ESR1 polymorphisms and statin therapy: a sex-specific approach.

Lipid-lowering therapy has shown a high degree of variability in clinical response and there is evidence that the variability in drug response between individuals is due to genetic factors. Thirteen single nucleotide polymorphisms (SNPs) within the ESR1 gene were evaluated with basal lipid and lipoprotein levels, as well as response to lipid-lowering therapy, in 495 hypercholesterolemic individuals of European descent receiving simvastatin or atorvastatin. Significant associations were detected between rs4870061 (P=0.040, corrected P-value (PC)=0.440), rs1801132 (P=0.002, PC=0.022) and the SNP rs3020314 (P=0.013, PC=0.143) with triglyceride (TG) baseline levels. The rs4870061 was also associated with high-density lipoprotein cholesterol (HDL-C) baseline levels (P=0.045, PC=0.495). Regarding statin efficacy, rs2234693 C/C was associated with greater HDL-C increase (P=0.037; PC=0.407) and rs3798577 T allele was associated with greater total cholesterol (TC) reduction (P=0.019; PC=0.209) and greater TG reduction (P=0.026; PC=0.286). These associations suggest that ESR1 polymorphisms are in part responsible for the TC, HDL-C and TG variation levels and this effect may be sex-specific.

Low-grade inflammation markers in children and adolescents: Influence of anthropometric characteristics and CRP and IL6 polymorphisms.

Overweight and obesity are associated with chronic and subclinical inflammation due to an imbalance of inflammatory mediators. However, the association with gene polymorphism has been rarely studied in children. The aim of this study was to determine if serum concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) are related to the IL6 rs1800795, IL6 rs2069845 and CRP rs1205 polymorphisms (SNPs) according to body mass index (BMI) in a sample of children and adolescents. A cross-sectional study in 470 students between 7 and 17yearsof age of anthropometric characteristics, high sensitivity-CRP (Hs-CRP) and IL-6 levels and three SNPs genotyped. The prevalence ratio of hs-CRP>3mg/L in obese individuals was 4.15 (CI 2.43-7.06; p=0.01), and it was 1.91 (CI 1.03-3.55; p=0.03) in overweight individuals and 1.74 (CI 1.05-2.88 p=0.03) in females. Individuals with waist circumference (WC) and body fat percentage (BF%) alterations showed elevated levels of hs-CRP (p=4.3×10-5 and p=5.3×10-6). The combination of any two anthropometric measurement increases CRP levels, especially combinations with obesity body mass index (BMI): BMI+WC and BMI+BF%. Among the overweight/obesity group, T allele carriers of CRP rs1205 showed lower levels of hs-CRP (0.5, IQR=0.3-1.8mg/L) than CC homozygotes (1.5, IQR=0.4-3.4mg/L, p=0.018). Additionally, considering subjects with two or three anthropometric alterations for CRP rs1205: rs1205 T allele carriers had lower levels of hs-CRP (0.7, IQR=0.3-2.7mg/L) than CC homozygotes (1.2, IQR=0.5-3.5mg/L, p=0.02). In conclusion, carriers of the rs1205/T allele with higher BMIs had lower levels of hs-CRP. Schoolchildren who were overweight/obese had higher levels of CRP and IL-6, whereas individuals with WC and BF% alterations had higher levels of CRP.

Association of CYP7A1 -278A>C polymorphism and the response of plasma triglyceride after dietary intervention in dyslipidemic patients.

We investigated the effect of the -278A>C polymorphism in the CYP7A1 gene on the response of plasma lipids to a reduced-fat diet for 6 to 8 weeks in a group of 82 dyslipidemic males with a mean age of 46.0 +/- 11.7 years. Individuals who presented at least one high alteration in total cholesterol, low-density lipoprotein cholesterol or triglyceride values were considered to be dyslipidemic. Exclusion criteria were secondary dyslipidemia due to diabetes mellitus, renal, liver, or thyroid disease. None of the subjects were using lipid-lowering medication. Baseline and follow-up lipid concentrations were measured. The genotypes were determined by the digestion of PCR products with the BsaI restriction endonuclease. There were statistically significant reductions in plasma total cholesterol, low-density lipoprotein cholesterol and triglyceride concentrations after dietary intervention. The minor allele C has a frequency of 43%. Carriers of the C allele had significantly lower triglyceride concentrations (P = 0.02) than AA homozygotes. After adjustment of covariates, subjects with the AC and CC genotypes showed a greater reduction in triglyceride concentrations compared to subjects with the AA genotype. Multiple linear regression analyses showed that the AC and CC CYP7A1 genotypes accounted for 5.2 and 6.2% of triglyceride concentration during follow-up and adjusted percent of change of triglyceride concentration, respectively. The present study provides evidence that -278A>C polymorphism in the CYP7A1 gene can modify triglyceride concentrations in response to a reduced fat diet in a dyslipidemic male population. This gene represents a potential locus for a nutrigenetic directed approach.

Determinants of variable response to simvastatin treatment: the role of common variants of SCAP, SREBF-1a and SREBF-2 genes.

