymorphism exerts a gene-nutrition interaction on DNA methylation in the RFC1 gene, and that this interaction appears to be most prominent in NTD-affected births and in subjects with high tHcy concentrations.     

A novel mutation identified in PKHD1 by targeted exome sequencing: Guiding prenatal diagnosis for an ARPKD family

Autosomal recessive polycystic kidney disease (ARPKD) is a rare hereditary renal cystic disease involving multiple organs, mainly the kidney and liver. Parents who had an affected child with ARPKD are in strong demand for an early and reliable prenatal diagnosis to guide the future pregnancies. Here we provide an example of prenatal diagnosis of an ARPKD family where traditional antenatal ultrasound examinations failed to produce conclusive results till 26th week of gestation. Compound heterozygous mutations c.274C>T (p.Arg92Trp) and c.9059T>C (p.Leu3020Pro) were identified using targeted exome sequencing in the patient and confirmed by Sanger sequencing. Further, the mother and father were revealed to be carriers of heterozygous c.274C>T and c.9059T>C mutations, respectively. Molecular prenatal diagnosis was performed for the current pregnancy by direct sequencing plus linkage analysis. Two mutations identified in the patient were both found in the fetus. In conclusion, compound heterozygous PKHD1 mutations were elucidated to be the molecular basis of the patient with ARPKD. The newly identified c.9059T>C mutation in the patient expands mutation spectrum in PKHD1 gene. For those ultrasound failed to provide clear diagnosis, we propose the new prenatal diagnosis procedure: first, screening underlying mutations in PKHD1 gene in the proband by targeted exome sequencing; then detecting causative mutations by direct sequencing in the fetal DNA and confirming results by linkage analysis.     

Down-regulation of placental folate transporters in intrauterine growth restriction

Folate deficiency in pregnancy is associated with neural tube defects, restricted fetal growth and fetal programming of diseases later in life. Fetal folate availability is dependent on maternal folate levels and placental folate transport capacity, mediated by two key transporters, Folate Receptor-α and Reduced Folate Carrier (RFC). We tested the hypothesis that intrauterine growth restriction (IUGR) is associated with decreased folate transporter expression and activity in isolated syncytiotrophoblast microvillous plasma membranes (MVM). Women with pregnancies complicated by IUGR (birth weight <3rd percentile, mean birth weight 1804±110 g, gestational age 35.7±0.61 weeks, n=25) and women delivering an appropriately-for gestational age infant (control group, birth weight 25th–75th centile, mean birth weight 2493±216 g, gestational age 33.9±0.95 weeks, n=19) were recruited and placentas were collected at delivery. MVM was isolated and folate transporter protein expression was measured using Western blot and transporter activity was determined using radiolabelled methyltetrahydrofolic acid and rapid filtration. Whereas the expression of FR-α was unaffected, MVM RFC protein expression was significantly decreased in the IUGR group (−34%, P<.05). IUGR MVM had a significantly lower folate uptake compared to the control group (−38%, P<.05). In conclusion, placental folate transport capacity is decreased in IUGR, which may contribute to the restricted fetal growth and intrauterine programming of childhood and adult disease. These findings suggest that continuation of folate supplementation in the second and third trimester is of particular importance in pregnancies complicated by IUGR.     

Association between osteoporosis and polymorphisms of the bone Gla protein, estrogen receptor 1, collagen 1-A1 and calcitonin receptor genes in Turkish postmenopausal women

In this study, we have investigated the association between osteoporosis and osteocalcin (BGLAP) − 298 C>T, estrogen receptor 1 (ER1) 397 T>C, collagen type1 alpha 1 (Col1A1) 2046 G>T and calcitonin receptor (CALCR) 1340 T>C polymorphisms. Genomic DNA was obtained from 266 persons (158 osteoporotic and 108 healthy controls). Genomic DNA was extracted from EDTA-preserved peripheral venous blood of patients and controls by a salting-out method and analyzed by PCR-RFLP. As a result, there was no statistically significant difference in the genotype and allele frequencies of patients and controls for BGLAP − 298 C>T, Col1A1 2046 G>T, ER1 397 T>C and CALCR 1340 T>C polymorphisms. However, ER1 CC genotype compared with TT + TC genotypes was found to increase the two fold the risk of osteoporosis [p = 0.039, OR = 2.156, 95% CI (1.083–4.293)] and CALCR CC genotype compared with TT + TC genotypes was found to have protective effect against osteoporosis [p = 0.045, OR = 0.471, 95% CI (0.237–0.9372)]. In the combined genotype analysis, ER1/CALCR TCCC combined genotype was estimated to have protective effect against osteoporosis [p = 0.0125, OR = 0.323, 95% CI (0.1383–0.755)] whereas BGLAP/Col1A1 CCTT and ER1/CALCR CCTT combined genotypes were estimated as risk factors for osteoporosis in Turkish population (p = 0.027, p = 0.009 respectively).     

