Hipometilação do LINE-1 está Associada ao Risco de Doença Cardíaca Coronariana na População Chinesa / LINE-1 Hypomethylation is Associated with the Risk of Coronary Heart Disease in Chinese Population

Fundamentos: O nível de metilação global do ADN de leucócitos no sangue tem sido associado ao risco de doença arterial coronariana (DAC), com resultados inconsistentes em diferentes populações. Faltam dados semelhantes da população chinesa, onde diferentes fatores genéticos, de estilo de vida e ambientais podem afetar a metilação do ADN e sua relação com o risco de DCC. Objetivos: Analisar se a metilação global está associada ao risco de doença coronariana na população chinesa. Métodos: Foram incluídos um total de 334 casos de DCC e 788 controles saudáveis. A metilação global do ADN de leucócitos de sangue foi estimada por meio da análise das repetições do LINE-1 usando pirosequenciamento de bissulfito. Resultados: Em uma análise inicial restrita aos controles o nível do LINE-1 diminui significativamente com a idade avançada, colesterol total elevado, e diagnóstico de diabetes. Na análise de caso-controle, a redução da metilação do LINE-1 foi associada ao aumento do risco de DCC, tendo a análise por quartil revelado uma odds ratio (IC 95%) de 0,9 (0,6-1,4), 1,9 (1,3-2,9) e 2,3 (1,6 3.5) para o terceiro, segundo e primeiro (o mais baixo) quartil (P da tendência < 0,001), respectivamente, em comparação com o quarto (o mais alto) quartil. A metilação inferior (< mediana) do LINE-1 esteve associada a 2,2 vezes (IC 95% = 1,7-3,0) o aumento de risco de doença coronariana. As estimativas de risco de DCC menores relacionadas com o LINE-1 tenderam a ser mais fortes entre os indivíduos com maior tercil de homocisteína (P interação = 0,042) e naqueles com diagnóstico de hipertensão arterial (P interação = 0,012). Conclusão: A hipometilação do LINE-1 está ...

Background: Global methylation level in blood leukocyte DNA has been associated with the risk of coronary heart disease (CHD), with inconsistent results in various populations. Similar data are lacking in Chinese population where different genetic, lifestyle and environmental factors may affect DNA methylation and its risk relationship with CHD. Objectives: To examine whether global methylation is associated with the risk of CHD in Chinese population. Methods: A total of 334 cases with CHD and 788 healthy controls were included. Global methylation in blood leukocyte DNA was estimated by analyzing LINE-1 repeats using bisulfite pyrosequencing. Results: In an initial analysis restricted to control subjects, LINE-1 level reduced significantly with aging, elevated total cholesterol, and diagnosis of diabetes. In the case-control analysis, reduced LINE-1 methylation was associated with increased risk of CHD; analysis by quartile revealed odds ratios (95%CI) of 0.9 (0.6-1.4), 1.9 (1.3-2.9) and 2.3 (1.6-3.5) for the third, second and first (lowest) quartile (Ptrend < 0.001), respectively, compared to the fourth (highest) quartile. Lower (<median) LINE-1 methylation was associated with a 2.2-fold (95%CI = 1.7-3.0) increased risk of CHD. The lower LINE-1-related CHD risk estimates tended to be stronger among subjects with the highest tertile of homocysteine (Pinteraction = 0.042) and those with diagnosis of hypertension (Pinteraction = 0.012). Conclusion: LINE-1 hypomethylation is associated with the risk of CHD in Chinese population. Potential CHD risk factors such as older age, elevated total cholesterol, and diagnosis of diabetes may have impact on global DNA methylation, whereby exerting their effect on CHD risk. .

Diabetes & coronary heart disease: Current perspectives.

Coronary heart disease (CHD) is currently the leading cause of death worldwide and together with diabetes, poses a serious health threat, particularly in the Indian Asian population. Risk factor management has evolved considerably with the continued emergence of new and thought-provoking evidence. The stream of laboratory- and population-based research findings as well as unresolved controversies may pose dilemmas and conflicting impulses in most clinicians, and even in our more well-informed patients. As results of the most recent clinical trials on glycaemic control for macrovascular risk reduction are woven into concrete clinical practice guidelines, this paper seeks to sort through unwieldy evidence, keeping these findings in perspective, to deliver a clearer message for the context of South Asia and cardio-metabolic risk management.

