| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Genetic variation in the cholesterol 24-hydroxylase (CYP46) gene and the risk of Alzheimer's disease Desai, P., S. T. DeKosky, et al. (2002), Neurosci Lett 328(1): 9-12. Abstract: Alzheimer's disease (AD) is a complex, multifactorial disorder, with many genetic and environmental factors implicated in disease onset and pathology. Increasing evidence points to a link between brain cholesterol turnover and AD. The CYP46 gene encodes for the enzyme, cholesterol 24-hydroxylase, which plays a key role in brain cholesterol turnover. A polymorphism in Intron 2 (T-->C) in the CYP46 gene has recently been reported to be associated with the risk of AD. In the present study, we examined the association of this CYP46 polymorphism with sporadic late-onset AD (LOAD) in American White (434 cases, 401 controls) and African American (54 cases, 61 controls) cohorts. No significant association was observed between the CYP46 polymorphism and LOAD. When the data were stratified by the apolipoprotein E*4 carrier status, no significant difference was observed between cases and controls for the CYP46 single nucleotide polymorphism. In addition, no significant difference in genotype or allele frequency was observed when stratified by the presence or absence of the alpha1-antichymotrypsin*A allele. Our data indicate that the Intron 2 polymorphism of CYP46 does not affect the risk of AD in our sample. |
| Genetic variation in the rate-limiting enzyme in cholesterol catabolism (cholesterol 7alpha-hydroxylase) influences the progression of atherosclerosis and risk of new clinical events Hofman, M. K., H. M. Princen, et al. (2005), Clin Sci (Lond) 108(6): 539-45. Abstract: CHD (coronary heart disease) is a complex disorder which is, in part, related to serum cholesterol levels. The rate-limiting enzyme in the catabolism of cholesterol into bile acids is CYP7A1 (cholesterol 7alpha-hydroxylase). The effect of the CYP7A1 A-278C promoter polymorphism on the progression of atherosclerosis, risk of a new clinical event and the influence of this variant on cholesterol-lowering therapy was investigated in 715 male patients with coronary atherosclerosis participating in REGRESS (Regression Growth Evaluation Statin Study). Genotype distributions were as follows: 283 with AA; 330 with AC and 102 with CC. There were no significant differences in baseline characteristics and serum lipids between genotypes. After 2 years, CC carriers had more progression of diffuse and focal atherosclerosis compared with AA carriers, as indicated by a larger decrease in MSD (mean segment diameter; 0.09 mm compared with 0.06 mm respectively; P=0.009) and MOD (minimum obstruction diameter; 0.09 mm compared with 0.05 mm respectively; P=0.024). Inclusion of risk factors for CHD in the model showed the same trend, although not significant for MOD (P=0.01 for MSD, and P=0.06 for MOD). In addition, CC carriers had an almost 2-fold higher risk of a new clinical event compared with AA carriers RR (95% CI) 1.93 (1.11-3.36); P=0.02; where RR is relative risk and CI is confidence interval. Inclusion of risk factors for CHD in the model showed the same trend, although not significant RR (95% CI), 1.74 (0.96-3.12); P=0.06. In conclusion, we present evidence that the CC variant of the A-278C polymorphism in the rate-limiting enzyme in the catabolism of cholesterol, CYP7A1, increases the progression of atherosclerosis and possibly the risk of a new clinical event. |
| Genetic variation in total plasma and high density lipoprotein cholesterol and body weight in medium white turkeys Smith, E. J. and T. F. Savage (1992), Poult Sci 71(5): 807-12. Abstract: Plasma total cholesterol (PC) and its high density lipoprotein cholesterol (HDLC) fraction were determined in 700 16-wk-old Medium White turkeys in Generation 15 of selection for low and high semen ejaculate volumes (SEV). The birds examined were from pedigree matings involving 10 sires mated to 100 dams in each line. Mean PC and HDLC were not different between lines and between sexes within lines. Genetic parameters were estimated for PC, HDLC, and BW. Sire component heritabilities estimated based on pooled data from low and high SEV lines for PC and HDLC were -.03 and.26, respectively. Genetic correlations were.05 between PC and HDLC.13 between PC and BW; and -.34 between HDLC and BW. It was concluded that variation in PC in 16-wk-old Medium White turkeys is largely due to environmental variation and that the genetic component is largely nonadditive. However, a moderate additive genetic component was observed for HDLC. Further, determination of total PC and HDLC at 16 wk of age does not exhibit a potential value as an indicator of future SEV potential. |
