Genosets for APOE and CYP7A1-rs3808607 variants do not predict LDL cholesterol lowering upon intervention with plant sterols in a randomized, double-blind, placebo-controlled trial.

BACKGROUND: The consumption of 2 g/d plant sterols (PSs) reduces circulating LDL cholesterol by ≤10%. The degree of LDL cholesterol lowering was associated with specific apolipoprotein E [APOE, Reference SNP (rs)429358] and cholesterol 7α-hydroxylase (CYP7A1, rs3808607) genosets in previous post hoc analyses of randomized controlled trials. However, because post hoc analyses do not conform to the randomization model, there is a greater potential that the findings could be due to type I error, thus warranting validation through an a priori-designed intervention trial. OBJECTIVES: The GenePredict Plant Sterol study (GPS) was designed to validate associations of LDL cholesterol lowering with specific APOE and CYP7A1 genosets through a priori recruitment of individuals carrying prespecified genosets. METHODS: A 2-center, double-blind, placebo-controlled, randomized 2-period crossover dietary intervention with 2 g/d PS for 28 d with a minimum 28-d washout was undertaken from July 2017 to December 2019. A priori recruitment of individuals with slightly elevated LDL cholesterol was based on genosets of APOE isoforms and CYP7A1 rs3808607. Randomization was performed with stratification by sex and genoset. RESULTS: The recruitment target of 64 participants with prespecified genosets could not be reached, despite the screening of 477 individuals; 42 participants completed the intervention trial. Reductions in LDL cholesterol were similar across all 3 genosets (-0.298 ± 0.164, -0.357 ± 0.115, -0.293 ± 0.109 mmol/L; P = 0.0002 overall; P = 0.9126 for treatment × genoset), providing evidence that the shortfall in recruitment might not have stopped the trial from meeting the objective. CONCLUSIONS: APOE and CYP7A1 genotypes did not influence the efficacy of LDL cholesterol reductions upon dietary intervention with PSs. Findings of previous post hoc analyses could not be validated in a trial using a priori genotype-based recruitment. Obtaining adequate numbers of participants is challenging in trials using genoset-based recruitment, even for common variants.

Common Genetic Variations Involved in the Inter-Individual Variability of Circulating Cholesterol Concentrations in Response to Diets: A Narrative Review of Recent Evidence.

The number of nutrigenetic studies dedicated to the identification of single nucleotide polymorphisms (SNPs) modulating blood lipid profiles in response to dietary interventions has increased considerably over the last decade. However, the robustness of the evidence-based science supporting the area remains to be evaluated. The objective of this review was to present recent findings concerning the effects of interactions between SNPs in genes involved in cholesterol metabolism and transport, and dietary intakes or interventions on circulating cholesterol concentrations, which are causally involved in cardiovascular diseases and established biomarkers of cardiovascular health. We identified recent studies (2014-2020) that reported significant SNP-diet interactions in 14 cholesterol-related genes (NPC1L1, ABCA1, ABCG5, ABCG8, APOA1, APOA2, APOA5, APOB, APOE, CETP, CYP7A1, DHCR7, LPL, and LIPC), and which replicated associations observed in previous studies. Some studies have also shown that combinations of SNPs could explain a higher proportion of variability in response to dietary interventions. Although some findings still need replication, including in larger and more diverse study populations, there is good evidence that some SNPs are consistently associated with differing circulating cholesterol concentrations in response to dietary interventions. These results could help clinicians provide patients with more personalized dietary recommendations, in order to lower their risk for cardiovascular disease.

Nutrigenetics of Blood Cholesterol Concentrations: Towards Personalized Nutrition.

PURPOSE OF THE REVIEW: To summarize achievements made in the field of nutrigenetics to personalized nutrition. Moreover, the limitations and challenges observed to enable clinical utilization are discussed. RECENT FINDINGS: Currently, with the availability of low-cost genetic testing and new bioinformatics tools, significant developments have occurred to allow issues inherent to the highly complex nature of genetic data to be tackled. Moreover, new statistical methods have uncovered combinatory patterns of SNPs that collectively explain the high interindividual variability in response to dietary interventions. Yet, the application of these results to personalized dietary recommendations is not straightforward. Data from gene-nutrient interaction studies have provided evidence to understand the inter-individual variation differences in blood cholesterol responses. A need exists for guidelines and regulations in order to apply nutrigenetics to personalized nutrition. Moreover, a multisystem approach including genetics, microbiome and environment is needed to achieve possible practical applications.

Serum Lipid Concentrations and FADS Genetic Variants in Young Mexican College Students: The UP-AMIGOS Cohort Study.

BACKGROUND: Recent genome-wide association studies in the Mexican population have identified several genetic loci associated with blood lipid levels in adults. However, studies focusing on the fatty acid desaturase (FADS) gene cluster have been understudied in this population, even though it seems associated with lipid profiles in other ethnicities. The aim of this study was to test associations between single nucleotide polymorphisms (SNPs) in the FADS cluster (rs174546, rs1535, rs174548, rs174550, rs174450, and rs174618) and serum lipid profiles in young Mexicans. METHODS: Anthropometrics, serum lipid profiles, and FADS SNPs were measured in 998 subjects in the UP-AMIGOS cohort study. Genotype-phenotype (total cholesterol [TC], triglyceride [TG], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and very-low-density lipoprotein [VLDL]) associations were assessed using PLINK adjusted for sex, age, and body mass index (BMI). RESULTS: Among 6 FADS SNPs, we found that carriers of the C-allele of the FADS1-rs174546 showed a significant association with lower TG concentrations (ß = -12.6 mg/dL, p = 0.009) and lower VLDL concentrations (ß = -2.52 mg/dL, p = 0.005). We found that rs174546, rs1535, and rs174550 were in high linkage disequilibrium (r2 > 0.80). There were no significant associations between rs174550, rs174548, and rs174618 and lipid profiles. CONCLUSION: A genetic variant in the FADS1 (rs174546) gene is a major contributor of plasma TG and VLDL concentrations in healthy young Mexicans.

