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1.
Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.
van Leeuwen, EM, Karssen, LC, Deelen, J, Isaacs, A, Medina-Gomez, C, Mbarek, H, Kanterakis, A, Trompet, S, Postmus, I, Verweij, N, et al
Nature communications. 2015;:6065
Abstract
Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.
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2.
Non-cholesterol sterol levels predict hyperglycemia and conversion to type 2 diabetes in Finnish men.
Cederberg, H, Gylling, H, Miettinen, TA, Paananen, J, Vangipurapu, J, Pihlajamäki, J, Kuulasmaa, T, Stančáková, A, Smith, U, Kuusisto, J, et al
PloS one. 2013;(6):e67406
Abstract
We investigated the levels of non-cholesterol sterols as predictors for the development of hyperglycemia (an increase in the glucose area under the curve in an oral glucose tolerance test) and incident type 2 diabetes in a 5-year follow-up study of a population-based cohort of Finnish men (METSIM Study, N = 1,050) having non-cholesterol sterols measured at baseline. Additionally we determined the association of 538,265 single nucleotide polymorphisms (SNP) with non-cholesterol sterol levels in a cross-sectional cohort of non-diabetic offspring of type 2 diabetes (the Kuopio cohort of the EUGENE2 Study, N = 273). We found that in a cross-sectional METSIM Study the levels of sterols indicating cholesterol absorption were reduced as a function of increasing fasting glucose levels, whereas the levels of sterols indicating cholesterol synthesis were increased as a function of increasing 2-hour glucose levels. A cholesterol synthesis marker desmosterol significantly predicted an increase, and two absorption markers (campesterol and avenasterol) a decrease in the risk of hyperglycemia and incident type 2 diabetes in a 5-year follow-up of the METSIM cohort, mainly attributable to insulin sensitivity. A SNP of ABCG8 was associated with fasting plasma glucose levels in a cross-sectional study but did not predict hyperglycemia or incident type 2 diabetes. In conclusion, the levels of some, but not all non-cholesterol sterols are markers of the worsening of hyperglycemia and type 2 diabetes.
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3.
Quantitative assessment of the effect of ABCA1 gene polymorphism on the risk of Alzheimer's disease.
Wang, XF, Cao, YW, Feng, ZZ, Fu, D, Ma, YS, Zhang, F, Jiang, XX, Shao, YC
Molecular biology reports. 2013;(2):779-85
Abstract
ATP-binding cassette transporter A1 (ABCA1) is a membrane-associated protein which has attracted considerable attention as a candidate gene for Alzheimer's disease (AD) based on its function as a key factor in lipid metabolism by mediating cellular cholesterol efflux, the rate-limiting step in the production of nascent high-density lipoprotein (HDL) particles. The relationship between ABCA1 common variations (R219 K rs2230806, I883 M rs4149313 and R1587 K rs2230808) and AD has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 13 studies involving a total of 12,248 subjects to evaluate the effect of ABCA1 on genetic susceptibility for AD. Overall, the summary OR of AD was 1.01 (95 % CI: 0.93-1.10; P = 0.77), 1.10 (95 % CI: 0.96-1.26; P = 0.16), and 1.08 (95 % CI: 0.96-1.23; P = 0.21) for R219 K, I883 M and R1587 K polymorphism, respectively. No significant results were observed in dominant and recessive when compared with wild genotype for these polymorphisms. In the stratified analyses by ethnicity and sample size, no evidence of any gene-disease association was obtained. In conclusion, the present meta-analysis does not support the notion that common SNPs on ABCA1 is a major genetic risk factor for AD.
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4.
High intestinal cholesterol absorption is associated with cardiovascular disease and risk alleles in ABCG8 and ABO: evidence from the LURIC and YFS cohorts and from a meta-analysis.
Silbernagel, G, Chapman, MJ, Genser, B, Kleber, ME, Fauler, G, Scharnagl, H, Grammer, TB, Boehm, BO, Mäkelä, KM, Kähönen, M, et al
Journal of the American College of Cardiology. 2013;(4):291-9
Abstract
OBJECTIVES This study sought to determine whether high intestinal cholesterol absorption represents a cardiovascular risk factor and to link ABCG8 and ABO variants to cardiovascular disease (CVD). BACKGROUND Plant sterol-enriched functional foods are widely used for cholesterol lowering. Their regular intake yields a 2-fold increase in circulating plant sterol levels that equally represent markers of cholesterol absorption. Variants in ABCG8 and ABO have been associated with circulating plant sterol levels and CVD, thereby suggesting atherogenic effects of plant sterols or of cholesterol uptake. METHODS The cholestanol-to-cholesterol ratio (CR) was used as an estimate of cholesterol absorption because it is independent of plant sterols. First, we investigated the associations of 6 single nucleotide polymorphisms in ABCG8 and ABO with CR in the LURIC (LUdwisghafen RIsk and Cardiovascular health study) and the YFS (Young Finns Study) cohorts. Second, we conducted a systematic review and meta-analysis to investigate whether CR might be related to CVD. RESULTS In LURIC, the minor alleles of rs4245791 and rs4299376 and the major alleles of rs41360247, rs6576629, and rs4953023 of the ABCG8 gene and the minor allele of rs657152 of the ABO gene were significantly associated with higher CR. Consistent results were obtained for rs4245791, rs4299376, rs6576629, and rs4953023 in YFS. The meta-analysis, including 6 studies and 4,362 individuals, found that CR was significantly increased in individuals with CVD. CONCLUSIONS High cholesterol absorption is associated with risk alleles in ABCG8 and ABO and with CVD. Harm caused by elevated cholesterol absorption rather than by plant sterols may therefore mediate the relationships of ABCG8 and ABO variants with CVD.
