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Lipid Metabolizing Genes

Lipid Metabolizing Genes. Cholesterol Metabolism. CETP Cholesterol ester transfer protein Closely linked to HDL-C HDL-C functions in reverse cholesterol transport Removes excess cholesterol from periphery Excess cholesterol is esterified to make cholesterol esters CETP and HDL-C

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Lipid Metabolizing Genes

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  1. Lipid Metabolizing Genes

  2. Cholesterol Metabolism • CETP • Cholesterol ester transfer protein • Closely linked to HDL-C • HDL-C functions in reverse cholesterol transport • Removes excess cholesterol from periphery • Excess cholesterol is esterified to make cholesterol esters • CETP and HDL-C • Cholesterol esters may be transferred from HDL-C to LDL-C • Performed by CETP

  3. CETP • Overactive CETP transfers more cholesterol from HDL-C to LDL-C • Underactive CETP results in more cholesterol remaining with HDL-C • CETP Inhibitors (Stein & Stein,Athersclerosis 2005) • Increase HDL-C • Reduce CVD risk

  4. CETP and genetic variants +16/Ex14 +9/3’ +383/In8 VNTR-1946 -629/Prom +82/Ex15 +199/In12 +279/In1 1 2 12 13 14 15 16 3 4 5 11 6 7 8 9 10 Taq1B MspI I405V R451Q Thompson et al. 2003 Atherosclerosis

  5. CETP 279 G→A • Commonly referred to as Taq1B SNP • Associated with lower CETP mass and higher HDL • Intronic SNP • No obvious link to functional activity • Linked to another common SNP? • Linked SNP tend to be inherited together • Linkage Disequilibrium

  6. Linkage Disequilibrium • SNPs are often inherited together and travel as blocks from generation to generation, this is known as linkage disequilibrium (Duff 2006, AJCN) • Linkage disequilibrium can be described as the inheritance of same chromosome SNPs together at a frequency greater than chance. • Occurs when genotype frequencies at one locus are dependent on genotype frequencies at the second (locushttp://www.evotutor.org/EvoGen/EG4A.html) • Can arise from physical linkage, genetic drift and selection on multilocus genotypes • Two loci are in linkage equilibrium if genotype frequencies at one locus are independent of genotype frequencies at the second locus (locushttp://www.evotutor.org/EvoGen/EG4A.html)

  7. Haplotypehttp://www.genome.gov/10001665 • Groups of co-inherited SNPs on the same chromosome (Duff 2006, AJCN) • There could be many haplotypes in a chromosome region • Recent studies are finding only a few common haplotypes. • For CETP • CETP 279G→A is closely linked to -629C→A (Klerkx et al 2003; Human molecular genetics) • Four possible haplotypes for these 2 SNPs • GC, GA, AC, AA • Likely only two are common • GC (normal), AA (variant)

  8. Haplotype Example 1 • Region with 6 SNPs • DNA bases that are same are not shown • First SNP has alleles A and G • Second SNP has alleles C and T • 4 possible haplotypes for these 2 SNPs • AC, AT, GC, GT • Only AC and GT are common • These SNPs are said to be highly associated with each other (ie, in linkage disequilibrium)

  9. Haplotype Example 2 • If a region has only a few haplotypes • Only a few SNPs need to be typed to determine which haplotype a chromosome has • Example below • Determine SNP 1 and 4 and will know haplotype • Saves time and money

  10. CETP and Haplotype Knoblauch et al. 2002

  11. Knoblauch et al. 2002

  12. Examination of haplotype yields a more significant effect than examination of SNPs individually.

  13. 123456 1 2 3 4 5 6 A/C G/A Linkage Disequilibrium 279 A allele is always inherited with the -629 C allele. “A” allele is a marker only (not a functional SNP)

  14. Lipid Metabolizing Genes

  15. LPL (Lipoprotein Lipase) • Hydrolyzes triglycerides of chylomicrons (CM) and VLDL TG degradative products CM CM Remnant Liver Intestine LPL TG degradative products Liver LDL Tissues VLDL LPL

  16. LPL Activity • Positive relationship with HDL-C • > LPL activity > serum HDL-C • Via contributing surface components to HDLC • Negative relationship with TGs • >LPL activity < serum TGs

  17. LPL GeneKnoblauch et al. 2002, Human Molecular Genetics LPL 1595 C→G Cytogenic Location: 8p22

  18. LPL C1595G • More commonly referred to as the 447 Serine→Stop substitution (S447X) • Located in exon 9 • Produces a truncated protein lacking two amino acids (serine-glycine) at the carboxy terminus • Appears to be a functional polymorphism

  19. X447 allele (LPL 1595 G allele) • Associated with • Increased enzyme activity • Lower serum TGs • Higher serum HDL-C • Reduced risk of CAD (OR = 0.4) • Frequency is higher in Caucasians than African Americans (Chen et al. 2001; Atherosclerosis)

  20. HDL-C and TGs in carriers and non-carriers of the LPL 1595 G allele P<0.01 P<0.05 Combined data from adult Causasian and African American men and women (Chen et al. 2001; Atherosclerosis)

  21. Lipid Metabolizing Genes

  22. Apolipoprotein CIII (ApoC-III) • Located on Chromosome 11 • 11p21 (short arm) • Mainly synthesized in liver • Lesser degree in intestine • Component of TG rich lipoproteins (VLDL and CMs) and HDL • Function is poorly understood

  23. Proposed Function(s) • Triglyceride Metabolism • Invitro Studies • Non-competitive inhibitor of LPL • Reduced VLDL and CM catabolism • Mice studies • Overexpression of human apo C-III resulted in marked hypertriglyceridemia • Humans • Elevated apoC-III levels are associated with hypertriglyceridemia

  24. ApoC-III 3175 C→G • Exon 4 of Chromosome 11p21 • Variant is transcribed but not translated • Does not change protein sequence • May be linked to another variant that alters (increases) Apo C3 expression • Commonly referred to as SstI • Identified with SstI (restriction enzyme) • May also include variants at -641, -482, -455, 1100 • Group is often referred to as Sst1 S1/S2 site (Tobin et al. 2004) • Linked to elevated triglycerides • Associated with premature heart disease in some studies

  25. 186 ± 189 (n=23) 135 ± 105 (n=122) ApoC-III 3175 C→G and TGs in controls • Additional Comments • Frequency of G allele • tended (P=0.06) to be • higher in cases with CVD • More studies are needed to • determine how a mutation at • this site may be linked to other • mutations that affect protein • function. Ordovas et al. 1991 Atherosclerosis

  26. ApoC3 and Haplotype and CVD riskC(-641)A, C(-482)T, T(-455)C, C1100T, C3175G, T3206G Tobin et al. 2004 European Heart Journal

  27. Lipid Metabolizing Genes

  28. Personalized Dietary Recommendations • CETP 279 G→A • Non-carriers • More likely to have low HDL-C • Diet has little impact on HDL-C • Increase consumption of MUFAs (?) • Be active (30 min /day) • Weight loss if appropriate (i.e, BMI range 19-26) • LPL 1595 C→G • Non-carriers • More likely to have low HDL-C and high TGs • Restrict saturated fats (i.e, < 20 g/d) • Restrict refined CHO intake (i.e., ≤ 40 g /d) • Achieve or maintain appropriate body weight (i.e, BMI range 19-26) • Fish oil capsules? • APO C3 3175 C→G • Carriers • More likely to have high TGs • Restrict saturated fats (i.e., ≤ 20 g/d) • Restrict refined CHO intake • Achieve or maintain appropriate body weight • Fish oil capsules?

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