CETP Rs5882 Research Articles

Genetic polymorphisms and their correlation with dyslipidemia in Chinese patients diagnosed with diabetes mellitus.

Dyslipidemia is a common complication in patients with diabetes mellitus (DM) that increases the risk of cardiovascular disease. Genetic polymorphisms have been implicated in the development of dyslipidemia. To investigate the association between polymorphisms of candidate genes involved in lipid metabolism and dyslipidemia in Chinese patients with DM. A cross-sectional study was conducted on 1098 Chinese patients with DM recruited from multiple healthcare centers. Demographic and clinical data were collected, and dyslipidemia was defined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Genomic DNA was extracted from blood samples and genotyping for selected polymorphisms of candidate genes (APOE, LPL, CETP, and others) was performed using PCR and DNA sequencing techniques. Statistical analyses were performed using logistic regression models adjusted for potential confounding factors. The study population consisted of 578 males (52.6%) and 520 females (47.4%), with a mean age of 58.4 ± 12.2 years. The prevalence of dyslipidemia was 64.8%. Significant associations were found between dyslipidemia and the APOE rs7412 T/T, APOE rs429358 C/C, LPL rs328 G/G, and CETP rs708272 G/G genotypes after adjusting for covariates. Subgroup analyses showed generally consistent associations across subgroups, although some variations in effect sizes were observed. This study identified significant associations between genetic polymorphisms of APOE, LPL, and CETP genes and dyslipidemia in Chinese patients with DM.

Association of the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) Polymorphisms With Risk of Coronary Artery Disease in Iranian Patients.

Coronary artery disease (CAD) is a devastating illness and a leading cause of death worldwide, primarily caused by atherosclerosis resulting from a genetic-environmental interaction. This study aimed to investigate the relationship between the ESR1 (rs9340799), OLR1 (rs3736234), LIPC (rs2070895), VDR (rs2228570), and CETP (rs708272) polymorphisms, lipid profile parameters, and CAD risk in a southeast Iranian population. A total of 400 subjects (200 CAD patients with hyperlipidemia and 200 healthy controls) were enrolled in this case-control study. Five selected polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. For all single nucleotide polymorphisms (SNPs), the population under study was in the Hardy-Weinberg equilibrium. The T-risk allele frequency of rs2228570 was associated with an increased risk of CAD. The TT and CT genotypes of rs2228570 had also been associated with the risk of CAD. Additionally, the TT genotype was associated with higher serum low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels. The GG genotype of the rs3736234 was associated with higher body mass index (BMI) and triglyceride (TG) levels, and the AA genotype of the rs708272 was associated with higher HDL-c levels. Based on these findings, we propose that the VDR (rs2228570) polymorphism was associated with serum HDL-c and LDL-c levels and may serve as potential risk factors for CAD within the Iranian population. Moreover, rs3736234 and rs708272 influence the concentrations of TG and HDL-c, respectively. These findings provided insights into the complex interplay between genetic variations, cardiovascular risk, and lipid metabolism.

Population-Based Impact of Smoking, Drinking, and Genetic Factors on HDL-Cholesterol Levels in J-MICC Study Participants.

Environmental and genetic factors are suggested to exhibit factor-based association with HDL-cholesterol (HDL-C) levels. However, the population-based effects of environmental and genetic factors have not been compared clearly. We conducted a cross-sectional study using data from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study to evaluate the population-based impact of smoking, drinking, and genetic factors on low HDL-C. Data from 11,498 men and women aged 35-69 years were collected for a genome-wide association study (GWAS). Sixty-five HDL-C-related SNPs with genome-wide significance (P < 5 × 10-8) were selected from the GWAS catalog, and seven representative SNPs were defined, and the population-based impact was estimated using population attributable fraction (PAF). We found that smoking, drinking, daily activity, habitual exercise, egg intake, BMI, age, sex and the SNPs CETP rs3764261, APOA5 rs662799, LIPC rs1800588, LPL rs328, ABCA1 rs2575876, LIPG rs3786247, and APOE rs429358 were associated with HDL-C levels. The gene-environmental interactions on smoking and drinking were not statistically significant. The PAF for low HDL-C was the highest in men (63.2%) and in rs3764261 (31.5%) of the genetic factors, and the PAFs of smoking and drinking were 23.1% and 41.8%, respectively. The present study showed that the population-based impact of genomic factor CETP rs3764261 for low HDL-C was higher than that of smoking and lower than that of drinking.

