Fabiana Michelsen de Andrade

Association between APOC1 Polymorphism and Alzheimer’s Disease: A Case-Control Study and Meta-Analysis

Background Previous association studies examining the relationship between the APOC1 polymorphism and susceptibility to Alzheimer’s disease (AD) have shown conflicting results, and it is not clear if an APOC1 variant acts as a genetic risk factor in AD etiology across multiple populations. Methods To confirm the risk association between APOC1 and AD, we designed a case-control study and also performed a meta-analysis of previously published studies. Results Seventy-nine patients with AD and one hundred fifty-six unrelated controls were included in case-control study. No association was found between the variation of APOC1 and AD in stage 1 of our study. However, our meta-analysis pooled a total of 2092 AD patients and 2685 controls. The APOC1 rs11568822 polymorphism was associated with increased AD risk in Caucasians, Asians and Caribbean Hispanics, but not in African Americans. APOE ε4 carriers harboring the APOC1 insertion allele, were more prevalent in AD patients than controls (χ2 = 119.46, OR = 2.79, 95% CI = 2.31–3.36, P<0.01). Conclusions The APOC1 insertion allele, in combination with APOE ε4, likely serves as a potential risk factor for developing AD.

Interação entre qualidade do meio ambiente, estresse e a variação do gene APOE na determinação da suscetibilidade à fibromialgia

INTRODUCAO: A fibromialgia se trata de uma desordem multifatorial, cuja etiologia reside na interacao entre a susceptibilidade genetica e o ambiente. No entanto, poucos trabalhos procuram detectar quais seriam os fatores considerados de risco. OBJETIVO: Investigar a influencia genetica e sua interacao com qualidade ambiental e com estresse como possiveis fatores de risco para o desenvolvimento da fibromialgia. PACIENTES E METODOS: Neste estudo transversal, foram investigados dois grupos de mulheres, sendo 47 com diagnostico clinico de fibromialgia, e 41 mulheres do grupo controle, todas da comunidade de Novo Hamburgo, RS. O polimorfismo do gene da apolipoproteina E (APOE) foi analisado, a partir do DNA extraido do sangue total de ambas as amostras. Os fatores ambientais foram avaliados atraves do inventario de sintomas para adultos de Lipp (ISSL), para a averiguacao do estresse comportamental, e da aplicacao do dominio V do WHOQOL-100. RESULTADOS: Dentre as pacientes, foram encontradas mais mulheres com niveis altos de estresse, quando comparado a amostra controle (P < 0,001); alem disto, os escores medios do dominio V do WHOQOL-100, que avalia qualidade do meio ambiente, foram inferiores neste grupo (P < 0,001). As frequencias genotipicas e alelicas do gene APOE foram similares entre os dois grupos. A analise multivariada demonstrou que baixos escores do WHOQOL-100, aumentaram a chance de desenvolvimento da doenca em 57,7 vezes (P < 0,001), e que altos niveis de estresse foram significativamente relacionados com a doenca (OR = 197,2; P < 0,001). Essa abordagem apontou para uma interacao entre estresse e a presenca do alelo E*2 (P = 0,028). A doenca foi muito mais frequente em pacientes com altos niveis de estresse que nao eram portadoras do alelo E*2 (OR estimado = 265,1), quando comparada a pacientes com o mesmo nivel de estresse e portadoras do alelo E*2 (OR estimado = 1,06). CONCLUSAO: A presenca do alelo E*2 pode indicar possivel acao protetora para a relacao entre fibromialgia e estresseINTRODUCTION Fibromyalgia is a multifactorial disease, of which etiology is based on interaction between genetic susceptibility and environment. However, few studies attempted to identify the risk factors. OBJECTIVE To investigate the genetic influence and its interaction with environmental quality and stress, as possible risk factors for fibromyalgia development. PATIENTS AND METHODS This cross-sectional study investigated two groups of women, of which 47 had a clinical diagnosis of fibromyalgia, and 41 women comprising thre control group, all from the town of Novo Hamburgo, RS. The apolipoprotein E (APOE) gene polymorphism was analyzed in DNA extracted from total blood, in both samples. Environmental factors were studied through Lipps Inventory of Stress Symptoms for Adults and by applying the WHOQOL-100 domain V. RESULTS Among the patients, more women had high stress levels when compared to the control sample (P < 0.001); moreover, the average scores of the WHOQOL-100 domain V, which analyze environment quality, were lower in this group (P < 0.001). APOE genotypic and allelic frequencies were similar between the two groups. Multivariate analysis showed that low WHOQOL-100 scores increase the chance of disease development by 57.7 times (P < 0.001), and that high stress levels were related with the disease (OR = 197.2; P < 0.001). This approach pointed out an interaction between stress and presence of E*2 allele (P = 0.028). Fibromyalgia was much more frequent in patients with high stress levels that were E*2 non-carriers (estimated OR = 265.1), when compared to patients with the same stress level, but E*2 carriers (estimated OR = 1.06). CONCLUSION E*2 allele presence could have a protective action regarding the association between fibromyalgia and stress.

