Family history of cardiovascular disease and non-HDL cholesterol in prepubescent non-obese children / Importância clínica da história familiar de doença cardiovascular e da dosagem do colesterol não HDL em crianças eutróficas

Summary Objective: To describe the values of non-HDL cholesterol (NHDL-c) and the frequency of a family history of early cardiovascular disease (family HCVD) in healthy prepubescent children. Analyze the association between NHDL-c and family HCVD, and possible associations with other risk factors for cardiovascular disease (CVD). Method: Cross-sectional study including 269 prepubescent (aged 6-10 years) schoolchildren with a normal body mass index (+1SD<BMI>-2SD). Data collected: Family HCVD; weight and height, waist circumference and systemic blood pressure; lipid profile (total cholesterol TC, HDL-c, triglycerides and LDL-c), NHDL-c calculation (CT-HDL-c, cut-off = 145 mg/dL) and insulin resistance (HOMA-IR). Results: High levels were found for NHDL-c in 10 (3.7%) of these schoolchildren, and family early HCVD was found in 46 (17.1%) of them. There was a weak association between family HCVD and NHDL-c (Cramer’s-V-test = 0.120; p=0.050). Among the children with NHDL-c≥145 mg/dL, 4 (40%) have family HCVD. The presence of family HCVD was not associated with the variables being studied. The variables independently associated with NHDL-c ≥ 145 mg/dL were: HOMA-IR (OR=1.7; 95CI 1.1-2.6) and diastolic blood pressure (OR=1.1; 95CI 1.02-1.2). Conclusion: NHDL-c values were associated with blood pressure and insulin resistance. Family HCVD was not associated with other classic risk factors for CVD, even though the frequency found was five times higher than that of high NHDL-c.

Resumo Objetivos: descrever os valores do colesterol não HDL (NHDL-c) e a frequência de história cardiovascular familiar precoce (HDCV familiar) em crianças eutróficas e pré-púberes. Analisar a associação entre o NHDL-c e o HDCV familiar e possíveis associações com outros fatores de risco para doenças cardiovasculares (DCV). Método: estudo transversal com 269 escolares (6-10 anos) pré-púberes e com índice de massa corporal normal (+1DP<IMC>-2DP). Dados coletados: HDCV familiar; peso e estatura, circunferência abdominal e pressão arterial sistêmica; perfil lipídico (colesterol total – CT, HDL-c, triglicérides e LDL-c), cálculo do NHDL-c (CT-HDL-c, ponto de corte 145 mg/dL) e resistência à insulina (HOMA-IR). Resultados: observaram-se valores elevados de NHDL-c em 10 (3,7%) e presença de HDCV familiar precoce em 46 (17,1%) crianças. Houve fraca associação entre HDCV familiar e NHDL-c (Cramer’s-V-test = 0,120; p=0,050). Entre as crianças com NHDL-c ≥145 mg/dL, quatro (40%) tinham HDCV familiar. A presença de HDCV familiar não se associou com as variáveis estudadas. As variáveis que se associaram de forma independente com o NHDL-c ≥145 mg/dL foram HOMA-IR (OR=1,7; IC95% 1,1-2,6) e pressão arterial diastólica (OR=1,1; IC95% 1,02-1,2). Conclusão: os valores de NHDL-c se associaram com pressão arterial e resistência insulínica. HDCV familiar não se associou com outros fatores de risco clássicos para DCV, embora a frequência encontrada tenha sido quase cinco vezes superior à de NHDL-c elevado.

História natural da hipercolesterolemia familiar / Natural history of familial hypercholesterolemia

A hipercolesterolemia familiar (HF), uma das mais comuns doenças genéticas, é caracterizada por hipercolesterolemia, geralmente expressiva, que se associa ao desenvolvimento prematuro da aterosclerose e suas complicações. Embora sua base genética esteja associada a variantes dos genes que codificam o receptor da lipoproteína de baixa densidade (LDL), da apolipoproteína B (ApoB), da pró-proteína convertase subtilisina/kexina tipo 9 (PCSK9) ou da proteína adaptadora do receptor da LDL, a doença é mais frequentemente relacionada as mutações do receptor da LDL. Ela pode se expressar por níveis muito elevados de colesterol das LDL em sua forma homozigótica (rara) ou com muito mais frequência e com menor gravidade pela forma heterozigótica. Esta última também pode apresentar níveis muito elevados de LDL-C, na dependência da variante genética envolvida, bem como de contribuição de outros genes que influenciem, adicionalmente, o metabolismo lipídico. O diagnóstico é baseado nos níveis de LDL-C, na presença de sinais físicos da hipercolesterolemia, na precocidade da doença coronariana no paciente ou em seus familiares e no diagnóstico genético. A doença geralmente é subdiagnosticada e subtratada, o que contribui para formas mais graves de apresentação clínica da doença aterosclerótica. Sua história natural está associada principalmente à doença coronariana prematura, em geral após a quarta década de vida, mas incidindo de forma ainda muito mais prematura na condição homozigótica, com desfechos cardiovasculares ou revascularizações nas duas primeiras décadas de vida