The effect of the association between CETP variant type and alcohol consumption on cholesterol level differs according to the ALDH2 variant type

Alcohol consumption is associated with a high increased lipid profile and this association may depend on genetic risk factors. In this study, we aimed to assess the effects of genetic variation associated with alcohol consumption on lipid profiles using data from two Korean population studies. We performed a genotype association study using the HEXA (n = 51,349) and KNHANES (n = 9158) data. Genotype analyses of the two sets of Korean population data showed associations of increased total cholesterol and high-density lipoprotein (HDL)-cholesterol with CETP rs708272. The HEXA and KNHANES populations revealed differences in HDL cholesterol according to the presence of CETP rs708272, independent of ALDH2 rs671 and alcohol consumption. In contrast, total cholesterol levels were associated with alcohol consumption and ALDH2 rs671 in men with CETP rs708272 (CT and TT genotypes). Furthermore, in drinkers with ALDH2 rs671 (GA and AA genotypes), higher total cholesterol was associated with the CETP rs708272 TT minor homozygous genotype based on both HEXA and KNHANES data. Our findings demonstrated that alcohol consumption and genetic variation in either CETP or ALDH2 may be associated with cholesterol levels. We hope these findings will provide a better understanding of the relationship between alcohol consumption and cholesterol according to each individual’s genetic background.

T and genetic variations between Asian and Caucasian polypoidal choroidal vasculopathy

PurposeTo compare phenotypic and genetic variations in polypoidal choroidal vasculopathy (PCV) between Caucasian and Asian patients.MethodsWe analysed phenotypic and genotypic data from two sites, Association for Innovation and Biomedical Research...

Association between Polygenic Risk Score and One-Year Outcomes Following As-Needed Aflibercept Therapy for Exudative Age-Related Macular Degeneration.

We investigated whether polygenic risk score (PRS) was associated with one-year outcome of as-needed aflibercept therapy for exudative age-related macular degeneration (AMD), including AMD (n = 129) and polypoidal choroidal vasculopathy (n = 132). A total of 261 patients were treated with as-needed intravitreal aflibercept injection (IAI) after three monthly IAIs and the completion of a one-year follow-up. One hundred and seventy-two healthy volunteers served as controls. Genotyping of ARMS2 A69S (rs10490924), CFH I62V (rs800292), SKIV2L-C2-CFB (rs429608), C3 (rs2241394), ADAMTS-9 (rs6795735) and CETP (rs3764261) was performed for all participants. A total of 63 PRSs were quantified. There was a positive association between the PRS involving ARMS2, CFH, C3, and ADAMTS-9 and best-corrected visual acuity at twelve months (p = 0.046, multiple regression analysis). When comparing PRSs of patients requiring retreatment and of patients without retreatment, 35 PRSs were significantly greater in patients requiring retreatment than in patients without requiring retreatment, with the PRS involving ARMS2 and CFH being most significantly associated (p = 1.6 × 10−4). The number of additional injections was significantly associated with 40 PRSs and the PRS involving ARMS2 and CFH showed a most significant p-value (p = 2.42 × 10−6). Constructing a PRS using a combination with high-risk variants might be informative for predicting the response to IAI for exudative AMD.