Influência de combinações genéticas nos níveis de HDL-c em uma população do sul do Brasil / Influence of genetic combinations on HDL-C levels in a Southern Brazilian population / Influencia de combinaciones genéticas en los niveles de HDL-c en una población del sur del Brasil

FUNDAMENTO: Baixos níveis de HDL-c são importantes preditores de doença coronariana, a primeira causa de morte no mundo todo. Muitos fatores afetam os níveis de HDL-c, tais como os polimorfismos de genes que codificam proteínas-chave para a via de transporte reverso de colesterol. OBJETIVO: Investigar a influência de sete polimorfismos dos genes CETP, APOA1, ABCA1 e SCARB1 genes nos níveis de HDL-c em uma população da região sul do Brasil. MÉTODOS: Os polimorfismos foram investigados em uma amostra de 500 indivíduos de descendência europeia, mas os níveis de HDL-c de somente 360 indivíduos foram ajustados para cofatores usando regressão linear múltipla no estudo de associação. A amostra foi dividida em tercis de acordo com os níveis ajustados de HDL-c e frequências de alelos e haplótipos foram comparadas entre o 1º e o 3º tercis dos níveis ajustados de HDL-c. RESULTADOS: Quando as combinações dos alelos de risco foram testadas, a frequência de combinações alélicas em três genes (haplótipo 1 do gene APOA1, variante 2S do gene SCARB1, e alelo B1 do gene CETP) foi significantemente mais alta no tercil inferior dos níveis ajustados de HDL-c (28,3 por cento) do que no tercil superior (14,9 por cento; p=0,008), o que indica que a presença dessas variantes aumentou 2,26 vezes a chance de ter níveis de HDL-C < 39,8 mg/dl. CONCLUSÃO: Espera-se que esses marcadores, quando estudados separadamente, tenham uma pequena influência na característica que está sendo analisada, mas uma influência maior foi detectada quando os marcadores foram estudados em combinação. Em uma população da região sul do Brasil, nossos dados mostraram uma influência significante das combinações das variantes dos genes APOA1, SCARB1 e CETP nos níveis de HDL-c.

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 percent) than in the upper tertile (14.9 percent; 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: Bajos niveles de HDL-c son importantes predictores de enfermedad coronaria, la primera causa de muerte en todo el mundo. Muchos factores afectan los niveles de HDL-c, tales como los polimorfismos de genes que codifican proteínas-clave para la vía de transporte reverso de colesterol. OBJETIVO: Investigar la influencia de siete polimorfismos de los genes CETP, APOA1, ABCA1 y SCARB1 genes en los niveles de HDL-c en una población de la región sur del Brasil. MÉTODOS: Los polimorfismos fueron investigados en una muestra de 500 individuos de descendencia europea, pero los niveles de HDL-c de solamente 360 individuos fueron ajustados para cofactores usando regresión lineal múltiple en el estudio de asociación. La muestra fue dividida en terciles de acuerdo con los niveles ajustados de HDL-c y frecuencias de alelos y haplotipos fueron comparadas entre el 1º y el 3º terciles de los niveles ajustados de HDL-c. RESULTADOS: Cuando las combinaciones de los alelos de riesgo fueron probadas, la frecuencia de combinaciones alélicas en tres genes (haplotipo 1 del gen APOA1, variante 2S del gen SCARB1, y alelo B1 del gen CETP) fue significativamente más alta en el tercil inferior de los niveles ajustados de HDL-c (28,3 por ciento) que en el tercil superior (14,9 por ciento; p=0,008), lo que indica que la presencia de esas variantes aumentó 2,26 veces la posibilidad de tener niveles de HDL-C < 39,8 mg/dl. CONCLUSIÓN: Se espera que esos marcadores, cuando sean estudiados separadamente, tengan una pequeña influencia en la característica que está siendo analizada, pero una influencia mayor fue detectada cuando los marcadores fueron estudiados en combinación. En una población de la región sur del Brasil, nuestros datos mostraron una influencia significativa de las combinaciones de las variantes de los genes APOA1, SCARB1 y CETP en los niveles de HDL-c.

Serum insulin levels in non-obese, non-diabetic Asian Indians with acute coronary and non-coronary events.