Genetic changes in human fetuses from spontaneous abortion after in vitro fertilization detected by comparative genomic hybridization

The in vitro fertilization (IVF) technique is becoming a very important approach for infertile disease therapy, but approximately 30% of pregnancies are spontaneously aborted in the first trimester. It is believed that chromosomal abnormality is the major reason for early spontaneous abortion. Although some reports have mentioned cytogenetic changes in spontaneously aborted embryos after IVF, little is known about the comprehensive cytogenetic alterations in these aborted embryos. Here we use the comparative genomic hybridization (CGH) technique to analyze the genetic alterations in 41 spontaneously aborted human specimens after IVF. In this study, 25 of 41 cases (61%) showed chromosomal changes. Among them, autosomes and sex chromosomes were involved in 16 and 11 cases, respectively. Several nonrandom chromosomal changes were identified, including loss of one sex chromosome (six cases) and gains of 22 (four cases), Y (four cases), 21 (three cases), 4 (two cases), and 13 (two cases). Our data support the opinion that chromosome abnormality is one of the major causes of early spontaneous abortion after IVF. The association between chromosome changes in these spontaneously aborted fetuses and maternal age, infertility patterns, infertility causes, and IVF patterns (routine IVF and other methods, including intracytoplasmic sperm injection, egg donation, and embryo donation) were also studied. No significant correlation was found.     

Polymorphisms of metal transporter genes DMT1 and ATP7A in Wilson's disease

Wilson's disease (WND) is an inherited disorder of copper metabolism. Divalent metal transporter1 (DMT1) and ATP7A play important roles in metal transport in humans. The frequency of two single nucleotide polymorphisms of the DMT1 gene: DMT1 IVS4 C>A, DMT1 11245 T>C and two of the ATP7A gene: rs1062472 T>C, ATP7A rs 2227291 G>C have been evaluated in a population of 108 Wilson's disease patients and 108 sex- and age-matched healthy volunteers. The DMT1 IVS4 C(+) allele occurred more frequently in WND than in the healthy controls. The allele frequencies of other studied polymorphisms in WND group were in line with frequencies obtained for healthy volunteers. Neither of the polymorphisms had an impact on the age at onset or clinical phenotype of WND.     

Analysis of functional consequences of haplogroup J polymorphisms m.4216T > C and m.3866T > C in human MT-ND1: Mutagenesis of homologous positions in Escherichia coli

MtDNA sequence variation is presumed to be neutral in effect, but associations with diseases and mtDNA haplogroups have been reported. The aim here was to evaluate the functional consequences of m.4216T > C present in haplogroup J. Furthermore, we evaluated m.3866T > C in MT-ND1, a variant detected in a child belonging to haplogroup J and with an isolated complex I deficiency. Homologous substitutions were introduced into Escherichia coli. NADH dehydrogenase domain activity of NDH-1 with either one or both mutations was markedly decreased suggesting that m.4216T > C and m.3866T > C may have an effect on the structural integrity of complex I.     

Genetic polymorphisms in the CYP1A1 and CYP1B1 genes and susceptibility to bladder cancer: a meta-analysis