Familial hypercholesterolemia (FH), one of commonest genetic disorders, is characterized by a usually significant degree of hypercholesterolemia, associated with the premature development of atherosclerosis and related complications. Although the genetic basis of FH is mainly attributable to polymorphisms of the genes that encode the receptor of low-density lipoprotein (LDL), apolipoprotein B (ApoB), proprotein convertase subtilisin/kexin type 9 (PCSK9), or the LDL-receptor adaptor protein, the disorder is more commonly related to LDL receptor mutations. The disorder can be expressed as very high LDL-cholesterol levels in its homozygous (rare) form, or much more frequently but with less severity, in the heterozygous form. It can also present very high LDL-cholesterol levels, depending on the genetic variant involved, and the contribution of other genes that also influence the lipid metabolism. The diagnosis is based on LDL-cholesterol levels, the presence of physical signs of hypercholesterolemia, premature coronary heart disease in the patient or their relatives, or genetic diagnosis. The disease is usually underdiagnosed and undertreated, which contributes to more severe forms, of clinical presentation of atherosclerotic disease. Its natural history is associated mainly with premature coronary disease, usually after the fourth decade of life, or even earlier in homozygous subjects, with cardiovascular events or the need of revascularization in the first two decades of life

A high-carbohydrate diet enhances the adverse effect of the S2 allele of APOC3 SstI polymorphism on the TG/HDL-C ratio only in young Chinese females

Both genetic background and diet have profound effects on plasma lipid profiles. We hypothesized that a high-carbohydrate (high-CHO) diet may affect the ratios of serum lipids and apolipoproteins (apo) differently in subjects with different genotypes of the SstI polymorphism in the apoCIII gene (APOC3). Fifty-six healthy university students (27 males and 29 females, 22.89 ± 1.80 years) were given a washout diet of 54 percent carbohydrate for 7 days, followed by a high-CHO diet of 70 percent carbohydrate for 6 days without total energy restriction. Serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apoB100, apoAI, and the APOC3 SstI polymorphism were analyzed. The ratios of serum lipids and apoB100/apoAI were calculated. At baseline, the TG/HDL-C ratio was significantly higher in females, but not in males, with the S2 allele. The differences in the TG/HDL-C ratio between genotypes remained the same after the washout and the high-CHO diet in females. When compared with those before the high-CHO diet, the TC/HDL-C (male S2 carriers: 3.13 ± 1.00 vs 2.36 ± 0.65, P = 0.000; male subjects with the S1S1 genotype: 2.97 ± 0.74 vs 2.09 ± 0.55, P = 0.000; female S2 carriers: 2.68 ± 0.36 vs 2.24 ± 0.37, P = 0.004; female subjects with the S1S1 genotype: 2.69 ± 0.41 vs 2.09 ± 0.31, P = 0.000) and LDL-C/HDL-C (male S2 carriers: 1.44 ± 0.71 vs 1.06 ± 0.26, P = 0.012; male subjects with the S1S1 genotype: 1.35 ± 0.61 vs 1.01 ± 0.29, P = 0.005; female S2 carriers: 1.18 ± 0.33 vs 1.00 ± 0.18, P = 0.049; female subjects with the S1S1 genotype: 1.18 ± 0.35 vs 1.04 ± 0.19, P = 0.026) ratios were significantly decreased after the high-CHO diet regardless of gender and of genotype of the APOC3 SstI polymorphism. However, in female S2 carriers, the TG/HDL-C (1.38 ± 0.46 vs 1.63 ± 0.70, P = 0.039) ratio was significantly increased after the high-CHO diet. In conclusion, the high-CHO diet has favorable effects on the TC/HDL-C and LDL-C/HDL-C ratios regardless of gender and of genotype of the APOC3 SstI polymorphism. Somehow, it enhanced the adverse effect of the S2 allele on the TG/HDL-C ratio only in females.

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.

The Association Between Apolipoprotein E Genotype and Lipid Profiles in Healthy Woman Workers / 예방의학회지

OBJECTIVES: Plasma lipid profiles and Apolipoprotein E (ApoE) are established risk factors for cardiovascular disease (CVD). The knowledge of lipid profile may estimate the potential victims of cardiovascular disease before its initiation and progression and offers the opportunity for primary prevention. The most common ApoE polymorphism has been found to influence plasma lipid concentrations and its correlation with CVD has been extensively investigated in the last decade. METHODS: The ApoE polymorphism and its influence on plasma lipid were investigated in healthy woman workers. The information on confounding factors was obtained through a self-administered questionnaire and ApoE polymorphism was investigated using PCR. RESULTS: The relative frequencies of alleles E2, E3 and E4 for the study population (n=305) were 0.127, 0.750 and 0.121, respectively. ApoE polymorphism was associated with variations in plasma HDL-cholesterol lipid profile. In order to estimate the independent effects of alleles E2 and E4, as compared with E3, on lipid profile, multiple regression was performed after adjustment for confounding variables such as age, BMI, blood pressure, education status, insulin, fasting glucose, HOMA-IR, menopause. ApoE2 had a negative association with HDL cholesterol and ApoE4 had a positive association with LDL cholesterol. CONCLUSIONS: This study identified that the ApoE and CVD risk factors contribute to the lipid profiles, similar to other studies. The analysis including dietary intake and other gene in further studies may help to identify clear effects on lipid profiles as risk factor for CVD.