| Genetic variation of low-density lipoprotein-cholesterol and its clinical implications Cheng, T. O. (2005), Chin Med J (Engl) 118(5): 355-9. |
| Genetic variation of the cholesterol ester transfer protein gene and the prevalence of coronary artery disease. The AtheroGene case control study Blankenberg, S., L. Tiret, et al. (2004), Z Kardiol 93 Suppl 4: IV16-23. Abstract: BACKGROUND: Various functional polymorphisms of the cholesteryl ester transfer protein (CETP) gene influence CETP activity and the concentration of high-density lipoprotein (HDL) cholesterol. Beside other functional variants mainly the promoter polymorphism CETP/C-629A is currently discussed as a risk factor of coronary artery disease (CAD). We evaluated in a large case-control study the impact of various CETP genotypes and haplotypes on HDL concentration and the prevalence of CAD. METHODS AND RESULTS: In 1214 patients with documented CAD as well as 754 population controls we determined the CETP/C-629A, TaqIB, I405V, R451Q, and A373P polymorphisms. All genotypes have an impact on the HDL concentration; univariate genotype and haplotype analyses demonstrate a significant effect of A-allel carriers on the elevation of HDL concentration. In addition, among all genotypes determined, the C-629A polymorphism is associated with the prevalence of CAD in a codominant fashion. Homozygous A-allel carriers reveal a relative risk of 0.6 (95% CI 0.44-0.82; P = 0.005) compared to the wild type. Adjustment for classical risk factors did not alter this association significantly, whereas after controlling for HDL concentration no independent significance between CETP/C-629A genotype and prevalence of CAD was observed anymore. CONCLUSION: CETP genotypes have an significant but moderate impact on systemic HDL-cholesterol concentration. The A-allel of the CETP/C-629A polymorphism is associated with a reduced CAD risk. This risk reduction is probably mediated by elevated HDL-concentration. Whether genotyping of the CETP/C-629A polymorphism provides information over and above that obtained by HDL-cholesterol measurement has to be further investigated in various prospective studies. |
| Genetic variations in the cholesteryl ester transfer protein gene and high density lipoprotein cholesterol levels in Taiwanese Chinese Hsu, L. A., Y. L. Ko, et al. (2002), Hum Genet 110(1): 57-63. Abstract: This study analyzed the association of the I14A mutation, the D442G mutation, and the TaqIB polymorphism of the cholesteryl ester transfer protein (CETP) gene in 718 Chinese individuals with high-density lipoprotein cholesterol levels (HDL-C) living in Taiwan. The analysis revealed that the I14A mutation was not present in any of the 110 subjects with HDL-C levels above 60 mg/dl. By contrast, the D442G mutation was present in 48 of the 718 (6.7%) subjects tested. Significantly higher HDL-C levels were noted for bearers of the D442G mutation compared with non-bearers; however, this association was weaker for males and for subjects carrying the TaqIB1 allele. The TaqIB2 allele was also associated with higher HDL-C levels. From multivariate analysis, independent associations were demonstrated for the TaqIB2 polymorphism and the D442G mutation, and elevated HDL-C levels. For obese subjects, however, the presence of the TaqIB2 or D442G allele was not associated with increased HDL-C levels. For subjects with triglycerides at a concentration greater than 150 mg/dl, the association of both alleles with HDL-C levels was also diminished. Thus, genetic variation at the CETP gene locus may account for a significant proportion of the difference in HDL-C levels; however, it seems reasonable to suggest that the effects of the allele interact with genetic variations expressed within the sample population, and with sex, obesity, and plasma triglyceride levels. |
| Genetic variations of cholesterol ester transfer protein gene in Koreans Hong, S. H., Y. R. Kim, et al. (2001), Hum Biol 73(6): 815-21. Abstract: An absence of cholesterol ester transfer protein (CETP, protein; CETP, gene) results in an increase of the apolipoprotein AI levels and a decrease in the low density lipoprotein (LDL) levels. Thus, the CETP polymorphism is important in the assessment of risk of atherosclerosis. This study was conducted to elucidate the genotype distributions of the CETP polymorphism and association with plasma lipid levels in Koreans. The genotypes of the TaqI A and B polymorphic loci were associated with plasma triglyceride levels in the control and coronary artery disease (CAD) groups. There was linkage disequilibrium between TaqI A and B loci in the control group (chi2 = 5.58, p < 0.05). Association studies of the CETP polymorphism have been carried out mainly with Caucasian populations; however, the results have not been consistent among different populations. A possible explanation for this diversity among populations may be differences in genetic backgrounds, which may be more important than environmental factors. We discuss the reasons for the incompatibility of the CETP polymorphism among populations. |