Circulating Triglycerides and the Association of Triglycerides with Dietary Intake Are Altered by Alpha-2-Heremans-Schmid Glycoprotein Polymorphisms.

BACKGROUND: Circulating fetuin-A (FetA) inhibits insulin receptor signaling and activates the toll-like receptor 4 proinflammatory cascade; thus, it may contribute to metabolic syndrome. Polymorphisms in alpha-2-Heremans-Schmid glycoprotein (AHSG), the gene which codes FetA, may influence metabolic syndrome progression in higher-risk ethnic groups. We aimed to identify whether individual variation in AHSG influences biomarkers of metabolic disease and obesity in young Mexican adults. METHODS: The participants were Mexican college applicants (18-25 years, n = 641). Dietary intake, anthropometric data, and blood for the analysis of biomarkers and genetics were collected. Single nucleotide polymorphisms (SNPs) in AHSG (rs2518136 and rs4917) were genotyped. RESULTS: Neither AHSG SNP was associated with body mass index (BMI) or waist circumference. rs4917 C allele carriers had lower triglycerides (TG) than T allele homozygotes (98.85 ± 2.3 vs. 112.2 ± 5.2 mg/dL, p = 0.0113). BMI was strongly associated with TG (p < 0.0001) regardless of genotype. The relationship between circulating TG and dietary intake of carbohydrates and saturated fat was significant in rs4917 CT allele heterozygotes only (p = 0.03 and p = 0.02, respectively). CONCLUSIONS: rs4917 T allele carriers had higher TG. This relationship was exaggerated in individuals with overweight and obesity. Dietary intake was significantly associated with TG in only those with heterozygosity at rs4917, suggesting that these individuals may be more susceptible to dietary interventions.

Blueberry Consumption Affects Serum Uric Acid Concentrations in Older Adults in a Sex-Specific Manner.

Blueberries are rich in antioxidants and may protect against disease. Uric acid accounts for about 50% of the antioxidant properties in humans. Elevated levels of serum uric acid (SUA) or hyperuricemia is a risk factor for cardiovascular disease (CVD). The aim was to determine the effect of blueberries on SUA in older adults. Participants (n = 133, 65-80 years) experiencing mild cognitive impairment (MCI) were randomized in a double-blind 6-month clinical trial to either blueberry or placebo. A reference group with no MCI received no treatment. The mean (SD) SUA at baseline were 5.45 (0.9), 6.4 (1.3) and 5.8 (1.4) mg/dL in reference, placebo, and treatment groups, respectively. Baseline SUA was different in men and women (6.25 (1.1) vs. 5.35 (1.1), p = 0.001). During the first three months, SUA decreased in the blueberry group and was significantly different from the placebo group in both men and women (p < 0.0003). Sex-specific differences became apparent after 3 months, when only men showed an increase in SUA in the blueberry group and not in the placebo (p = 0.0006) between 3 and 6 months. At 6 months SUA had rebounded in both men and women and returned to baseline levels. Baseline SUA was correlated with CVD risk factors, waist circumference and triglycerides (p < 0.05), but differed by sex. Overall, 6 m SUA changes were negatively associated with triglycerides in men, but not in women. Group-wise association between 6 m SUA changes and CVD risk factors showed associations with diastolic blood pressure, triglycerides and high-density lipoprotein (HDL) cholesterol in women of the Blueberry group but not in men or any sex in the placebo group. In summary, blueberries may affect SUA and its relationship with CVD risk in a sex-specific manner.

Assessment of cardiovascular disease risk factors in a genetically homogenous population of Parsi Zoroastrians in the United States: A pilot study.

OBJECTIVE: Genetically isolated and homogenous populations are ideal for detecting genes underlying common complex diseases. The use of isolated populations with reduced disease heterogeneity has led to significant gene discoveries in the past. The aim of this pilot study was to assess the prevalence of cardiovascular disease (CVD) risk phenotypes in a genetically homogenous population of Parsi Zoroastrians in the United States. METHODS: Anthropometrics, blood pressure, and medical history were collected from 152 men and 186 women participating in a pilot study as part of the Parsi Family Study. The relative pairs used in the study included 60 parent-off springs, 28 siblings, 6 grandparent-grandchild, 7 avuncular, 18 half-siblings, 7 half-avuncular, and one half-first cousin. Estimates of genetic and environmental influence were calculated using a maximum likelihood-based variance components method implemented in SOLAR. RESULTS: The prevalence of overweight/obesity in adults (62%) was on par with current US prevalence. Hypertension and prehypertension were prevalent in 16% and 46% of the participants, respectively. The quantitative genetic analysis revealed significant heritabilities for all anthropometric phenotypes (P < 0.05). Significant phenotypic correlations were found between blood pressure and anthropometric phenotypes (P < 0.001), whereas significant genetic correlation was found for only diastolic blood pressure and fat free mass (rhoG = -0.88, P < 0.05). CONCLUSION: These preliminary data show significant additive genetic effects on CVD-related phenotypes in this population. Our findings represent the first epidemiological data in Parsi Zoroastrians in the United States and offer excellent promise for future genetic studies in this population. Am. J. Hum. Biol. 28:440-443, 2016. © 2016 Wiley Periodicals, Inc.