The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of the apolipoprotein E polymorphism in determining levels, variability, and covariability of cholesterol, betalipoprotein, and triglycerides in a sample of unrelated individuals

Boerwinkle, Eric; Visvikis, S.; Welsh, D.; Steinmetz, J.; Hanash, Samir M.; Sing, Charles F.

doi:10.1002/ajmg.1320270310

Cited by 194 publications

(108 citation statements)

References 24 publications

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“…The results of the present study provide further evidence that multiple rare variants contribute to variations in plasma lipoprotein levels in the population, but, in this case, the effect on phenotype is more modest. The average reduction in plasma LDL-C levels associated with the variant NPC1L1 alleles was Ϸ10%, which resembles the magnitude of the effect of common genetic variants in APOE (20) but is less than the 40% reductions in LDL-C we observed in heterozygotes with null mutations in PCSK9 (18). Taken together, these data suggest that the genetic architecture of plasma LDL-C levels is not adequately described by the common disease-common variant model or by the common disease-rare variant model.…”

Section: Discussionmentioning

confidence: 75%

Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels

Cohen

Pertsemlidis

Fahmi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

352

272

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An approach to understand quantitative traits was recently proposed based on the finding that nonsynonymous (NS) sequence variants in certain genes are preferentially enriched at one extreme of the population distribution. The NS variants, although individually rare, are cumulatively frequent and influence quantitative traits, such as plasma lipoprotein levels. Here, we use the NS variant technique to demonstrate that genetic variation in NPC1L1 contributes to variability in cholesterol absorption and plasma levels of low-density lipoproteins (LDLs). The ratio of plasma campesterol (a plant sterol) to lathosterol (a cholesterol precursor) was used to estimate relative cholesterol absorption in a population-based study. Nonsynonymous sequence variations in NPC1L1 were five times more common in low absorbers (n ‫؍‬ 26 of 256) than in high absorbers (n ‫؍‬ 5 of 256) (P < 0.001). The rare variants identified in low absorbers were found in 6% of 1,832 AfricanAmericans and were associated with lower plasma levels of LDL cholesterol (LDL-C) (96 ؎ 36 mg͞dl vs. 105 ؎ 36 mg͞dl; P ‫؍‬ 0.005). These data, together with prior findings, reveal a genetic architecture for LDL-C levels that does not conform to current models for quantitative traits and indicate that a significant fraction of genetic variance in LDL-C is due to multiple alleles with modest effects that are present at low frequencies in the population.cholesterol absorption ͉ complex trait ͉ genetic architecture ͉ mutation ͉ plant sterol T he plasma level of low-density lipoprotein cholesterol (LDL-C) is clinically important and genetically complex. This trait provides an excellent model system for genetic dissection: LDL-C levels are simple to measure, relatively stable within an individual, and strongly influenced by genetic variation. Moreover, many genes controlling LDL metabolism have been identified, providing candidates for genetic analysis. One factor that contributes to differences in plasma levels of LDL-C is the efficiency of intestinal cholesterol absorption, which ranges from 29% to 80% among healthy individuals (1). Pharmacological blockade of cholesterol absorption leads to reduced plasma LDL-C levels (2), raising the possibility that genetic variation may produce the same result.Cholesterol absorption is heritable in humans (3), but the genetic basis of this variation is not known. Recently the Niemann-Pick Type C1 Like 1 (NPC1L1) protein was shown to facilitate cholesterol absorption in mice (4, 5), making it an excellent candidate gene for variation in cholesterol absorption. In the present study, we screened the gene encoding NPC1L1 for sequence variations in subsets of individuals estimated to have the highest and lowest rates of sterol absorption. To estimate sterol absorption we measured the ratio of campesterol to lathosterol (Ca:L ratio) in plasma (6). Campesterol, a plant sterol, is absorbed entirely from the diet. Lathosterol is an intermediate in cholesterol biosynthesis, and its concentration in plasma is correlated with rates of endoge...