DNA methyltransferase haplotype is associated with Alzheimer's disease.

Epigenetic mechanisms have been implicated in syndromes associated with neuropsychiatric disorders, but little is known about the role of epigenetics in Alzheimers disease (AD). DNA methylation, one of the main epigenetic mechanisms, is a complex process carried out by specific enzymes, such as DNMT1 and DNMT3B. This study aimed to investigate the association between DNMT1 and DNMT3B polymorphisms and AD. Two hundred and ten elderly subjects (108 healthy controls and 102 with AD-NINCDS/ARDA, DSM-IV-TR criteria) were assessed. DNA was obtained from whole blood, and genotypes were detected by an allelic discrimination assay using TaqMan(®) MGB probes on a real-time PCR system. The polymorphisms studied were rs2162560, rs759920 (DNMT1) and rs998382, rs2424913, rs2424932 (DNMT3B). For both genes, the polymorphisms were in strong linkage disequilibrium. Carriers of the DNMT3B TGG haplotype were associated with AD (OR=3.03, 95% CI 1.63 to 5.63, P<0.001). No significant difference between AD and the control group were observed for DNMT1 polymorphisms. This study is one of the first describing a significant association between DNMT3B polymorphisms and AD. This enzyme, which is responsible for methylation in a general way, may be involved in AD.

Genomic instability in patients with type 2 diabetes mellitus on hemodialysis

Objective A previous study by our research group evaluated the levels of DNA damage using the comet assay in hemodialysis patients with type 2 diabetes mellitus. The same blood samples were also evaluated using the cytochalasin B micronucleus assay. A comparison of the results of the two assays is presented here. Methods Whole blood samples were collected from 22 type 2 diabetes mellitus patients on hemodialysis and from 22 control subjects. Samples were collected from patients early in the morning on Mondays, before the first weekly hemodialysis session. The cytokinesis-block micronucleus assay (CBMN) was used to evaluate genomic instability. Results The frequencies of micronuclei and nuclear buds were higher in patients than in controls (p-value = 0.001 and p-value < 0.001, respectively). There was a correlation between the frequency of micronuclei and DNA damage with the results of the comet assay (p-value < 0.001). The difference in the frequency of micronuclei and nuclear buds between patients and controls was more pronounced in the group with higher median comet values than in the group with lower comet values. Conclusion Our results suggest that the increased rates of DNA damage as measured by the comet assay and influenced by the weekly routine therapy of these patients has a mutagenic effect, thereby increasing the risk of cancer in this group.

SLC30A3 and SEP15 gene polymorphisms influence the serum concentrations of zinc and selenium in mature adults

Because of their numerous roles in several biological processes, zinc and selenium are the most commonly studied micronutrients in the elderly. Therefore, we hypothesized that the polymorphisms in the genes that are responsible for the transport of zinc and selenium may have a genotype-dependent effect on the serum concentration of these micronutrients. The objective of this study was to determine the effects of solute carrier family 30 member 3 (SLC30A3) and 15-kd selenoprotein (SEP15) polymorphisms on zinc and selenium concentrations, respectively, in the serum. This cross-sectional study included 110 individuals who were aged 50 years or older. Serum micronutrient concentrations were determined by flame atomic absorption spectrophotometry (for zinc) and by atomic absorption spectrophotometry with a graphite furnace (for selenium). The single-nucleotide polymorphisms, rs73924411 and rs11126936 of the SLC30A3 gene and rs5859, rs5854, and rs561104 of the SEP15 gene, were examined by real-time polymerase chain reaction. Regarding rs11126936, the serum zinc concentration was lower in CC homozygotes (0.75 ± 0.31 mg/L) than in A carriers (0.89 ± 0.28 mg/L, P = .016). Concerning rs561104, the serum selenium concentration was higher in CC homozygotes (5.65 ± 1.11 μg/dL) compared with T carriers (4.88 ± 1.25 μg/dL, P = .044). Our results demonstrate the influence of SLC30A3 and SEP15 gene polymorphisms on the serum concentrations of zinc and selenium, respectively. The effects of these associations should be further investigated to help elucidate the modes of action of trace elements and to identify biomarkers, which could ultimately define the optimal intake of these micronutrients at the molecular level. More research must be performed before the roles of these polymorphisms in the serum concentrations of zinc and selenium can be fully understood.

