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Lipoprotein subclass concentrations are modifiable markers of cardiovascular disease risk. Fenofibrate is known to show beneficial effects on lipoprotein subclasses, but little is known about the role of genetics in mediating the responses of lipoprotein subclasses to fenofibrate. A recent genomewide association study (GWAS) associated several single nucleotide polymorphisms (SNPs) with lipoprotein measures, and validated these associations in two independent populations. We used this information to construct genetic risk scores (GRSs) for fasting lipoprotein measures at baseline (pre-fenofibrate), and aimed to examine whether these GRSs also associated with the responses of lipoproteins to fenofibrate. Fourteen lipoprotein subclass measures were assayed in 817 men and women before and after a three week fenofibrate trial. We set significance at a Bonferroni corrected alpha <0.05 (p < 0.004). Twelve subclass measures changed with fenofibrate administration (each p = 0.003 to <0.0001). Mixed linear models which controlled for age, sex, body mass index (BMI), smoking status, pedigree and study-center, revealed that GRSs were associated with eight baseline lipoprotein measures (p < 0.004), however no GRS was associated with fenofibrate response. These results suggest that the mechanisms for changes in lipoprotein subclass concentrations with fenofibrate treatment are not mediated by the genetic risk for fasting levels. [ABSTRACT FROM AUTHOR]

High levels of HDL cholesterol (HDL-C) have traditionally been linked to lower incidence of cardiovascular disease, prompting the search for effective and safe HDL-C raising pharmaceutical agents. Although drugs such as niacin and fibrates represent established therapeutic approaches, HDL-C response to such therapies is variable and heritable, suggesting a role for pharmacogenomic determinants. Multiple genetic polymorphisms, located primarily in genes encoding lipoproteins, cholesteryl ester transfer protein, transporters and CYP450 proteins have been shown to associate with HDL-C drug response in vitro and in epidemiologic studies. However, few of the pharmacogenomic findings have been independently validated, precluding the development of clinical tools that can be used to predict HDL-C response and leaving the goal of personalized medicine to future efforts. [ABSTRACT FROM AUTHOR]

Adipose (adp) is an obesity gene in Drosophila and mice with crucial functions in fat metabolism. We investigated the correlation between genetic variation of the WDTC1 locus, the ortholog of adp, and human obesity. Five WDTC1 single-nucleotide polymorphisms (SNPs) were genotyped in 935 and 1,115 adults of two ethnically diverse US populations. In the Boston Puerto Rican population, we demonstrated that two WDTC1 SNPs strongly associated with obesity. Homozygote and heterozygote carriers of the major allele i22835A, representing ~96% of the population, had significantly higher mean BMI (31.5 and 31.0 kg/m2, respectively) than noncarriers (28.6 kg/m2). Conversely, homozygotes of the minor allele i22835G were leaner and were 74% less likely to be overweight or obese (odds ratio (OR) = 0.26, P = 0.003) compared to homozygote carriers of the major allele. Haplotype analyses based on two SNPs further supported these findings. In addition, we found a strong interaction of monounsaturated fatty acid (MUFA) intake by genotype in this population. As dietary MUFA intake increased, minor allele carriers of SNP i22835A>G had higher BMIs, whereas major allele carriers had lower BMIs. A white population also exhibited a pattern of association between WDTC1 genotypes and obesity although of a different nature. Those WDTC1 variants which associated with obesity likely have experienced strong positive selection in human history, when food supply was unpredictable. Given the high frequency of the major alleles in both populations, we suggest that WDTC1 variation may be an important risk factor contributing to obesity in these populations.Obesity (2009) 17 3, 593–600. doi:10.1038/oby.2008.561 [ABSTRACT FROM AUTHOR]