Association of ESR1 (rs2234693 and rs9340799), CETP (rs708272), MTHFR (rs1801133 and rs2274976) and MS (rs185087) polymorphisms with Coronary Artery Disease (CAD)

BackgroundCoronary artery disease (CAD) is a complex disease resulting from the cumulative and interactive effects of large number of genes along with environmental exposure. Therefore, the present study was envisaged as an effort to study the association of candidate genes ESR1 (rs2234693 and rs9340799), CETP (rs708272), MTHFR (rs1801133 and rs2274976) and MS (rs185087) polymorphisms with the risk of CAD, targeting the populations of Jammu (JandK).MethodA total of 400 confirmed CAD patients and 400 healthy controls were enrolled for the present study. Genotyping was done by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP).ResultsESR1 gene (rs9340799) polymorphism was found to be associated with CAD in all the genetic models. The haplotype analysis of ESR1 (rs2234693 and rs9340799) gene revealed that C-G haplotype was conferring approximately 5-fold risk and T-A haplotype was adding 1.4-fold risk towards the disease. ‘T’ allele of MTHFR rs1801133 SNP was observed to be responsible for development of CAD in our study population (p < 0.0001). In case of MTHFR (rs1801133 and rs2274976) gene, the haplotype T-G was observed to confer 4.7-fold risk towards CAD whereas haplotype C-G provided nearly a 1.7 fold protection towards development of CAD. For MS gene, rs185087 was also found to be associated with CAD in a co-dominant (p = 0.003 and p = 0.03), dominant (p = 0.001) and allelic models (p = 0.001). The gene-gene interaction revealed strong epistasis between single nucleotide polymorphisms (SNPs), ESR1 rs9340799 and MTHFR rs2274976. Furthermore, the dendrogram for gene-environment dataset indicated moderately synergistic interaction between CETP rs708272 and physical inactivity.ConclusionIn the study under reference, a significant association of ESR1-XbaI (rs9340799), MTHFR C677T (rs1801133) and MS A2756G (rs185087) gene polymorphisms with the susceptibility of CAD in the population of Jammu region (JandK) has been observed.

Association of genetic variants at CETP, AGER, and CYP4F2 locus with the risk of atrophic age-related macular degeneration.

BackgroundAge‐related macular degeneration (AMD) is the leading cause of blindness in the elderly individuals. The etiology of AMD includes environmental and genetic factors.MethodsWe aimed to determine the association between CETP (rs5882; rs708272; rs3764261; rs1800775; rs2303790), AGER (rs1800624; rs1800625), and CYP4F2 (rs1558139) gene polymorphisms and development of atrophic AMD. About 52 patients with atrophic AMD and 800 healthy control subjects were evaluated. The genotyping of single‐nucleotide polymorphisms in CETP, AGER, and CYP4F2 was carried out using the real‐time‐PCR method.ResultsGenetic risk models in the analysis of CETP rs5882 revealed statistically significant variables with increased risk of atrophic AMD in the codominant (p < .001), dominant (p < .001), recessive (p < .001), and additive (p < .001) models with the highest 25.4‐fold increased risk of atrophic AMD in the codominant model (p < .001). The AGER rs1800625 was associated with a highly increased risk of atrophic AMD in the codominant (p < .001), recessive (p < .001), and additive (p < .001) genetic models.ConclusionWe identified two polymorphisms with a higher risk of atrophic AMD (CETP rs5882 and AGER rs1800625).

Genetic factors associated with response to as-needed aflibercept therapy for typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy

In the present study, we investigated the association between susceptible genetic variants to age-related macular degeneration (AMD) and response to as-needed intravitreal aflibercept injection (IAI) therapy for exudative AMD including both typical neovascular AMD and polypoidal choroidal vasculopathy (PCV) over 12-months. A total of 234 patients with exudative AMD were initially treated with 3 monthly IAI and thereafter as-needed IAI over 12 months. Seven variants of 6 genes including ARMS2 A69S (rs10490924), CFH (I62V:rs800292 and rs1329428), C2-CFB-SKIV2L(rs429608), C3 (rs2241394), CETP (rs3764261) and ADAMTS-9 (rs6795735) were genotyped for all participants using TaqMan technology. After adjusting for age, gender, baseline BCVA and AMD subtype, A (protective) allele of C2-CFB-SKIV2L rs429608 was associated with visual improvement at 12-month (P = 0.003). Retreatment was associated with T(risk) allele of ARMS2 A69S (P = 2.0 × 10−4; hazard ratio: 2.18:95%CI: 1.47-3.24) and C(risk) allele of CFH rs1329428 (P = 2.0 × 10−3; hazard ratio: 1.74:95%CI: 1.16–2.59) after adjusting for the baseline confounders. The need for additional injections was also associated with T allele of ARMS2 A69S (P = 1.0 × 10−5) and C allele of CFH rs1329428 (P = 3.0 × 10−3) after adjusting for the baseline confounders. The variants of ARMS2 and CFH are informative for both physicians and patients to predict recurrence and to quantify the need for additional injections.