[Genetic linkage analysis of HDL-C in 91 Iranian families with metabolic syndrome with Haseman-Elston regression methods]

Metabolic syndrome [Mets] is a common phenotype, which is affected on 32% of Iranian population. It is associated with an increased risk for cardiovascular disease. Low HDL-C is the most frequent phenotype in this disease. In this study in order to find some chromosomal region in related to the HDL-C in families with metabolic syndrome, twelve microsatellite markers were investigated in 91 families and done the Haseman-Elston Regression methods [oHE, sHE, rHE, W2, W3, tHE]. Finally, the results of these methods are compared. For analysis of the data, these softwares were used: power. HE [inR], Excel, PowerMarker, SPSS, S.A.G.E. In results of 4 methods, from these 7 methods, genetic linkage of HDL-C is significant with D11S1998 marker [p<0.05]. Other studies also show this result. These results can help me in future studies in Iranian population. Results show in which theoretical power of these methods is better, the empirical significance become less and this is an evidence for accepting significant linkage between D11S1998 marker and location of HDL-C gene

Effect of estrogen receptor-alpha (ESR1) gene polymorphism on high density lipoprotein levels in response to hormone replacement therapy

Studies have shown that estrogen replacement therapy and estrogen plus progestin replacement therapy alter serum levels of total, LDL and HDL cholesterol levels. However, HDL cholesterol levels in women vary considerably in response to hormone replacement therapy (HRT). A significant portion of the variability of these levels has been attributed to genetic factors. Therefore, we investigated the influence of estrogen receptor-alpha (ESR1) gene polymorphisms on HDL levels in response to postmenopausal HRT. We performed a prospective cohort study on 54 postmenopausal women who had not used HRT before the study and had no significant general medical illness. HRT consisted of conjugated equine estrogen and medroxyprogesterone acetate continuously for 1 year. The lipoprotein levels were measured from blood samples taken before the start of therapy and after 1 year of HRT. ESR1 polymorphism (MspI C>T, HaeIII C>T, PvuII C>T, and XbaI A>G) frequencies were assayed by restriction fragment length polymorphism. A general linear model was used to describe the relationships between HDL levels and genotypes after adjusting for age. A significant increase in HDL levels was observed after HRT (P = 0.029). Women with the ESR1 PvuII TT genotype showed a statistically significant increase in HDL levels after HRT (P = 0.032). No association was found between other ESR1 polymorphisms and HDL levels. According to our results, the ESR1 PvuII TT genotype was associated with increased levels of HDL after 1 year of HRT.

[Investigation on two polymorphisms effective on HDL-C concentration in patients with coronary artery disease using restriction fragment length polymorphism]

High density lipoprotein cholesterol [HDL-C] is a known inverse predictor of coronary heart disease [CHD]. Cholesteryl ester transfer protein [CETP] and hepatic lipase [HL] are key proteins in HDL-C metabolism so that decreased CETP or HL activity is associated with high HDL-C. -629C/A polymorphism in promoter of CETP gene and-514C/T in promoter of HL gene were previously reported to reduce related protein level in plasma. In this study association of these polymorphisms with CHD related to HDL-C level were investigated. In this analytical-descriptive study 321 subjects underwent coronary angiography and divided in two groups base on angiogram [non CAD = 135 and CAD = 186]. Serum lipids profile was measured by standard procedure and genotype was detected using PCR-RFLP method. Overall the CETP genotype frequencies were in CAD patients: 58.8% [n=110], 28.9% [n=54] and 12.3% [n=23] and in non CAD patients: 45.2% [n=61], 41.5% [n=56] and 13.3% [n=18] for AA, CA and CC respectively. HL genotype frequencies were in CAD patients: 61.6% [n=114], 33.5% [n=62] and 4.9% [n=9] and in non CAD patients: 65.9% [n=89], 27.4% [n=37] and 6.7% [n=9] for CC, CT and TT respectively. In control group HDL-C concentration was higher for AA than CC genotype in -629C/A, and also for TT than CC genotype in -514C/T. Allele A in all subjects and T allele in woman were higher in CAD than non CAD group. A high increase in HDL-C level [10. mg/dl] was observed in individuals with CETP-AA/LIPC-TT and CETP-CA/LIPC-TT relative to CETP-CC/LIPC-CC across all subjects [P< 0.001] but there was no difference in CAD prevalence. Allele A from -629C/A, and T from -514C/T even with the increasing of HDL-C concentration had higher frequency in CAD than non CAD group. Therefore, it seems that HDL-C didn't protect coronary artery when CETP or HL activity was reduced by these polymorphisms