The scavenger receptor class B type 1 ( SCARB1) gene is a key component in the reverse cholesterol transport pathway and thus plays an important role in lipid metabolism. Studies suggest that the SCARB1 gene may contribute to variation in plasma lipid levels at fasting; however, the results have been inconsistent, and it is unclear whether SCARB1 may also influence lipid response to dietary and pharmacologic interventions. In this study, we examined genetic variation in the SCARB1 gene in participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study for associations with basal lipid levels, changes in lipid measures after dietary fat intake, and fenofibrate treatment. We found that the exon 1 variant SCARB1_G2S was significantly associated with postfenofibrate change for triglycerides (TG) ( P = 0.004). Subjects bearing SCARB1_G2S minor allele A tend to have higher responsiveness to fenofibrate in lowering TG. In summary, our study suggested that the SCARB1 gene may serve as a useful marker that predicts variation in baseline lipid levels, postprandial lipid response, and response to fenofibrate intervention. [ABSTRACT FROM AUTHOR]

Chronic inflammation has been identified as an important component of the metabolic syndrome (MetS). Therefore, environmental and genetic factors contributing to the variation of inflammatory responses could affect individuals' susceptibility to MetS. We investigated the association between common IL β genetic polymorphisms, inflammation, and the MetS, and the modulation of diet-related variables (i.e., erythrocyte membrane fatty acid composition) in a white U.S. population. ILβ single nucleotide polymorphisms (SNP) )-1473G > C, -511G > A, -31T> C, 3966C > T, 6054G > AL clinical and biochemical measurements were characterized in a total of 1120 subjects 1540 males and 580 females) participating in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. The 6054 G > A SNP was significantly associated with plasma C-reactive protein (P = 0.054), adiponectin (P = 0.021), and the prevalence of MetS IP = 0.0041. Moreover, there was a significant interaction between the 6054G > A SNP and erythrocyte membrane (n-3) PUFA (P = 0.019). Among subjects with low (n-3) PUFA content (below the median), the 6054 G allele was associated with increased risk of the MetS (OR = 3.29, 95%Cl = 1.49-7.26 for GG and OR = 1.95, 95%C) = 0.85-4.46 for GA, P< 0.001) compared with the AA genotype, but there were no significant genotype associations among subjects with high (n-3) PUFA content (above the medianl. Furtheranalyses supported a significant haplotype global effect on the MetS (P= 0.017) among subjects with low (n-3) PUFA content. These results suggested that IL β genetic variants were associated with measures of chronic inflammation and the MetS risk, and that genetic influences were more evident among subjects with low (n-3) PUFA intake. [ABSTRACT FROM AUTHOR]

Points out that a major focus of the revised guidelines of the U.S. National Cholesterol Education Program Adult Treatment Panel III for cholesterol testing and management is on primary prevention in persons with multiple risk factors. Expansion of the clinical indications for intensive cholesterol lowering; Risk management; Framingham risk score; Options of managing risk of coronary heart disease.

Focuses on the increased risk of myocardial infarction, gastrointestinal hemorrhage and cancer, with the use of calcium channel antagonists for the treatment of hypertension. Information on a study carried out; Results of the study; Discussion based on the results of the study.

Introduction: In collaboration with the Minnesota Hmong community, we have previously discovered significant differences in allele frequencies for key Single Nucleotide Variations (SNVs) within Very Important Pharmacogenes (VIPs) between Hmong and East Asians. Recognizing the potential clinical implications of these observed differences, we sought to validate these observations in a Hmong cohort residing in California, the state with the largest Hmong population in the US. Robust validation of these differences would affect motivation for clinicians treating individuals who identify as Hmong to consider pharmacogenomic (PGx) testing as a means to improve clinical decision making when using therapeutic agents in this unique population., Method: Guided by California Hmong community leaders and utilizing the basic approach of community-based participatory research, demographic, clinical information and a buccal swab was obtained from Hmong adults residing in California. A commercial PGx testing panel was performed on these samples and specific allele frequencies of interest were compared between California and Minnesota Hmong. Allele frequency differences between California Hmong, East Asians and Europeans, were also compared. Return-of-PGx-results and presentations of group data were made to members of the Hmong along with PGx educational sessions to help interpret the observations., Results: In 118 California Hmong who completed the study, the allele frequencies for SNV's were similar to previous Minnesota Hmong results. Furthermore, out of the 18 SNVs that were not previously reported in Hmong, allele frequencies were statistically different in 38% (7/18) of SNVs comparing California Hmong to East Asians, and in 77.8% (14/18) SNVs comparing California Hmong to Europeans., Conclusion: These results validate the original study's findings that Hmong people living in different US locations have similar allele frequencies for key PGx genes. Further, for many of these PGx genes, their allele frequencies are significantly different compared to either East Asians or Europeans. Clinicians should consider these important differences when prescribing medications for people who identify as Hmong., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sun, Thao, Culhane-Pera, Yang, Thor, Yang, Xiong, Vang and Straka.)