The influence of gene polymorphisms on postprandial triglyceride response after oral fat tolerance test meal in patients with diabetes mellitus.

We evaluated the influence of CETP (rs5882 and rs708272), APOE (rs7412, rs429358) and LPL (rs328) gene polymorphisms on triglyceride (TG) response to oral fat tolerance test (OFTT) meal in patients with well-controlled type 2 diabetes mellitus (T2DM). Fifty-one men underwent OFTT and according to postprandial TG response patients were divided into two subgroups (positive [TG≥220mg/dL, 31 patients] and negative [TG<220mg/dL, 20 patients]). All patients were genotyped, and study variants were detected using polymerase chain reaction (PCR) and restricted fragment length polymorphism (RFLP) analysis. Patients with genotype SS of LPL gene compared with genotype SX had more frequently positive response to OFTT (P=.04) and lower high-density lipoprotein cholesterol (HDL-C) concentration (P=.03). Patients with positive response to OFTT and genotype SS of LPL gene compared with genotype SX had lower AUC (area under the curve)-TG, 1744 (368) vs 1887 (807) mg/dL/h, respectively, P=.04. CETP and APOE gene polymorphisms had no influence on postprandial TG response to OFTT. In patients with well-controlled T2DM, LPL but not CETP and APOE gene polymorphisms influenced TG postprandial response. Particularly, S447 allele carriers of LPL gene presented more frequently positive postprandial TG response to OFTT compared with 447X allele carriers. No differences were found between allele carriers of patients with negative response to OFTT in any other studied gene polymorphism.

Genome-Wide Association Study of Metabolic Syndrome Reveals Primary Genetic Variants at CETP Locus in Indians.

Indians, a rapidly growing population, constitute vast genetic heterogeneity to that of Western population; however they have become a sedentary population in past decades due to rapid urbanization ensuing in the amplified prevalence of metabolic syndrome (MetS). We performed a genome-wide association study (GWAS) of MetS in 10,093 Indian individuals (6617 MetS and 3476 controls) of Indo-European origin, that belong to our previous biorepository of The Indian Diabetes Consortium (INDICO). The study was conducted in two stages—discovery phase (N = 2158) and replication phase (N = 7935). We discovered two variants within/near the CETP gene—rs1800775 and rs3816117—associated with MetS at genome-wide significance level during replication phase in Indians. Additional CETP loci rs7205804, rs1532624, rs3764261, rs247617, and rs173539 also cropped up as modest signals in Indians. Haplotype association analysis revealed GCCCAGC as the strongest haplotype within the CETP locus constituting all seven CETP signals. In combined analysis, we perceived a novel and functionally relevant sub-GWAS significant locus—rs16890462 in the vicinity of SFRP1 gene. Overlaying gene regulatory data from ENCODE database revealed that single nucleotide polymorphism (SNP) rs16890462 resides in repressive chromatin in human subcutaneous adipose tissue as characterized by the enrichment of H3K27me3 and CTCF marks (repressive gene marks) and diminished H3K36me3 marks (activation gene marks). The variant displayed active DNA methylation marks in adipose tissue, suggesting its likely regulatory activity. Further, the variant also disrupts a potential binding site of a key transcription factor, NRF2, which is known for involvement in obesity and metabolic syndrome.