Genomic instability in human lymphocytes from male users of crack cocaine

Recent research suggests that crack cocaine use alters systemic biochemical markers, like oxidative damage and inflammation markers, but very few studies have assessed the potential effects of crack cocaine at the cellular level. We assessed genome instability by means of the comet assay and the cytokinesis-block micronucleus technique in crack cocaine users at the time of admission to a rehabilitation clinic and at two times after the beginning of withdrawal. Thirty one active users of crack cocaine and forty control subjects were evaluated. Comparison between controls and crack cocaine users at the first analysis showed significant differences in the rates of DNA damage (p = 0.037). The frequency of micronuclei (MN) (p < 0.001) and nuclear buds (NBUDs) (p < 0.001) was increased, but not the frequency of nucleoplasmic bridges (NPBs) (p = 0.089). DNA damage decreased only after the end of treatment (p < 0.001). Micronuclei frequency did not decrease after treatment, and nuclear buds increased substantially. The results of this study reveal the genotoxic and mutagenic effects of crack cocaine use in human lymphocytes and pave the way for further research on cellular responses and the possible consequences of DNA damage, such as induction of irreversible neurological disease and cancer.

The lactase persistence genotype is a protective factor for the metabolic syndrome

The Metabolic Syndrome (MetS) is defined as a pattern of metabolic disturbances, which include central obesity, insulin resistance and hyperglycemia, dyslipidemia, and hypertension. Milk has been promoted as a healthy beverage that can improve the management of MetS. Most human adults, however, down-regulate the production of intestinal lactase after weaning. Lactase encoded by the LCT gene is necessary for lactose digestion. The -13910C > T SNP (rs4988235) is responsible for the lactase persistence phenotype in European populations. We herein investigated whether the lactase persistence genotype is also associated with the MetS in subjects from a Brazilian population of European descent. This study consisted of 334 individuals (average age of 41 years) genotyped by PCR-based methods for the -13910C > T SNP. Clinical data were assessed and the genotypes were tested for their independent contribution to the MetS using chi-square tests and multiple logistic regression analysis. Univariate analyses showed that hypertension and MetS prevalence were higher in individuals with the lactase non-persistence genotype than in lactase persistence subjects. Furthermore, lactase persistence was associated with a lower risk for MetS (OR = 0.467; 95% CI 0.264–0.824; p = 0.009). These results suggest that LCT genotypes can be a valuable tool for the management of MetS treatment.

Sintomas respiratórios em trabalhadores de carvoarias nos municípios de Lindolfo Collor, Ivoti e Presidente Lucena, RS

OBJECTIVE To determine the prevalence of respiratory symptoms and smoking, as well as pulmonary function parameters among charcoal production workers in three cities in southern Brazil. METHODS This was an observational study including 67 individuals. Data were obtained by means of interviews and spirometry. RESULTS Of the 67 workers, 50 (75.0%) were male; mean age, 46.52 +/- 13.25 years; mean BMI, 25.7 +/- 3.85 kg/m(2); FEV1, 3.24 +/- 0.82 L (93.2 +/- 16.0% of predicted); FVC, 4.02 +/- 0.92 L (95.5 +/- 14.3% of predicted); and FEV1/FVC, 80.31 +/- 9.82. The most common upper airway symptoms were sneezing and nasal secretion-in 24 workers (35.82%)-whereas the most common lower airway symptom was cough-in 15 (22.38%).Of the 67 workers, 21 (31.34%) were smokers. In comparison with the nonsmokers, the smokers more often presented with cough (OR = 5.00; p = 0.01), nasal obstruction (OR = 3.50; p = 0.03), nasal itching (OR = 8.80; p = 0.01) and wheezing (OR = 10.0; p = 0.03), as well as presenting with lower FEV1 values (2.93 +/- 0.80 vs. 3.38 +/- 0.80 L; p = 0.04). We detected occupational rhinitis in 14 workers (20.85%), asthma in 4 (5.97%) and COPD in 4 (5.97%). CONCLUSIONS Respiratory symptoms and airflow reduction were more common in the smoking workers. Controlling the progression of the pyrolysis did not increase the prevalence of respiratory symptoms in the charcoal production workers studied.