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Section: Discussionmentioning

confidence: 75%

Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels

Cohen

Pertsemlidis

Fahmi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

352

272

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“…Since members of the same colony were more highly related than individuals from different colonies, including the colony term would, in part, account for non-independence between members of the same colony, although the relationships between individuals were complex (Fujiwara et al 1989;Hegele et al 1994Hegele et al , 1995. When a significant association was identified with ANOVA, the average effects of the alleles on plasma lipoprotein traits were estimated using the following formulas (Boerwinkle et al 1987 where α 2 , α 3 , α 4 are the average effects of three alleles at one locus; f 22 , f 23 , etc. are the expected relative genotype frequencies; ȳ 22 , ȳ 23 etc.…”

Section: Discussionmentioning

confidence: 99%

Association and linkage of LDLR gene variation with variation in plasma low density lipoprotein cholesterol

et al. 1998

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The role of common variation in the low density lipoprotein (LDL) receptor gene (LDLR) as a determinant of variation in plasma LDL cholesterol in normolipidemic populations is not well established. To address this question, we used both association and linkage analysis to evaluate the relationship between plasma LDL cholesterol and genetic variation in LDLR and in three other candidate genes for lipoprotein metabolism, namely, APOE, PON1, and LPL. We studied a sample of 719 normolipidemic Alberta Hutterites, who comprised 1217 sib pairs. Variation in each of the four candidate genes was significantly associated with variation in plasma LDL cholesterol, but the average effects of the alleles were small. In contrast, sib pair analysis showed that only the LDLR gene variation was linked with variation in plasma LDL cholesterol (P ϭ 0.026). Thus, the common LDLR gene variation was both associated with and linked to variation in plasma LDL cholesterol, suggesting that there is a functional impact of structural variation in LDLR on plasma LDL cholesterol in this study sample. However, the absence of linkage of variation in LDL cholesterol with the other three candidate genes, in particular APOE, is consistent with a lower sensitivity of linkage analysis compared with association analysis for detecting modest effects on quantitative traits. Attributes such as the genetic structure of the study sample, the amount of variance attributable to the locus, and the information content of the marker appear to affect the ability to detect genotype-phenotype relationships using linkage analysis.

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“…The most common ApoE is the E3 isoform, 15 whereas ApoE2 and ApoE4 arise from a mutational variation of a single amino acid located within the receptor-binding region of the protein, with consequentially altered receptor binding properties. 93 ApoE2 has a much lower, and ApoE4 a much higher, receptor binding affinity than ApoE3.…”

Section: Apoe Polymorphism and The Transport Of Lutein And Zeaxanthinmentioning

confidence: 99%

Transport and Retinal Capture of Lutein and Zeaxanthin with Reference to Age-related Macular Degeneration

Loane

Nolan

O'Donovan

et al. 2008

Survey of Ophthalmology

100

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Abstract. Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly population in the western world. The etiology and pathogenesis of this disease remain unclear. However, there is an increasing body of evidence supporting the hypothesis that the macular pigment carotenoids, lutein and zeaxanthin, play an important role in protection against AMD, by filtering out blue light at a pre-receptoral level, or by quenching free radicals. Lutein and zeaxanthin are dietary xanthophyll carotenoids, which are delivered to the retina via plasma lipoproteins. The biological mechanisms governing retinal capture and accumulation of lutein and zeaxanthin, to the exclusion of other carotenoids, are still poorly understood. Although these mechanisms remain unclear, it is possible that selective capture of these carotenoids is related to lipoprotein, or apolipoprotein, function and profile. Xanthophyll-binding proteins appear to play an important role in the retinal capture of the xanthophyll carotenoids. The Pi isoform of GSTP1 has been isolated as a specific binding protein for zeaxanthin. The binding protein responsible for retinal uptake of lutein remains elusive. This article reviews the literature germane to the mechanisms involved in the capture, accumulation and stabilization of lutein and zeaxanthin by the retina, and the processes involved in their transport in serum. (Surv Ophthalmol 53:68--81, 2008 The central retina, known as the macula, is responsible for central and color vision because of its high concentration of cone photoreceptors. The macula is characterized by a yellow color, attributable to the presence of macular pigment. 81 Macular pigment (MP) is composed of lutein and zeaxanthin, two hydroxycarotenoids, which are entirely of dietary origin. 17 The concentration of MP peaks at the center of the macula, known as the fovea, where zeaxanthin is the dominant carotenoid. In contrast, lutein dominates in the parafoveal region. 16,82 Dietary sources 68

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The use of measured genotype information in the analysis of quantitative phenotypes in man. II. The role of the apolipoprotein E polymorphism in determining levels, variability, and covariability of cholesterol, betalipoprotein, and triglycerides in a sample of unrelated individuals

Cited by 194 publications

References 24 publications

Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels

Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels

Association and linkage of LDLR gene variation with variation in plasma low density lipoprotein cholesterol

Transport and Retinal Capture of Lutein and Zeaxanthin with Reference to Age-related Macular Degeneration

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