Genetic Variants in Lipid Metabolism Pathways Interact with Diet to Influence Blood Lipid Concentrations in Adults with Overweight and Obesity (P15-015-19)

ObjectivesThere is substantial controversy regarding the role of saturated (SFA) and unsaturated fat intake for optimal cardiometabolic health due to the heterogeneity of blood lipid changes in clinical trials. This variance may be due to genetic differences. Studying physiologically relevant variants can elucidate the mechanisms between genotype and metabolism. The objective of this study was to determine relationships between genetic variation, fat intake, and blood lipid concentrations. MethodsDNA, blood lipid concentrations (total cholesterol, high-density lipoprotein cholesterol [HDL], and triglycerides [TG]), and 7-day diet records were obtained from 87 adults (25–45 years) with overweight or obesity. Resting energy expenditure (REE) was measured using indirect calorimetry and used to determine implausible intake using a modified Goldberg method (kilocalories/REE). Genetic variants included 22 single nucleotide polymorphisms (SNPs) from genes in lipid metabolism pathways. Variants were analyzed with dietary fat intake (total fat, SFA, monounsaturated fat [MUFA], and polyunsaturated fat) via regression analyses. ResultsNine SNPs (ANGPTL3 rs10889337, ANGPTL4 rs7255436, APOE rs1044250, CETP rs5882, FADS1 rs174548 and rs174550, LPL rs13702 and rs328, PPARG rs12639162) were associated with one or more blood lipid traits. Two significant diet-gene interactions were detected: the interaction of total fat intake and LPL rs13702 was associated with HDL concentrations (P = 0.01), and the interaction of MUFA intake and CETP rs5882 was associated with TG concentrations (P = 0.01). Carriers of the minor allele that reported higher total fat intake exhibited higher HDL concentrations, while minor allele carriers with higher MUFA intake exhibited lower TG concentrations. ConclusionsInteractions between diet and genes in lipid metabolism pathways were predictors of blood lipid concentrations in adults. Fat intake may not affect blood lipid concentrations uniformly across all individuals. Therefore, personalized diet recommendations for chronic disease prevention are warranted. Funding SourcesSupport is provided by the Hass Avocado Board, the Division of Nutritional Sciences at the University of Illinois at Urbana-Champaign, the USDA National Institute of Food and Agriculture Hatch Project, and the Agriculture and Food Research Initiative. Supporting Tables, Images and/or Graphs▪▪

Associations of cholesteryl ester transfer protein (CETP) gene variants with pituitary adenoma.

The aim was to evaluate the association of CETP (rs5882 and rs708272) single nucleotide polymorphisms with the presence, invasiveness, hormonal activity and recurrence of pituitary adenoma (PA). The study group included 142 patients with PA and the control group, 753 healthy subjects. The genotyping of CETP (rs5882 and rs708272) was performed using a real-time PCR method. After statistical analysis we found that CETP rs708272 genotype G/A under the over-dominant model was associated with the decreased odds of PA (OR=0.637; 95%CI: 0.443-0.917; P=0.015), active PA (OR=0.538; 95%CI: 0.335-0.865; P =0.01) and non-recurrent PA (OR=0.602; 95% CI: 0.402 - 0.902; P =0.014). When compared to controls, the rs708272 genotype G/A was less frequent in the active PA subgroup (37.5% vs 52.7%, P =0.009) and the non-recurrent PA subgroup (40.2% vs 52.7%, P=0.013), while the rs5882 genotype A/A was less frequent in the non-recurrent PA subgroup (37.5% vs 46.2%, P=0.015). Our study showed that CETP rs708272 genotype G/A may be associated with a decreased risk of PA.

There is an association between a genetic polymorphism in the ZNF259 gene involved in lipid metabolism and coronary artery disease