The current meta-analysis of case–control studies was conducted to evaluated the relationships of genetic polymorphisms in the CYP1A1 and CYP1B1 genes with the susceptibility to bladder cancer, aiming at determine whether these polymorphisms may contribute to the pathogenesis of bladder cancer. Related articles were determined via searching the following electronic databases without any language restrictions: PubMed, CISCOM, CINAHL, Web of Science, Google Scholar, EBSCO, Cochrane Library, and CBM databases for relevant articles published before November 1st, 2013. STATA 12.0 software was also selected to deal with statistical data. The relationships were evaluated using the pooled odds ratios (ORs) and their 95 % confidence intervals (CI). Eleven case–control studies with a total of 2,609 bladder cancer patients and 2,634 healthy subjects met the inclusion criteria. The results of our meta-analysis demonstrated that CYP1A1 genetic polymorphisms were associated with increased risks of bladder cancer (allele model: RR = 1.18, 95 % CI 1.07–1.30, P = 0.001; dominant model: RR = 1.15, 95 % CI 1.05–1.27, P = 0.003; respectively), especially among 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms. A subgroup analysis by ethnicity was conducted to investigate its effect on susceptibility to bladder cancer. The subgroup analysis results revealed positive significant correlations between CYP1A1 genetic polymorphisms and bladder cancer risk among Asians (allele model: RR = 1.26, 95 % CI 1.10–1.44, P = 0.001; dominant model: RR = 1.22, 95 % CI 1.08–1.38, P = 0.001), but not among Caucasians (all P < 0.05). Nevertheless, we observed no significant correlations between CYP1B1 genetic polymorphisms and bladder cancer risk (all P > 0.05). Our meta-analysis indicates that CYP1A1 genetic polymorphisms may be involved in the pathogenesis of bladder cancer, especially among 11599G>C, 2455A>G, 3810T>C, and 113T>C polymorphisms. However, CYP1B1 genetic polymorphisms may not be important determinants of bladder cancer susceptibility.     

Genetic variants in transforming growth factor-β gene (TGFB1) affect susceptibility to schizophrenia

Immense body of evidence indicates that dysfunction of immune system is implicated in the etiology of schizophrenia. The immune theory of schizophrenia is supported by alterations in cytokine profile in the brain and peripheral blood. Given the strong genetic background of schizophrenia, it might be assumed that aberrant production of cytokines might be the consequence of genetic factors. This study aimed at investigating the association between schizophrenia susceptibility and selected functional polymorphisms in genes encoding cytokines including: interleukin-2 (IL2 ?330T>G, rs2069756), interleukin-6 (IL-6 ?174G>C, rs1800795), interferon-γ (IFNG +874T>A, rs2430561) as well as for the first time transforming growth factor-β1 (TGFB1 +869T>C, rs1800470 and +916G>C, rs1800471). We recruited 151 subjects with schizophrenia and 279 controls. There was a significant difference in the genotype distribution and allelic frequency of the TGFB1 +869T>C between patients with schizophrenia and healthy controls (p < 0.05). The risk of schizophrenia was more than two-fold higher in carriers of T allele (CT+TT genotypes) than individuals with CC genotype. Given documented gender differences in incidence of schizophrenia, we conducted separate analyses of male and female participants. We have shown that the association was significant in females, while in males it reached a trend toward statistical significance. To the best of our knowledge, it is the first report showing the association between TGFB1 +869T>C polymorphism and schizophrenia.     

The SLC19A1 80G>A polymorphism is not associated with male infertility

Previous studies have revealed that genetic factors may be involved in regulating folate turnover, e.g. methylenetetrahydrofolate reductase polymorphism in the development of male infertility. Folate transporter, encoded by the SLC19A1 gene, commonly referred to as reduced folate carrier (RFC) is a transmembrane protein, which transfers hydrophilic folates across the cell membrane. It was hypothesized that common polymorphism within the SLC19A1 gene (rs1051266:G>A, 80G>A) may alter RFC function. The aim of this study was to investigate a potential association between the SLC19A1 80G>A polymorphism and male infertility in a case–control study. The SLC19A1 80G>A polymorphism was determined by means of a polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay in 213 infertile Caucasian men and 226 ethnically matched controls. The distribution of SLC19A1 genotypes in the infertile men was as follows: GG 26.8%, GA 51.2%, AA 22.1% and in fertile men: GG 24.8%, GA 50.4%, AA 24.8%, and was comparable in the both the evaluated groups. Odds ratios (95% confidence interval, CI): 0.90 (0.59–1.38) and 0.88 (0.56–1.36) for dominant and recessive models remained non-significant, also after adjustment for age: 0.89 (0.57–1.37) and 0.80 (0.51–1.25), respectively. Our study demonstrated that polymorphism 80G>A of the SLC19A1 gene is not associated with male infertility.     