Significant insulin resistance and hyperinsulinemia has been observed to be associated with coronary heart disease in epidemiological studies, particularly so in Asian Indians. This study attempted to investigate if hyperinsulinemia accompanies acute cardiovascular events in Asian Indians, and that it is not a metabolic response to acute stress alone. To test this hypothesis, a case-control study was carried out in a tertiary referral hospital in northern India. Group I (n = 19), consisting of non-diabetic, non-hypertensive, non-obese patients presenting with first episode of acute coronary event (first episode of angina or myocardial infarction) were compared with non-diabetic, non-hypertensive, non-obese patients of group II (n = 21) presenting with non-cardiovascular emergencies (severe abdominal pain e.g. uncomplicated ureteric colic or non-specific intestinal colic. Blood was analysed for glycosylated haemoglobin, fructosamine and insulin levels within 24 hours of the acute event. Elevated serum fructosamine was observed in 11 (57.8%) subjects in group I and 9 (42.9%) in group II (p = NS). Glycosylated haemoglobin was 6.8 +/- 0.1 percent in group I versus 5.9 +/- 0.04 percent in group II (p < 0.01). Three out of 11 subjects in group I and 1/9 subjects in group II having elevated serum fructosamine level also had increased glycosylated haemoglobin level. Five (26.3%) subjects in group I and 2 (9.5%) in group II with elevated glycosylated haemoglobin level were excluded from the analysis as these patients might have been diabetic. Mean serum insulin values were significantly higher in group I (161.3 +/- 8.15 micro IU/mL and 17.5 +/- 1.9 micro IU/mL in groups I and II, respectively; p < 0.001). Eleven (57.8%) subjects in group I had insulin values above 100 uIU/ml. The present study indicates that significant hyperinsulinemia accompanies acute cardiovascular events and it is not an acute response to pain or stress hyperglycemia. Markedly high insulin levels observed in these patients may have a potential role in the pathophysiology of acute coronary event, and may be further studied as a possible prognostic marker.

Apolipoprotein(a) polymorphism and its association with plasma lipoprotein(a) levels: a north Indian study.

Elevated levels of lipoprotein(a) has been regarded as an independent risk factor for coronary, peripheral and cerebral atherosclerosis. The enormous intra-personal variation in the plasma concentration of lipoprotein(a) is almost entirely controlled by the apolipoprotein(a) i.e. gene locus on the chromosome 6q 26-27. The apolipoprotein(a) molecule is highly polymorphic and is known to exist in multiple, genetically determined isoforms. These polymorphisms may be responsible for difference in promoter activity, variable size of apolipoprotein(a) and thereby variation in plasma lipoprotein(a) concentration. We studied the effect of two types of polymorphisms, (i) variation in length of the pentanucleotide repeat in the 5' flanking region starting -1373 bp upstream of AUG codon, and (ii) the Kringle-4 type 2 size polymorphism, on plasma lipoprotein(a) levels in North Indian population. The study group consisted of 88 angiographically assessed male coronary artery disease patients (age range 30-70 years) and 83 age- and sex-matched healthy controls. The pentanucleotide repeat polymorphism was analysed using polymerase chain reaction. In all, 8/11 pentanucleotide repeat isoforms were observed. Using SDS-agarose gel electrophoresis and immunoblotting isoforms having 12-50 Kringle-4 type 2 repeats were detected. Our study indicates a strong association of elevated plasma lipoprotein(a) concentration with coronary artery disease. An inverse correlation was seen between lipoprotein concentration and isoform size for both the pentanucleotide repeat polymorphism and the Kringle-4 type 2 polymorphisms; statistically significant difference (p = 0.001) was, however, observed only for the later.

Ausência de fatores de risco de doença coronária em indios Yanomami e influência da aculturaçäo na pressäo arterial / Absence of coronary heart disease risk factors in yanomami indians and influence of aculturation on blood pressure

Objetivo - Investigar a hipótese de que a hipertensão arterial e a doença coronária são "doenças da civilização", analisando a distribuição dos antecedentes dessas doenças em uma população indígena e observando a influência da aculturação na pressão arterial. Métodos - Foram examinados 725 índios Yanomami de ambos os sexos, habitantes de oito aldeias nos Estados de Roraima e Amazonas. Foram feitas medidas referentes a todos os clássicos fatores de risco de doença coronária e foram colhidas amostras de urina para a dosagem de eletrólitos. Resultados - Não foi encontrado nenhum dos conhecidos fatores de risco de doença coronária. Os níveis de pressão arterial foram baixos e não aumentaram com a idade. Houve influência da aculturação na pressão arterial e essa influência foi medida, pelo menos em parte, pelo aumento do peso corporal e ingestão de sódio. Conclusão - A ausência, em uma população indígena relativamente isolada, de hipertensão e de outros fatores de risco de doença coronária e o aumento de pressão arterial com a aculturação sugerem, fortemente, que essas doenças são "doenças da civilização"

Purpose - To investigate the hypothesis that hypertension and coronary heart disease are "civilization diseases", analyzing the distribution of their antecedents in an Indian population and observing the influence of acculturation on blood pressure. Methods - Seven-hundred and twentyfive Yanomami indians of both sexes, ages above 14 years, inhabitants of eight villages in Roraima and Amazon states were examined. Measures related to all classical coronary risk factors were carried out and urine samples were collected to measure electrolytes. Results - None of the known coronary risk factors were found. The blood pressure levels were low and did not increase with increasing age. There was influence of acculturation on blood pressure and it was in part mediated by increase in body weight and sodium intake. Conclusion - The absence of hypertension and other coronary risk factors and the increase of blood pressure with acculturation, among an isolated population, strongly suggest that these diseases are "civilization diseases