BackgroundRecent genome-wide association studies (GWAS) have identified several genetic variants that influence the risk of dyslipidemia and coronary artery disease (CAD). In this study, we have examined the potential association of five SNPs variants related to lipid pathway, previously identified in GWAS studies (ZNF259 C>G, CETP I405VA/G, LPA C>T, LPLS447X and PSRC1 A>G) with CAD. MethodsTwo hundred and ninety subjects including 194 patients with coronary artery disease and 96 controls were enrolled, followed by the analyses of anthropometric/biochemical parameters. Genotyping was carried out using Taq-Man real-time PCR based method. The association of the genetic polymorphisms with CAD was determined using univariate and multivariate analyses. ResultsCAD patients had a higher (p < 0.05) fasting blood glucose (FBG), total cholesterol (TC), high sensitivity C-reactive protein (hs-CRP), low-density lipoprotein cholesterol (LDL-C) and waist circumference. Results showed that subjects with CETP rs5882 genetic variant, AA&AG genotypes, had a higher risk of developing Coronary artery disease [OR: 2.1, 95% CI (1.2–4.1), p value = 0.015]. Also subjects who carried the G allele of the ZNF259 polymorphism were at an increased the risk of developing CAD [OR 1.86, 95% CI: 1.06–3.25, p value = 0.029] and had an increased TC, LDL and TG levels (p < 0.05). Furthermore, no statistically significant association was found between genetic polymorphisms of PSRC1 A>G, LPL S447X and LPA C>T and CAD. ConclusionWe identified a relationship between a genetic variant in CETP and ZNF259 gene with CAD and CAD and lipid profile, respectively. Further investigation in a larger population may help to investigate the value of emerging marker as a risk stratification marker in CAD and its risk factors.

Generalizability and applicability of results obtained from populations of European descent regarding the effect direction and size of HDL-C level-associated genetic variants to the Hungarian general and Roma populations

ObjectivesLarge-scale association studies that mainly involve European populations identified many genetic loci related to high-density lipoprotein cholesterol (HDL-C) levels, one of the most important indicators of the risk for cardiovascular diseases. The question with intense speculation of whether the effect estimates obtained from European populations for different HDL-C level-related SNPs are applicable to the Roma ethnicity, the largest minority group in Europe with a South Asian origin, was addressed in the present study. DesignThe associations between 21 SNPs (in the genes LIPC(G), CETP, GALNT2, HMGCP, ABCA1, KCTD10 and WWOX) and HDL-C levels were examined separately in adults of the Hungarian general (N = 1542) and Roma (N = 646) populations by linear regression. Individual effects (direction and size) of single SNPs on HDL-C levels were computed and compared between the study groups and with data published in the literature. ResultsSignificant associations between SNPs and HDL-C levels were more frequently found in general subjects than in Roma subjects (11 SNPs in general vs. 4 SNPs in Roma). The CETP gene variants rs1532624, rs708272 and rs7499892 consistently showed significant associations with HDL-C levels across the study groups (p ˂ 0.05), indicating a possible causal variant(s) in this region.Although nominally significant differences in effect size were found for three SNPs (rs693 in gene APOB, rs9989419 in gene CETP, and rs2548861 in gene WWOX) by comparing the general and Roma populations, most of these SNPs did not have a significant effect on HDL-C levels.The β coefficients for SNPs in the Roma population were found to be identical both in direction and magnitude to the effect obtained previously in large-scale studies on European populations. ConclusionsThe effect of the vast majority of the SNPs on HDL-C levels could be replicated in the Hungarian general and Roma populations, which indicates that the effect size measurements obtained from the literature can be used for risk estimation for both populations.

Weight gain prevention buffers the impact of CETP rs3764261 on high density lipoprotein cholesterol in young adulthood: The Study of Novel Approaches to Weight Gain Prevention (SNAP)

Background and AimsTwo weight gain prevention strategies, one targeting small changes to diet and physical activity and a second targeting large changes, significantly reduced weight gain in young adulthood. We examined whether weight gain prevention blunts genetic risk for body weight increase and/or high density lipoprotein cholesterol (HDL-C) lowering over two years. Methods and ResultsParticipants were 524 male and female young adults (mean age = 28.2, SD = 4.3; mean BMI = 25.5, SD = 2.6). Obesity-related SNPs accounting for ≥ 0.04% of the variance were genotyped and combined into a genetic risk score. For HDL-C, SNPs within CETP, LIPC and FADS2 were genotyped. The obesity-related genetic risk score did not predict change in BMI independently or in interaction with treatment arm. However, consistent with the prior literature, each copy of the HDL-C risk, C, allele at CETP rs3764261 was associated with lower HDL-C at baseline. Moreover, significant interaction between SNP and treatment arm for change in HDL-C was observed (p = 0.02). In the control group, HDL-C change was dependent upon rs3764261 (p = 0.004) with C allele carriers showing a continued reduction in HDL-C. In contrast, within the two intervention groups, HDL-C increased on average with no differential effect of rs3764261 (p > 0.24). Notably, even among carriers of the CC genotype, small and large change arms were associated with increased HDL-C and the control arm a reduction (p = 0.013). ConclusionsThe C allele at CETP rs3764261 is a strong risk factor for low HDL-C in young adulthood but weight gain prevention may mitigate this risk. Clinical Trial Registry number and websiteclinicaltrials.gov Identifier: NCT01183689, https://clinicaltrials.gov/