Detection of exonic variants within the melanocortin 1 receptor (MC1R) gene in Black Silky,White Leghorn and Golden duckwing Araucana chicken

The melanocortin 1 receptor (MC1R) gene can be considered a candidate functional gene for the pigmentation of plumage color. The aim of this study was to investigate the association between the genotype frequencies of g.69 T>C, g.376 G>A and g.427 A>G SNPs within the MC1R gene in Black silky (O), Golden duckwing Araucana (GA) and White Leghorn (W). The CC and AA genotype frequencies of g.69 T>C and g.427 A>G SNPs in White Leghorn (W) were both 1.000, and the TT genotype frequency of the g.69 T>C SNP in Golden duckwing Araucana (GA) was also 1.000. The GG and AA genotype frequencies of g.376 G>A and g.427 A>G SNPs in Black silky (O) were both 0.100. When a haplotype is observed using a combination of markers, a Golden duckwing Araucana (GA) can especially be distinguished when it is a TAG, TGG and TAA type in the SNP combination of the MC1R gene. In case of the CAA types, only White Leghorn (W) could specifically be distinguished. Therefore, three SNPs in MC1R may provide identification in chicken breeds.     

Association study of microRNA polymorphisms with risk of idiopathic recurrent spontaneous abortion in Korean women

Aim

The aim of this study was to investigate the association of microRNA polymorphisms (miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G) in Korean patients with recurrent spontaneous abortion (RSA).

Methods

We conducted a case-control study of 564 Korean women: 330 patients with at least two unexplained consecutive pregnancy losses and 234 healthy controls with at least one live birth and no history of pregnancy loss.

Results

RSA patients exhibited significantly different frequencies of the miR-196a2CC (TT+TC vs. CC; adjusted odds ratio [AOR], 1.587; 95% confidence interval [CI], 1.042-2.417) and miR-499AG+GG genotypes (AOR, 1.671; 95% CI, 1.054-2.651) compared with the control group. The combination of miR-196a2CC and miR-499AG+GG showed synergistic effects (AOR, 3.541; 95% CI, 1.645-7.624).

Conclusion

miR-196a2CC, miR-499AG+GG, and the miR-196a2CC/miR-499AG+GG combination are significantly associated with idiopathic RSA in Korean women.     

Association analysis of v-AKT murine thymoma viral oncogene homolog 1 (AKT1) polymorphisms and type 2 diabetes mellitus in the Korean population

V-AKT murine thymoma viral oncogene homolog 1 (AKT1) is an important downstream target of the insulin-signaling pathway and may be an important regulator of pancreatic beta cell growth. This study investigated the association of theAKT1 gene with susceptibility to type 2 diabetes mellitus and its related traits. By sequencing theAKT1 gene in 24 unrelated individuals, we iden-tified 32 genetic variations including 30 single nucleotide polymorphisms and 2 deletions. For the association analysis, we selected seven single nucleotide polymorphisms (rs10138227, ?726G>A; rs3730358, +12574C>T; rs2494737, +12656T>A; rs2498796, +15761T>C; rs2498799, +19087 A>G; rs2494732, +19789G>A; rs3803304, +19835G>C) based on minor allele frequency (>0.05) and linkage disequilibrium status. The study included 483 type 2 diabetes patients (206 men and 277 women with mean age 64±2.8 years and mean age at onset 56 ± 8.1 years) and 1,138 non-diabetic control subjects (516 men and 622 women with mean age 64 ±2.9 years). Two single nucleotide polymorphisms (rs2498796, +15761T>C and rs2494732, +19789G>A) were found to be associated with risk of type 2 diabetes mellitus, and showed an increased risk of type 2 diabetes mellitus in a recessive model (OR=1.343, 95% CI 1.021–1.765,p=0.035 and OR=1.534, 95% CI 1.058–2.225,p=0.024, respectively). These SNPs were also associated with diabetes-related traits such as levels of fasting blood glucose and hemoglobin A1c. In addition, type 2 diabetes mellitus patients who also have dyslipidemia or high blood pressure showed significant association with single nucleotide polymorphisms in AKT1 when compared with healthy controls. These results indicate that genetic variation in AKT1 influences the development of type 2 diabetes mellitus in the Korean population.     