The fibric acid derivative, fenofibrate (FF) has been used in the US since 1998 to manage patients with dyslipidemia. Typical changes in serum lipids as result a of FF treatment include clinically important mean reductions of serum triglycerides (TG) by a mean change of -93.7 mg/dL (-39.3%), increases of high density lipoprotein cholesterol (HDLC) by +5.5 mg/dL (+12.4%), and reductions in low density lipoprotein cholesterol (LDLC) by -17.9 mg/dL (-12.3%). The greatest reductions in serum TG are usually observed in subjects with elevated baseline TGs including those with the metabolic syndrome (MetS). Although statins remain the mainstay of therapy for most dyslipidemic patients, their combined use with FF would be expected to address residual risk resulting from less than optimal TG and HDLC levels in such patients. Clinical trials examining the cardiovascular benefits of FF alone or combined with statins have produced mixed results. These observations underscore our lack of understanding of which patients may benefit from FF therapy and which do not. Although FF's basic mechanism of action is known to involve PPAR-alpha agonist activity resulting in altered transcription of several genes, the actual genetic bases for variability in lipid response is poorly understood. Studies, such as our GOLDN study and others designed to better understand the genetic determinants of variability in the response to FF treatment and lipid levels. As a result several important genetic determinants of lipid levels have been identified. For example, in the GOLDN study SNPs from different genes were significantly associated with baseline lipid levels before treatment (APOA5- rs662799, rs3135506; APOC3- rs5128, rs2854117, rs4520); APOA4- rs5104; PPARA- rs9626730, rs135543, rs11703495; LPL- rs1801177), after treatment PPARA- rs11708495; LPL- rs1801177, and appeared to modulate overall response to FF treatment (NOS3- rs1799983). In this article, we will review the literature leading up to the contemporary use of FF as an agent to manage patients with dyslipidemia and focus on emerging understanding of the genetic variability in response to FF treatment. On the basis of the available evidence, we conclude that FF is of benefit in the treatment of dyslipidemia, especially among those with MetS. However, more work is needed to specifically identify which individuals derive a benefit from FF administration in terms of clinical outcomes and which do not - particularly in the context of type 2 diabetes., Competing Interests: CONFLICTS OF INTERESTS None to declare.

Adipose (adp) is an obesity gene in Drosophila and mice with crucial functions in fat metabolism. We investigated the correlation between genetic variation of the WDTC1 locus, the ortholog of adp, and human obesity. Five WDTC1 single-nucleotide polymorphisms (SNPs) were genotyped in 935 and 1,115 adults of two ethnically diverse US populations. In the Boston Puerto Rican population, we demonstrated that two WDTC1 SNPs strongly associated with obesity. Homozygote and heterozygote carriers of the major allele i22835A, representing approximately 96% of the population, had significantly higher mean BMI (31.5 and 31.0 kg/m(2), respectively) than noncarriers (28.6 kg/m(2)). Conversely, homozygotes of the minor allele i22835G were leaner and were 74% less likely to be overweight or obese (odds ratio (OR) = 0.26, P = 0.003) compared to homozygote carriers of the major allele. Haplotype analyses based on two SNPs further supported these findings. In addition, we found a strong interaction of monounsaturated fatty acid (MUFA) intake by genotype in this population. As dietary MUFA intake increased, minor allele carriers of SNP i22835A>G had higher BMIs, whereas major allele carriers had lower BMIs. A white population also exhibited a pattern of association between WDTC1 genotypes and obesity although of a different nature. Those WDTC1 variants which associated with obesity likely have experienced strong positive selection in human history, when food supply was unpredictable. Given the high frequency of the major alleles in both populations, we suggest that WDTC1 variation may be an important risk factor contributing to obesity in these populations.

