A Polynesian-specific missense CETP variant alters the lipid profile.

Identifying population-specific genetic variants associated with disease and disease-predisposing traits is important to provide insights into the genetic determinants of health and disease between populations, as well as furthering genomic justice. Various common pan-population polymorphisms at CETP associate with serum lipid profiles and cardiovascular disease. Here, sequencing of CETP identified a missense variant rs1597000001 (p.Pro177Leu) specific to Maori and Pacific people that associates with higher HDL-C and lower LDL-C levels. Each copy of the minor allele associated with higher HDL-C by 0.236 mmol/L and lower LDL-C by 0.133 mmol/L. The rs1597000001 effect on HDL-C is comparable with CETP Mendelian loss-of-function mutations that result in CETP deficiency, consistent with our data, which shows that rs1597000001 lowers CETP activity by 27.9%. This study highlights the potential of population-specific genetic analyses for improving equity in genomics and health outcomes for population groups underrepresented in genomic studies.

Physical inactivity and excessive sucrose consumption are associated with higher serum lipids in subjects with Taq1B CETP polymorphism.

BACKGROUND: Dyslipidaemias result from the interaction between genetic and environmental factors, including diet disequilibrium and physical inactivity. Among the genetic factors associated with serum lipids, the Taq1B CETP polymorphism has been investigated. The B1 allele has been considered as a risk factor for dyslipidaemia because of its association with greater CETP levels and higher serum triglycerides. The present study aimed to determine the role of the Taq1B polymorphism with lipid and anthropometric variables and its interaction with diet and physical activity. METHODS: In total, 215 subjects were enrolled in this cross-sectional study. Diet intake was evaluated using a 3-day food consumption record and physical activity was determined in accordance with World Health Organization recommendations. The Taq1B CETP polymorphism was determined by allelic discrimination. RESULTS: Subjects with the B1B2/B2B2 genotype, who had a sucrose consumption ≥5% of the total kcal day-1 , had higher levels of total cholesterol (TC) [165.55 (142.21-188.89) mg dL-1 versus 200.19 (184.79-215.60) mg dL-1 ; P for interaction = 0.034] and low-density lipoprotein [99.29 (75.52-123.05) mg dL-1 versus 128.64 (113.59-143.69) mg dL-1 ; P for interaction = 0.037] than subjects with the B1B1 genotype. Subjects who did not perform physical activity and had the B1B2/B2B2 genotype showed significantly higher levels of TC [177.48 (161.36-193.60) mg dL-1 versus 194.49 (185.43-203.56) mg mL-1 ; P for interaction = 0.033] than subjects with the B1B1 genotype. CONCLUSIONS: We provide evidence that subjects with inadequate environmental factors carriers of the polymorphic genotype had higher serum lipid levels than subjects with the B1B1 genotype.

Assessment of established HDL-C loci for association with HDL-C levels and type 2 diabetes in Pima Indians.

AIMS/HYPOTHESIS: Epidemiological studies in Pima Indians identified elevated levels of HDL-cholesterol (HDL-C) as a protective factor against type 2 diabetes risk in women. We assessed whether HDL-C-associated single-nucleotide polymorphisms (SNPs) also associate with type 2 diabetes in female Pima Indians. METHODS: Twenty-one SNPs in established HDL-C loci were initially analysed in 2,675 full-heritage Pima Indians. SNPs shown to associate with HDL-C (12 SNPs) were assessed for association with type 2 diabetes in 7,710 Pima Indians (55.6% female sex). The CETP locus provided the strongest evidence for association with HDL-C and was further interrogated by analysing tag SNPs. RESULTS: Twelve of the 21 SNPs analysed had a significant association with HDL-C in Pima Indians; five SNPs representing four loci (CETP, DOCK6, PPP1R3B and ABCA1) reached genome-wide significance. Three SNPs, at CETP, KLF14 and HNF4A, associated with type 2 diabetes only in female participants with the HDL-C-lowering allele increasing diabetes risk (p values: 3.2 × 10(-4) to 7.7 × 10(-5)); the association remained significant even after adjustment for HDL-C. Additional analysis across CETP identified rs6499863 as having the strongest association with type 2 diabetes in female participants (p = 5.0 × 10(-6)) and this association remained independent of the HDL-C association. CONCLUSIONS/INTERPRETATION: SNPs at the CETP, HNF4A and KLF14 locus are associated with HDL-C levels and type 2 diabetes (in female participants). However, since HNF4A and KLF14 are established loci for type 2 diabetes, it is unlikely that HDL-C solely mediates these associations.