The influence on DNA damage of glycaemic parameters, oral antidiabetic drugs and polymorphisms of genes involved in the DNA repair system

The hyperglycaemia seen in type 2 diabetes mellitus (DM2) is associated with increased oxidative stress and production of reactive oxygen species, both of which are factors that can provoke DNA damage. Notwithstanding, other factors, including medications and individual susceptibility, can also induce this type of DNA lesion. The objective of this study was, therefore, to investigate the influence of glycaemic control, oral antidiabetic drugs (metformin and glibenclamide) and polymorphisms of the XRCC1 and XRCC3 genes on the frequency of DNA damage in DM2 patients, which was accessed by the cytokinesis-block micronucleus cytome and the comet assays on the ex vivo mitogenically stimulated lymphocytes. The 53 people recruited to take part in the study were already on treatment with metformin and were followed for 5 months. Ten of these patients were put on combined treatment with the addition of glibenclamide. It was observed that the greater the plasma metformin concentration, the lower the frequency of micronuclei (MN) in the sample total (P = 0.009) and also that the subset of patients using combined treatment including glibenclamide had a significantly higher MN rate 90 days after starting combined treatment (P = 0.024). In the subset who only took metformin, the rate of MN was significantly higher among carriers of the 399Gln allele on the XRCC1 gene (P = 0.008). In addition, homozygotes for the 241Thr allele exhibited a significant increase in MN in the combined treatment group (P = 0.008). Our results suggest that different combinations of oral antidiabetic drugs and polymorphisms on genes involved in the DNA damage repair system could influence the frequency of this type of chromosome lesion, which can be a useful biomarker for assessing the risk of developing cancer.

Influence of genetic combinations on HDL-C levels in a Southern Brazilian population

BACKGROUND low HDL-C levels are important predictors of coronary disease, the first cause of death worldwide. Many factors affect HDL-C levels, such as polymorphisms of genes encoding for key proteins of the reverse cholesterol transport pathway. OBJECTIVE to investigate the influence of seven polymorphisms of the CETP, APOA1, ABCA1 and SCARB1 genes on HDL-C levels in a southern Brazilian population. METHODS the polymorphisms were investigated in a sample of 500 individuals of European descent, but HDL-C levels from only 360 individuals were adjusted for cofactors using multiple linear regressions in the association study. The sample was divided in tertiles according to adjusted HDL-C levels, and allele and haplotype frequencies were compared between the 1st and 3rd tertiles of adjusted HDL-C levels. RESULTS When combinations of risk alleles were tested, the frequency of allele combinations in three genes (haplotype 1 of APOA1 gene, variant 2S of SCARB1 gene, and allele B1 of CETP gene) was significantly higher in the lower tertile of adjusted HDL-C (28.3%) than in the upper tertile (14.9%; p=0.008), which indicated that the presence of these variants increased 2.26 times the chances of having HDL-C levels below 39.8 mg/dl. CONCLUSION these markers, when studied separately, are expected to have a small influence on the characteristic under analysis, but greater influence was detected when the markers were studied in combination. In a population of southern Brazilians, our data showed a significant influence of variant combinations of APOA1, SCARB1 and CETP genes on HDL-c levels.FUNDAMENTO: Baixos niveis de HDL-c sao importantes preditores de doenca coronariana, a primeira causa de morte no mundo todo. Muitos fatores afetam os niveis de HDL-c, tais como os polimorfismos de genes que codificam proteinas-chave para a via de transporte reverso de colesterol. OBJETIVO: Investigar a influencia de sete polimorfismos dos genes CETP, APOA1, ABCA1 e SCARB1 genes nos niveis de HDL-c em uma populacao da regiao sul do Brasil. METODOS: Os polimorfismos foram investigados em uma amostra de 500 individuos de descendencia europeia, mas os niveis de HDL-c de somente 360 individuos foram ajustados para cofatores usando regressao linear multipla no estudo de associacao. A amostra foi dividida em tercis de acordo com os niveis ajustados de HDL-c e frequencias de alelos e haplotipos foram comparadas entre o 1o e o 3o tercis dos niveis ajustados de HDL-c. RESULTADOS: Quando as combinacoes dos alelos de risco foram testadas, a frequencia de combinacoes alelicas em tres genes (haplotipo 1 do gene APOA1, variante 2S do gene SCARB1, e alelo B1 do gene CETP) foi significantemente mais alta no tercil inferior dos niveis ajustados de HDL-c (28,3%) do que no tercil superior (14,9%; p=0,008), o que indica que a presenca dessas variantes aumentou 2,26 vezes a chance de ter niveis de HDL-C < 39,8 mg/dl. CONCLUSAO: Espera-se que esses marcadores, quando estudados separadamente, tenham uma pequena influencia na caracteristica que esta sendo analisada, mas uma influencia maior foi detectada quando os marcadores foram estudados em combinacao. Em uma populacao da regiao sul do Brasil, nossos dados mostraram uma influencia significante das combinacoes das variantes dos genes APOA1, SCARB1 e CETP nos niveis de HDL-c.