| Genetically determined absence of HDL-cholesterol and coronary atherosclerosis Navalesi, R., R. Miccoli, et al. (1995), Lancet 346(8976): 708-9. |
| Genetics and cholesterol metabolism Kesaniemi, Y. A. (1996), Curr Opin Lipidol 7(3): 124-31. Abstract: The regulation of cholesterol metabolism by both genetic and environmental factors seems to be very complex. The recent research approach focusing on the genetic control of many key regulatory processes of cholesterol homeostasis has, however, started to elucidate the importance of genetic variation in susceptibility to a number of common clinical disorders such as hyperlipidemia, atherosclerosis, poor diet response, gallstone formation, colon tumours, and reduced lifespan. |
| Genetics and molecular biology: the ABC of cholesterol efflux and high-density lipoprotein formation Lorkowski, S. and P. Cullen (2004), Curr Opin Lipidol 15(5): 611-3. |
| Genetics and prevention: a new look at high-density lipoprotein cholesterol Genest, J., Jr. (2002), Cardiol Rev 10(1): 61-71. Abstract: Plasma level of high-density lipoprotein cholesterol is inversely correlated with coronary artery disease. High-density lipoprotein particles are thought to mediate the uptake of peripheral cholesterol and, through exchange of core lipids with other lipoproteins or selective uptake by specific receptors, return this cholesterol to the liver for bile acid secretion. During the past decade, high-density lipoprotein particles have been found to modulate thrombosis, cell adhesion molecule expression, vasomotor function, platelet function, and endothelial cell apoptosis and proliferation. Many of these effects involve the signal transduction pathway and gene transcription. Genetic disorders of high-density lipoproteins have been characterized at the molecular level. Mutations within the genes involved in the structure and metabolism of high-density lipoproteins can cause high-density lipoprotein deficiency or elevations in high-density lipoprotein cholesterol levels. Some mutations causing high-density lipoprotein deficiency are associated with premature coronary artery disease, whereas others, paradoxically, may be associated with longevity. Modulation of high-density lipoprotein metabolism for therapeutic purposes must take into account not only the cholesterol content of the particle but also its lipid (including phospholipid) composition, apolipoprotein content, size, and charge. |
| Genetics of increased HDL cholesterol levels: insights into the relationship between HDL metabolism and atherosclerosis Cuchel, M. and D. J. Rader (2003), Arterioscler Thromb Vasc Biol 23(10): 1710-2. |
| Genetics of responsiveness to high-fat and high-cholesterol diets in the mouse Paigen, B. (1995), Am J Clin Nutr 62(2): 458S-462S. Abstract: The natural variation among inbred strains of mice was used to elucidate the genetic factors underlying the responsiveness to high-fat and high-cholesterol diets. The nine strains examined are the progenitors of recombinant inbred strain sets: C57BL/6J, C57L/J, SWR/J, SJL/J, SM/J, A/J, AKR/J, C3H/HeJ, and DBA/2J. Plasma lipids, liver lipids, the prevalence of cholesterol gallstones, and the size of aortic fatty streak lesions were examined after 18 wk of consumption of the diet containing 15% fat and 1% cholesterol. The variation in aortic lesions found among inbred strains provided the basis for several additional studies that demonstrated the existence of eight genes affecting atherosclerosis. These genes, named Ath1 to Ath8, are briefly described. The genetic analysis of variation in gallstone formation demonstrated that more than one gene affects this phenotype. |