IL-1RN +2018T>C polymorphism is correlated with colorectal cancer

Epidemiological and experimental evidence indicates chronic inflammation as a risk factor for colorectal cancer. We investigated whether IL-1B ?511C>T (rs16944), IL-1B +3954C>T (rs1143634) and IL1-RN +2018T>C (rs419598) cytokine polymorphisms are correlated with colorectal cancer. Blood samples were obtained from 377 Romanian subjects: 144 patients with sporadic colorectal cancer and 233 healthy controls. Polymorphisms were analyzed by allelic discrimination TaqMan PCR assays with specific probes. The results of our study showed that IL-1RN +2018T>C polymorphism is associated with colorectal cancer. We found that there was a significant difference in the frequency of CC genotype between patients with colorectal cancer and the control group (OR 2.42, 95 % CI: 1.06–5.53, p = 0,034) when TT genotype was used as reference. Furthermore, in a stratified analysis, a positive association was found only for IL-1RN +2018CC genotype, that was limited to early I and II stages (OR 2.72, 95 % CI: 1.05–7.03, p = 0,033). We did not find any association between any of the IL-1B polymorphisms and colorectal cancer. In conclusion this study found that IL-1RN +2018T>C polymorphism is associated with colorectal cancer, mainly for localized disease.     

Impact of Single Nucleotide Polymorphisms of Base Excision Repair Genes on DNA Damage and Efficiency of DNA Repair in Recurrent Depression Disorder

Elevated level of DNA damage was observed in patients with depression. Furthermore, single nucleotide polymorphisms (SNPs) of base excision repair (BER) genes may modulate the risk of this disease. Therefore, the aim of this study was to delineate the association between DNA damage, DNA repair, the presence of polymorphic variants of BER genes, and occurrence of depression. The study was conducted on peripheral blood mononuclear cells of 43 patients diagnosed with depression and 59 controls without mental disorders. Comet assay was used to assess endogenous (oxidative) DNA damage and efficiency of DNA damage repair (DRE). TaqMan probes were employed to genotype 12 SNPs of BER genes. Endogenous DNA damage was higher in the patients than in the controls, but none of the SNPs affected its levels. DRE was significantly higher in the controls and was modulated by BER SNPs, particularly by c.977C>G–hOGG1, c.972G>C–MUTYH, c.2285T>C–PARP1, c.580C>T–XRCC1, c.1196A>G–XRCC1, c.444T>G–APEX1, c.-468T>G–APEX1, or c.*50C>T–LIG3. Our study suggests that both oxidative stress and disorders in DNA damage repair mechanisms contribute to elevated levels of DNA lesions observed in depression. Lower DRE can be partly attributed to the presence of specific SNP variants.     

Apolipoprotein A5 polymorphisms in Turkish population: association with serum lipid profile and risk of ischemic stroke

Atherosclerosis, a major cause of ischemic stroke, may be associated with variability of triglyceride (TG) levels. Apolipoprotein A5 (APOA5) genetic polymorphisms are associated with altered TG levels. The objective of this study was to investigate the coding region polymorphisms S19W (rs3135506) and G185C (rs2075291) and the promoter region polymorphism ?1131T>C (rs662799) of the APOA5 gene as risk factors for ischemic stroke in Turkish population. Study group consisted of 272 ischemic stroke patients and 123 controls. Genotypes were determined by real-time polymerase chain reaction (PCR) for S19W and PCR-restriction fragment length polymorphism analysis (PCR–RFLP) for ?1131T>C and G185C. 19W allele frequency was 0.090 in stroke patients and 0.062 in controls (P = 0.191). Minor allele frequencies of ?1131T>C and G185C in patients were 0.106 and 0.004, respectively, and were nearly the same in controls. Total cholesterol and LDL-cholesterol levels were significantly higher for stroke patients having at least one 19W allele compared to non-carriers. A significant difference was also found for LDL-cholesterol levels of stroke patients; higher in ?1131C allele carriers compared to wild type patients. There was a trend for higher frequency of ischemic stroke among ?1131C allele carrier hypertensive, diabetic or obese subjects compared to non-carriers. However, APOA5 genotypes were not associated with the risk of ischemic stroke by logistic regression analysis. The present study demonstrated that carrying rare alleles of APOA5 S19W, ?1131T>C and G185C alone do not constitute a risk for ischemic stroke in the studied Turkish subjects.