Association of genetic polymorphisms of PON1 and CETP with the presence of metabolic syndrome; the effects of genotypes on their serum activity and concentrations

BackgroundThe Metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease and type 2 diabetes. PON1 and CETP genes may be involved in the pathogenesis of lipid metabolism and thus MetS. Several single nucleotide polymorphisms of genes were demonstrated to affect their function. Curcumin (diferuloylmethane) is a yellow pigment of turmeric that has shown numerous pharmacological activity against obesity and related conditions through anti-oxidant/anti-inflammatory properties. ObjectiveWe aimed to assess the association of these polymorphisms with metabolic syndrome and to investigate if these genetic variants were associated with an altered activity of PON1 and the protein levels of CETP at base line and after Curcumin supplementation. MethodsThe genotypes of PON1 and CETP polymorphisms were determined in 81 patients with MetS and 100 healthy individuals using ARMS-PCR and PCR-RFLP techniques. ResultsIndividuals with different genotypes of the PON1 rs662, rs854560 and rs705379 polymorphisms did not differ with paraoxonase activity and CETP serum protein concentrations, either at baseline, or after intervention. Individuals with different PON1 rs854560 genotypes differ significantly in serum arylesterase activities (p = .037). There were statistically significant differences in genotype frequencies between cases and controls for CETP rs5882 genotypes (p-value = .034) but not in genotype frequencies and haplotypes for PON1 studied polymorphisms (p-value < .05). The odds ratio for CETP rs5882 was statistically significant using a dominant model. OR (95% CI) = 0.48 (025–0.92), p-value = .029. ConclusionsThere were no associations between the PON1 polymorphisms, or haplotypes with MetS. There was an association between CETPrs5882 and metabolic syndrome. AA genotype of CETPrs5882 appeared to be protective against MetS in our studied population. There were no association between the PON1 and CETP polymorphisms with PON1enzymatic activities and CETP protein levels at base line and after curcumin supplementation.

Genetic contribution to lipid levels in early life based on 158 loci validated in adults: the FAMILY study

The contribution of polymorphisms associated with adult lipids in early life is unknown. We studied 158 adult lipid polymorphisms in 1440 participants (544 children, 544 mothers and 324 fathers) of the Family Atherosclerosis Monitoring In early life (FAMILY) birth cohort. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) measurements were collected at birth, 3 and 5 years of age. Polymorphisms were genotyped using the Illumina Cardio-Metabochip array. Genotype scores (GS) were calculated for TC, HDL-C, LDL-C and TG. Linear and mixed-effects regressions adjusted for sex, age and population stratification were performed. The GS was associated with LDL-C level at 3 and 5 years (β = 0.017 ± 0.003, P = 2.9 × 10−8; β = 0.020 ± 0.003, P = 5.7 × 10−9) and from birth to 5 years (β = 0.013 ± 0.003, P = 2.6 × 10−7). The GS was associated with TC level at 3 and 5 years (β = 0.009 ± 0.002, P = 9.1 × 10−7; β = 0.009 ± 0.002, P = 7.7 × 10−6). CETP rs3764261 was associated with the HDL-C level from birth to 5 years (β = 0.064 ± 0.014, P = 7.4 × 10−6). AMPD3 rs2923084 was associated with the HDL-C level at 5 years (β = 0.096 ± 0.024, P = 9.7 × 10−5). Known loci associated with blood lipids in adults are associated with TC, LDL-C and HDL-C, but not TG in early life. Genetically predisposed children may benefit from early lipid lowering preventative strategies.

Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants

Background and aimsConventional coronary artery disease (CAD) risk factors like age, gender, blood lipids, hypertension and smoking have been the basis of CAD risk prediction algorithms, but provide only modest discrimination. Genetic risk score (GRS) may provide improved discrimination over and above conventional risk factors. Here we analyzed the genetic risk of CAD in subjects from Pakistan, using a GRS of 21 variants in 18 genes and examined whether the GRS is associated with blood lipid levels. Methods625 (405 cases and 220 controls) subjects were genotyped for variants, NOS3 rs1799983, SMAD3 rs17228212, APOB rs1042031, LPA rs3798220, LPA rs10455872, SORT1 rs646776, APOE rs429358, GLUL rs10911021, FTO rs9939609, MIA3 rs17465637, CDKN2Ars10757274, DAB2IP rs7025486, CXCL12 rs1746048, ACE rs4341, APOA5 rs662799, CETP rs708272, MRAS rs9818870, LPL rs328, LPL rs1801177, PCSK9 rs11591147 and APOE rs7412 by TaqMan and KASPar allele discrimination techniques. ResultsIndividually, the single SNPs were not associated with CAD except APOB rs1042031 and FTO rs993969 (p = 0.01 and 0.009 respectively). However, the combined GRS of 21 SNPs was significantly higher in cases than controls (19.37 ± 2.56 vs. 18.47 ± 2.45, p = 2.9 × 10−5), and compared to the bottom quintile, CAD risk in the top quintile of the GRS was 2.96 (95% CI 1.71–5.13). Atherogenic blood lipids showed significant positive association with GRS. ConclusionsThe GRS was quantitatively associated with CAD risk and showed association with blood lipid levels, suggesting that the mechanism of these variants is likely to be, in part at least, through creating an atherogenic lipid profile in subjects carrying high numbers of risk alleles.

Polymorphisms of lipid metabolism enzyme-coding genes in patients with diabetic dyslipidemia.

Objective:The polymorphisms/mutations of genes encoding proteins and enzymes involved in lipoprotein metabolism play important roles in the development of diabetic dyslipidemia. The aim of our study was to investigate the effects of LPL (rs320), LIPC (rs2070895), SCARB1 (rs5888), LCAT (rs2292318), CETP (rs708272), ADIPOQ (rs1501299), RETN (rs3745367), PON1 (rs662), and MNSOD (rs4880) gene polymorphisms on lipid metabolism and diabetic dyslipidemia.Methods:This case-control study included 217 patients with diabetic dyslipidemia and 212 healthy age- and gender-matched individuals. Genomic DNA isolation was performed from blood samples, and genotype analysis was performed using melting curve analysis on a LightCycler® 480 Instrument. The chi-square test was used to compare genotype distribution and allele frequencies between the groups.Results:Significant associations were observed between LPL (rs320) (p<0.001), LIPC (rs2070895) (p<0.001), SCARB1 (rs5888) (p<0.001), LCAT (rs2292318) (p<0.001), CETP (rs708272) (p<0.001), ADIPOQ (rs1501299) (p=0.01), RETN (rs3745367) (p<0.001), and MNSOD (rs4880) (p<0.001) polymorphisms and diabetic dyslipidemia. However, no association was observed between PON1 (rs662) polymorphisms and diabetic dyslipidemia (p=0.611).Conclusion:LPL (rs320), LIPC (rs2070895), SCARB1 (rs5888), LCAT (rs2292318), CETP (rs708272), ADIPOQ (rs1501299), RETN (rs3745367), and MNSOD (rs4880) polymorphisms play an important role in basic molecular metabolism in diabetic dyslipidemia. Therefore, these polymorphisms may be used as a predictive marker for diabetic dyslipidemia in high-risk patients. (Anatol J Cardiol 2017; 17: 313-21)