| Genetics of variation in HDL cholesterol in humans and mice Wang, X. and B. Paigen (2005), Circ Res 96(1): 27-42. Abstract: Plasma high-density lipoprotein cholesterol (HDL-C) concentrations are genetically determined to a great extent, and quantitative trait locus (QTL) analysis has been used to identify chromosomal regions containing genes regulating HDL-C levels. We discuss new genes found to participate in HDL metabolism. We also summarize 37 mouse and 30 human QTLs for plasma HDL-C levels, finding that all but three of the mouse QTLs have been confirmed by a second cross or a homologous human QTL, that the mouse QTL map is almost saturated because 92% of recently reported QTLs are repeats of those already found, and that 28 of the 30 human QTLs are located in regions homologous to mouse QTLs. This high degree of concordance between mouse and human QTLs suggests that the underlying genes may be the same. Strategies to more rapidly identify genes underlying mouse and human QTLs for HDL-C include focusing on the mouse and using mouse-human homologies, combining crosses, and haplotyping to narrow the region. Sequence analysis and expression studies can distinguish candidate genes consistent across multiple mouse crosses, and testing the candidate genes in human association studies can provide additional evidence for the candidacy of a gene. Together these strategies can accelerate the pace of finding genes that regulate HDL. |
| Genome scan for quantitative trait loci linked to high-density lipoprotein cholesterol: The NHLBI Family Heart Study Peacock, J. M., D. K. Arnett, et al. (2001), Arterioscler Thromb Vasc Biol 21(11): 1823-8. Abstract: We conducted a genome-wide linkage scan for quantitative trait loci influencing total HDL-cholesterol (HDL-C) concentration in a sample of 1027 whites from 101 families participating in the NHLBI Family Heart Study. To maximize the relative contribution of genetic components of variance to the total variance of HDL-C, the HDL-C phenotype was adjusted for age, age(2), body mass index, and Family Heart Study field center, and standardized HDL-C residuals were created separately for men and women. All analyses were completed by the variance components method, as implemented in the program GENEHUNTER using 383 anonymous markers typed at the NHLBI Mammalian Genotyping Service in Marshfield, Wis. Evidence for linkage of residual HDL-C was detected near marker D5S1470 at location 39.9 cM from the p-terminal of chromosome 5 (LOD=3.64). Suggestive linkage was detected near marker D13S1493 at location 27.5 cM on chromosome 13 (LOD=2.36). We conclude that at least 1 genomic region is likely to harbor a gene that influences interindividual variation in HDL cholesterol. |
| Genomewide scan for familial combined hyperlipidemia genes in finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels Pajukanta, P., J. D. Terwilliger, et al. (1999), Am J Hum Genet 64(5): 1453-63. Abstract: Familial combined hyperlipidemia (FCHL) is a common dyslipidemia predisposing to premature coronary heart disease (CHD). The disease is characterized by increased levels of serum total cholesterol (TC), triglycerides (TGs), or both. We recently localized the first locus for FCHL, on chromosome 1q21-q23. In the present study, a genomewide screen for additional FCHL loci was performed. In stage 1, we genotyped 368 polymorphic markers in 35 carefully characterized Finnish FCHL families. We identified six chromosomal regions with markers showing LOD score (Z) values >1.0, by using a dominant mode of inheritance for the FCHL trait. In addition, two more regions emerged showing Z>2.0 with a TG trait. In stage 2, we genotyped 26 more markers and seven additional FCHL families for these interesting regions. Two chromosomal regions revealed Z>2.0 in the linkage analysis: 10p11.2, Z=3.20 (theta=.00), with the TG trait; and 21q21, Z=2.24 (theta=.10), with the apoB trait. Furthermore, two more chromosomal regions produced Z>2.0 in the affected-sib-pair analysis: 10q11.2-10qter produced Z=2.59 with the TC trait and Z=2.29 with FCHL, and 2q31 produced Z=2.25 with the TG trait. Our results suggest additional putative loci influencing FCHL in Finnish families, some potentially affecting TG levels and some potentially affecting TC or apoB levels. |
| Genome-wide scan identifies novel QTLs for cholesterol and LDL levels in F2Dahl RxS-intercross rats Herrera, V. L., T. Didishvili, et al. (2004), Circ Res 94(4): 446-52. Abstract: Hypercholesterolemia is a significant risk factor for coronary artery disease development. Genes influencing nonmonogenic hypercholesterolemia susceptibility in humans remain to be identified. Animal models are key investigative systems because major confounding variables such as diet, activity, and genetic background can be controlled. We performed a 121-marker, total genome-analysis of an F2Dahl RxS-intercross selected for contrasting parental strain susceptibilities for hyperlipidemia on regular rat diets at 6 months of age. Quantitative traits studied were plasma total cholesterol, triglyceride, HDL, and LDL levels adjusted for obesity. Genome-wide analysis of 200 F2-intercross male rats detects two QTLs with highly significant linkage for total cholesterol (TC) on chromosome (chr) 5-133.3 Mbp (LOD 5.8), and chr5-54.2 Mbp (LOD 4.8), and two