Genetic variants affecting responses of plasma lipids and cholesterol kinetics to dietary cholesterol versus plant sterol consumption in a founder population

Alphonse, Peter AS

Genetic variants affecting responses of plasma lipids and cholesterol kinetics to dietary cholesterol versus plant sterol consumption in a founder population

dc.contributor.author	Alphonse, Peter AS
dc.contributor.examiningcommittee	Eck, Peter K (Human Nutritional Sciences) Suh, Miyoung (Human Nutritional Sciences) Beta,Trust (Food science) Fernandez, Maria Luz (Nutritional Sciences, University of Connecticut)	en_US
dc.contributor.supervisor	Jones, Peter J.H (Food science, Human Nutritional Sciences)	en_US
dc.date.accessioned	2016-09-20T14:58:41Z
dc.date.available	2016-09-20T14:58:41Z
dc.date.issued	2015-11-30	en_US
dc.degree.discipline	Human Nutritional Sciences	en_US
dc.degree.level	Doctor of Philosophy (Ph.D.)	en_US
dc.description.abstract	Lowering plasma LDL-cholesterol (LDL-C) and increasing HDL-cholesterol (HDL-C) concentrations remain the primary targets in cardiovascular disease (CVD) risk reduction. Dietary cholesterol and plant sterols differentially modulate cholesterol kinetics and lipoprotein distribution. Inter-individual variations in the rates of cholesterol absorption and synthesis, and the reciprocal interaction between them affect the responses to dietary sterols. Genetic heterogeneity profoundly influences such responsiveness. However, limited research exists on the genetic determinants of dietary cholesterol versus plant sterols responsiveness in healthy individuals, especially in a founder population, such as the Hutterites in Manitoba of European descent who practice a communal living system. Our study examined the differential effects of dietary cholesterol versus plant sterol consumption on plasma lipoprotein levels, subclasses, and cholesterol kinetics and assessed how genetic variants influenced these responses. A double-blind, randomized, crossover study with three interventional periods of 4 wk duration each was conducted. Healthy Hutterite individuals (n=49) from Manitoba consumed daily either 2 g of plant sterols or 600 mg of cholesterol incorporated into milkshakes, or a placebo during each period. Plasma lipid profile and lipoprotein subclass distribution were determined. Cholesterol absorption and synthesis were assessed by stable isotopic tracer techniques. Participants were genotyped for 38 candidate single nucleotide polymorphisms across 25 genes involved in cholesterol and lipoprotein metabolism. Dietary cholesterol consumption increased plasma TC, HDL-C concentrations and large HDL subclasses with no changes in cholesterol absorption or synthesis. In contrast, plant sterol intake failed to reduce LDL-C concentrations, with a modest reduction in cholesterol absorption, and did not affect lipoprotein subclasses. However, a large non-compensatory increase in cholesterol synthesis was observed due to plant sterol consumption. Gender and common genetic variants affected plasma HDL-C and HDL subclass distribution to dietary cholesterol and plant sterol consumption. ACAT2 and NPC1L1 gene variants affected plasma campesterol and β-sitosterol concentrations respectively, to plant sterol intake by modifying cholesterol absorption. In summary, our results demonstrate that dietary cholesterol and plant sterol intake differentially modulate cholesterol trafficking in a manner dependent on common genetic variants and gender in healthy individuals. Such knowledge facilitates the development of effective cholesterol lowering strategies for the alleviation of CVD burden.	en_US
dc.description.note	October 2016	en_US
dc.identifier.citation	Alphonse PA, Jones PJ (2016) Revisiting human cholesterol synthesis and absorption: The reciprocity paradigm and its key regulators. Lipids 51:519-536.	en_US
dc.identifier.uri	http://hdl.handle.net/1993/31823
dc.language.iso	eng	en_US
dc.publisher	Lipids-Springer	en_US
dc.rights	open access	en_US
dc.subject	Cholesterol	en_US
dc.subject	plant sterols	en_US
dc.subject	Hutterites	en_US
dc.subject	Genetics	en_US
dc.subject	SNP	en_US
dc.title	Genetic variants affecting responses of plasma lipids and cholesterol kinetics to dietary cholesterol versus plant sterol consumption in a founder population	en_US
dc.type	doctoral thesis	en_US
local.subject.manitoba	yes	en_US