We investigated the effect of single-nucleotide polymorphisms in sterol regulatory element-binding factors-1a and -2 (SREBF-1a and SREBF-2) and SREBF cleavage-activating protein (SCAP) genes on lipid-lowering response to simvastatin. In all, 146 hypercholesterolemic patients of European descent were prospectively treated with simvastatin 20 mg/day for over 6 months. Of these 99 subjects completed the 6-month follow-up. Plasma lipids and lipoproteins were measured before and throughout the study. The mean percentage decrease in plasma total cholesterol (TC) was greater in subject carriers of SCAP 2386G allele compared with those homozygous for 2386A allele (-29.6+/-13.4 vs -22.1+/-13.8%, P=0.007). About 61% of the 2386G carriers were above-average responders for TC levels (DeltaTC -27.8%), whereas only 29% of 2386A homozygous reached this reduction (P=0.009). Our data suggest that the SCAP 2386A>G gene polymorphism was a significant predictor of TC and triglyceride responses to simvastatin treatment.

Further evidence for the association between obesity-related traits and the apolipoprotein A-IV gene.

OBJECTIVE: To investigate associations and gene-environment interactions of APOA-IV gene polymorphisms with obesity-related phenotypes in a Brazilian population. METHODS: A total of 391 individuals (171 men and 220 women) were genotyped for Xbal, Thr347Ser and Gln360His polymorphisms by PCR-RFLP methods. Adjusted body mass index (BMI) and waist circumference (WC) were compared among genotypes/haplotypes by unpaired t-test or analysis of variance. Gene-environment interactions were tested by analysis of variance using a general linear model. RESULTS: Analysis of the APOA-IV gene variants separately showed that X*2 and 347Ser alleles were associated with higher BMI (P=0.02 for both polymorphisms). Haplotype analysis confirmed this association. For these polymorphisms, the effect on BMI appeared to depend on smoking status (test for interaction, P=0.007 and 0.02, respectively), the Thr347Ser variant was associated with a BMI increase in smokers only (P=0.002). At the single-locus level no association was observed between 360His allele and BMI; however, haplotype analyses showed an association of this gene variant and higher BMI. A trend for association with WC (P=0.05) was observed in male carriers of the 360His allele. The effect of this polymorphism also depended on smoking status (test for interaction, P=0.018). Nonsmoker male carriers of the 360His allele had a larger waist circumference than homozygotes for the Gln allele (P=0.003). CONCLUSION: Our data suggest that the APOA-IV gene polymorphisms investigated are associated with obesity-related traits. The effects of X*2 and 347Ser variants on BMI and the 360His variant on waist circumference depended on smoking status.

Beta-globin gene cluster haplotypes in two North American indigenous populations.

Haplotypes derived from five polymorphic restriction sites were determined in 50 Carrier-Sekani and 70 Mvskoke chromosomes, and the results were integrated with those previously obtained for 11 South American Indian populations. Eleven haplotypes were identified in the Mvskokes, while five were observed in the Carrier-Sekani. As in South American natives, haplotype 2 (+----) and 6 (-++ -+) were the most prevalent among the Mvskoke (46% and 30%, respectively). In the Carrier-Sekani, haplotype 2 was also the most common, but haplotype 5 (-+ -++) was somewhat more frequent (18%) than 6 (12%). High heterozygosities, as well as genetic differentiation, were observed among these two North American and two other South American groups (Mapuche and Xavante). They could be due to non-Indian admixture in the Mvskoke and Mapuche, but the findings in the other two populations require some other type of explanation.

Association of CYP7A1 -278A>C polymorphism and the response of plasma triglyceride after dietary intervention in dyslipidemic patients

We investigated the effect of the -278A>C polymorphism in the CYP7A1 gene on the response of plasma lipids to a reduced-fat diet for 6 to 8 weeks in a group of 82 dyslipidemic males with a mean age of 46.0 ± 11.7 years. Individuals who presented at least one high alteration in total cholesterol, low-density lipoprotein cholesterol or triglyceride values were considered to be dyslipidemic. Exclusion criteria were secondary dyslipidemia due to diabetes mellitus, renal, liver, or thyroid disease. None of the subjects were using lipid-lowering medication. Baseline and follow-up lipid concentrations were measured. The genotypes were determined by the digestion of PCR products with the BsaI restriction endonuclease. There were statistically significant reductions in plasma total cholesterol, low-density lipoprotein cholesterol and triglyceride concentrations after dietary intervention. The minor allele C has a frequency of 43 percent. Carriers of the C allele had significantly lower triglyceride concentrations (P = 0.02) than AA homozygotes. After adjustment of covariates, subjects with the AC and CC genotypes showed a greater reduction in triglyceride concentrations compared to subjects with the AA genotype. Multiple linear regression analyses showed that the AC and CC CYP7A1 genotypes accounted for 5.2 and 6.2 percent of triglyceride concentration during follow-up and adjusted percent of change of triglyceride concentration, respectively. The present study provides evidence that -278A>C polymorphism in the CYP7A1 gene can modify triglyceride concentrations in response to a reduced fat diet in a dyslipidemic male population. This gene represents a potential locus for a nutrigenetic directed approach.