QTLs with significant linkage for TC: on chromosome 8, chr8-60.4 Mbp (LOD 3.8), and chromosome 2, chr2-243.5 Mbp (LOD 3.4). A QTL for LDL with significant linkage is detected on chromosome 5, chr5-104 Mbp (LOD 3.7). These QTLs contribute from 7% to 12% of total trait variance, respectively, with Dahl-S allele effects resulting in increased TC and LDL levels consistent with hyperlipidemia susceptibility in the parental Dahl-S rat strain. Predicted QTL-peaks do not coincide with previous genome scans. Human homologues of two TC-QTLs span genes listed in a LocusLink profile for cholesterol. Only suggestive loci were detected for HDL and total triglyceride levels. Altogether, the data demonstrates the contribution of multiple QTLs to hypercholesterolemia making a multipathway pathogenic framework imperative. QTL-peak candidate genes delineated are syntenic between rat and human genomes, increasing clinical relevance and mandating further study. |
| Genome-wide scan on plasma triglyceride and high density lipoprotein cholesterol levels, accounting for the effects of correlated quantitative phenotypes Lin, J. P. (2003), BMC Genet 4 Suppl 1: S47. Abstract: BACKGROUND: Plasma triglyceride and high density lipoprotein cholesterol levels are inversely correlated and both are genetically related. Two correlated traits may be influenced both by shared and unshared genes. The power to detect unshared trait-specific genes may be increased by incorporating correlated traits as covariates. The power to localize the shared genes may be improved by bivariate analysis. Univariate genome scans were carried out on triglyceride (high density lipoprotein cholesterol) with and without using high density lipoprotein cholesterol (triglyceride) as a covariate, and bivariate linkage analysis on triglyceride and high density lipoprotein cholesterol using the 330 Framingham pedigrees of the Genetic Analysis Workshop 13 data. The results of five genome scans were compared to determine the chromosomal regions which may harbor the genes influencing variation specific to triglycerides, specific to high density lipoprotein cholesterol, or the covariation of both triglyceride and high density lipoprotein cholesterol. RESULTS: The results of our five genome scans identified some chromosomal regions with possible quantitative trait loci (QTL) that may specifically influence one trait, such as the regions on chromosome 1 (at 1 cM near marker 280we5), on high density lipoprotein cholesterol, or control the covariation of both traits, such as the regions on chromosome 7 (at 169 cM near marker GATA30D09), chromosome 12 (at 3 cM near marker GATA4H03), chromosome 20 (at 49 cM near marker GATA29F06), chromosome 2 (at 146 cM near marker GATA8H05), and chromosome 6 (at 148 cM near marker GATA184A08) on triglyceride and high density lipoprotein cholesterol. The one on chromosome 6 had a LOD score of 3.1 with the bivariate linkage analysis. CONCLUSION: There is strong evidence for a QTL on chromosome 6 near marker GATA184A08 appearing to influence the variation of high density lipoprotein cholesterol and triglycerides in the Framingham population. |
| Genomic organization of the human cholesterol-responsive ABC transporter ABCA7: tandem linkage with the minor histocompatibility antigen HA-1 gene Kaminski, W. E., A. Piehler, et al. (2000), Biochem Biophys Res Commun 278(3): 782-9. Abstract: We have recently cloned a novel cholesterol-responsive ABC transporter, designated ABCA7, which is predominantly expressed in human leukocytes. Here we report the structure of the human ABCA7 gene. The ABCA7 gene spans a region of approximately 32 kb and comprises 46 exons. Its putative promoter sequence contains potential binding sites for transcription factors with roles in hematopoiesis and cholesterol metabolism. Surprisingly, sequence analysis of the ABCA7 3' gene flanking region revealed that the terminal exon of ABCA7 borders immediately on the 5' end of the coding region of the recently identified human minor histocompatibility antigen HA-1. We demonstrate that the coding regions of ABCA7 and HA-1 are physically separated by a 1.7-kb intergene region. Subsequent genomic structure analysis showed that the HA-1 gene consists of 23 exons which extend across a 16-kb genomic region. Our results provide evidence that the genes for the human minor histocompatibility antigen HA-1 and the ABC transporter ABCA7 are arranged in a head-to-tail array and that both genes localize to a common locus of approximately 48 kb size on chromosome 19p13.3. |
| Genotypes of ALDH2 and the levels of serum gamma-GTP and HDL-cholesterol in ordinary drinkers Tsuritani, I., H. Tanaka, et al. (1993), Sangyo Igaku 35(1): 40-1. |