Ethnic differences in the association between lipid metabolism genes and lipid levels in black and white South African women.

OBJECTIVE: Dyslipidaemia can lead to the development of atherosclerosis and cardiovascular disease (CVD), however its prevalence has been shown to differ between ethnic groups in South Africa (SA). Therefore the aim of this study was to investigate ethnic differences in the association between serum lipid levels and polymorphisms within genes involved in lipid metabolism in black and white SA women. METHODS: In a convenient sample of 234 white and 209 black SA women of Xhosa ancestry, body composition (DXA) and fasting serum lipids were measured. Participants were genotyped for the cholesteryl ester transfer protein (CETP, rs708272, B1/B2), lipoprotein lipase (LPL, rs328, S/X), hepatic lipase (LIPC, rs1800588, C/T) and proprotein convertase subtilisin/kexin type 9 (PCSK9, rs28362286, C/X) polymorphisms. RESULTS: Compared to white women, black women had lower concentrations of serum total cholesterol (TC, P < 0.001), low density lipoprotein cholesterol (LDL-C, P < 0.001), high density lipoprotein cholesterol (HDL-C, P < 0.001) and triglycerides (TG, P < 0.001). There were significant differences in the genotype and allele frequency distributions between black and white women for the LPL S/X (P < 0.001), PCSK9 C679X (P = 0.002) and LIPC 514C/T (P < 0.001) polymorphisms. In black women only, there were genotype effects on serum lipid levels. Specifically, women with the LPL SX genotype had lower TC and LDL-C and higher HDL-C concentrations than those with the SS genotype and women with the CETP B2 allele had lower LDL-C concentrations than those with the B1B1 genotype. CONCLUSION: Polymorphisms within the LPL and CETP genes were associated with a more protective lipid profile in black, but not white SA women. This supports the hypothesis that the more favorable lipid profile of black compared to white SA women is associated with polymorphisms in lipid metabolism genes, specifically the LPL and CETP genes.

Review of the cost effectiveness of pharmacogenetic-guided treatment of hypercholesterolaemia.

Hypercholesterolaemia is a highly prevalent condition that has major health and cost implications for society. Pharmacotherapy is an important and effective treatment modality for hypercholesterolaemia, with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ('statins') the most commonly used class of drugs. Over the past decade, there has been intensive research to identify pharmacogenetic markers to guide treatment of hypercholesterolaemia. This study aimed to review the evidence of incremental cost, effect and cost effectiveness of pharmacogenetic-guided treatment of hypercholesterolaemia. Three cost-effectiveness analyses (CEAs) were identified that studied the value of screening for genotypes of angiotensin I converting enzyme (ACE), cholesteryl ester transfer protein (CETP), and kinesin family member 6 (KIF6) prior to initiating statin therapy. For all three CEAs, a major limitation identified was the reproducibility of the evidence supporting the clinical effect of screening for the pharmacogenetic marker. Associated issues included the uncertain value of pharmacogenetic markers over or in addition to existing approaches for monitoring lipid levels, and the lack of evidence to assess the effectiveness of alternative therapeutic options for individuals identified as poor responders to statin therapy. Finally, the economic context of the market for diagnostic tests (is it competitive or is there market power?) and the practicality of large-scale screening programmes to inform prescribing in a complex and varied market may limit the generalizability of the results of the specific CEAs to policy outcomes. The genotype of solute carrier organic anion transporter family member 1B1 (SLCO1B1) has recently been associated with increased risk of muscle toxicity with statin therapy and the review identified that exploration of cost effectiveness of this pharmacogenetic marker is likely warranted.

Simultaneous detection of multiple single-nucleotide polymorphisms by a simple membrane chip.

Technologies that screen multiple single-nucleotide polymorphisms (SNPs) could be very valuable in predicting patients' susceptibilities to diseases or responses to therapeutic interventions. In this study, we developed a chip that can accurately detect four SNPs at same time. This chip is cost-effective and user-friendly because it uses a detection protocol analogous to dot blotting and does not require sophisticated instruments. To establish this chip, we designed and blotted onto a nylon membrane SNP-specific oligonucleotide probes for human angiotensinogen, cholesteryl ester transfer protein, and apolipoprotein E. This chip detected the corresponding SNPs harbored within the angiotensinogen, cholesteryl ester transfer protein, and apolipoprotein E sequences from 20 donors. Importantly, the SNPs detected by our chip matched exactly with the direct sequencing results, thereby highlighting the accuracy of this chip. In conclusion, our chip is a robust tool for multiple SNP screening and holds the potential to future refinement in detecting diseases-associating genes in patients.