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5.
ATP-binding cassette transporter A1 R219K polymorphism and coronary artery disease in Chinese population: a meta-analysis of 5,388 participants.
Li, YY, Zhang, H, Qin, XY, Lu, XZ, Yang, B, Chen, ML
Molecular biology reports. 2012;(12):11031-9
Abstract
The ATP-binding cassette transporter A1 (ABCA1) R219K gene polymorphism has been suggested to lower the risk of coronary artery disease (CAD). However, research results remain debatable. Meta-analysis involving 2,730 CAD patients and 2,658 controls was performed to investigate the relationship between ABCA1 R219K gene polymorphism and CAD in Chinese population. A total of 14 studies which were obtained from electronic databases were analyzed. The pooled odds ratios (ORs) and their corresponding 95 % confidence intervals (95 % CIs) were estimated by a random effect model. A significant association between ABCA1 R219K gene polymorphism and CAD was found in the Chinese population under the following genetic models: an allelic genetic model (OR 0.70, 95 % CI 0.62-0.78, P < 0.00001), a recessive genetic model (OR 0.51, 95 % CI 0.41-0.64, P < 0.00001), an additive genetic model (OR 0.816, 95 % CI 0780-0.855, P = 0), a dominant genetic model (OR 1.326, 95 % CI 1.232-1.427, P = 0), a homozygote genetic model (OR 0.640, 95 % CI 0.575-0.712, P = 0), and a heterozygote genetic model (OR 0.640, 95 % CI 0.575-0.712, P = 0). The K allele of the ABCA1 R219K gene has a protective role for CAD risk in Chinese population and is possibly associated with decreased CAD susceptibility.
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6.
Associations of the ATP-binding cassette transporter A1 R219K polymorphism with HDL-C level and coronary artery disease risk: a meta-analysis.
Ma, XY, Liu, JP, Song, ZY
Atherosclerosis. 2011;(2):428-34
Abstract
OBJECTIVE Previous studies have evaluated the associations of the ATP-binding cassette transporter A1 (ABCA1) R219K polymorphism (rs2230806) with the level of high-density lipoprotein cholesterol (HDL-C) and the risk of developing coronary artery disease (CAD), but results from many small, underpowered studies are conflicting. The objective of this study was to overcome the limitations of individual study and provide solid epidemiologic evidence. METHODS We conducted a systematic review and meta-analysis of available studies to clarify the associations of the ABCA1 R219K polymorphism with HDL-C level and CAD risk. RESULTS Through retrieving PubMed, Embase, Web of Science, CBM and CNKI, we identified a total of 22 studies with 6597 cases and 15,369 controls for the association between the ABCA1 R219K polymorphism and CAD risk. The carriers of allele 219K were found to have a lower risk of CAD than the non-carriers: OR=0.76, 95% CI=0.68-0.85, P=3.78E-07, P(heterogeneity)=3.59E-08; meanwhile, 18 studies from 17 papers with 12,869 subjects were included in the association between the ABCA1 R219K polymorphism and the level of HDL-C. It was suggested that the carriers of KK genotype had higher level of HDL-C than those of RR genotype: SMD=0.19, 95% CI=0.06-0.32, P=0.005, P(heterogeneity)=3.19E-09. Subgroup analyzes by ethnicity certified that the effect on HDL level was just significant in Asians. Exclusion of the outlier studies effectively removed the heterogeneity and confirmed the total results. No publication bias was detected in this meta-analysis. CONCLUSIONS The synthesis of available evidence demonstrates that the ABCA1 R219K polymorphism is associated with a higher HDL-C level in Asians and a protective role for CAD risk both in Asians and Caucasians.
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7.
Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region.
Florez, JC, Burtt, N, de Bakker, PI, Almgren, P, Tuomi, T, Holmkvist, J, Gaudet, D, Hudson, TJ, Schaffner, SF, Daly, MJ, et al
Diabetes. 2004;(5):1360-8
Abstract
The genes for the sulfonylurea receptor (SUR1; encoded by ABCC8) and its associated islet ATP-sensitive potassium channel (Kir6.2; encoded by KCNJ11) are adjacent to one another on human chromosome 11. Multiple studies have reported association of the E23K variant of Kir6.2 with risk of type 2 diabetes. Whether and how E23K itself-or other variant(s) in either of these two closely linked genes-influences type 2 diabetes remains to be fully determined. To better understand genotype-phenotype correlation at this important candidate gene locus, we 1) characterized haplotype structures across the gene region by typing 77 working, high-frequency markers spanning 207 kb and both genes; 2) performed association studies of E23K and nearby markers in >3,400 patients (type 2 diabetes and control) not previously reported in the literature; and 3) analyzed the resulting data for measures of insulin secretion. These data independently replicate the association of E23K with type 2 diabetes with an odds ratio (OR) in the new data of 1.17 (P = 0.003) as compared with an OR of 1.14 provided by meta-analysis of previously published, nonoverlapping data (P = 0.0002). We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S) in the neighboring SUR1 gene (r(2) > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region are most likely responsible for the reported association. We show that E23K is also associated with decreased insulin secretion in glucose-tolerant control subjects, supporting a mechanism whereby beta-cell dysfunction contributes to the common form of type 2 diabetes. Like peroxisome proliferator-activated receptor gamma, the SUR1/Kir6.2 gene region both contributes to the inherited risk of type 2 diabetes and encodes proteins that are targets for hypoglycemic medications, providing an intriguing link between the underlying mechanism of disease and validated targets for pharmacological treatment.