Background: Hypertriglyceridemia is a risk factor for cardiovascular disease. Variation in the apolipoprotein A5 (APOA5) and glucokinase regulatory protein (GCKR) genes has been associated with fasting plasma triacylglycerol., Objective: We investigated the combined effects of the GCKR rs780094C-->T, APOA5 -1131T-->C, and APOA5 56C-->G single nucleotide polymorphisms (SNPs) on fasting triacylglycerol in several independent populations and the response to a high-fat meal and fenofibrate interventions., Design: We used a cross-sectional design to investigate the association with fasting triacylglycerol in 8 populations from America, Asia, and Europe (n = 7,730 men and women) and 2 intervention studies in US whites (n = 1,061) to examine postprandial triacylglycerol after a high-fat meal and the response to fenofibrate. We defined 3 combined genotype groups: 1) protective (homozygous for the wild-type allele for all 3 SNPs); 2) intermediate (any mixed genotype not included in groups 1 and 3); and 3) risk (carriers of the variant alleles at both genes)., Results: Subjects within the risk group had significantly higher fasting triacylglycerol and a higher prevalence of hypertriglyceridemia than did subjects in the protective group across all populations. Moreover, subjects in the risk group had a greater postprandial triacylglycerol response to a high-fat meal and greater fenofibrate-induced reduction of fasting triacylglycerol than did the other groups, especially among persons with hypertriglyceridemia. Subjects with the intermediate genotype had intermediate values (P for trend <0.001)., Conclusions: SNPs in GCKR and APOA5 have an additive effect on both fasting and postprandial triacylglycerol and contribute to the interindividual variability in response to fenofibrate treatment.

Background: Apolipoprotein A-II (APOA2) plays an ambiguous role in lipid metabolism, obesity, and atherosclerosis., Methods: We studied the association between a functional APOA2 promoter polymorphism (-265T>C) and plasma lipids (fasting and postprandial), anthropometric variables, and food intake in 514 men and 564 women who participated in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study. We obtained fasting and postprandial (after consuming a high-fat meal) measures. We measured lipoprotein particle concentrations by proton nuclear magnetic resonance spectroscopy and estimated dietary intake by use of a validated questionnaire., Results: We observed recessive effects for this polymorphism that were homogeneous by sex. Individuals homozygous for the -265C allele had statistically higher body mass index (BMI) than did carriers of the T allele. Consistently, after multivariate adjustment, the odds ratio for obesity in CC individuals compared with T allele carriers was 1.70 (95% CI 1.02-2.80, P = 0.039). Interestingly, total energy intake in CC individuals was statistically higher [mean (SE) 9371 (497) vs 8456 (413) kJ/d, P = 0.005] than in T allele carriers. Likewise, total fat and protein intakes (expressed in grams per day) were statistically higher in CC individuals (P = 0.002 and P = 0.005, respectively). After adjustment for energy, percentage of carbohydrate intake was statistically lower in CC individuals. These associations remained statistically significant even after adjustment for BMI. We found no associations with fasting lipids and only some associations with HDL subfraction distribution in the postprandial state., Conclusions: The -265T>C polymorphism is consistently associated with food consumption and obesity, suggesting a new role for APOA2 in regulating dietary intake.