The Identification of Genetic Hyperlipidemias Robert E.Ferrell, Ph.DRobert E.Ferrell Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh

Click for larger picture

Table Hyperlipidemic Disorders Generic Designation and Elevated Lipoprotein Class Syno nym Primary DisordersSecondary Disorders* Exogenous Hyperlipemia ( chylomicrons Type I Familial lipoprotein lipase deficiency C-II apolipoprotein deficiency Unclassified Dysglobuline mias Systemic lupus erythematosus

Table Hyperlipidemic Disorders (Cont.) Generic Desig. and Elev. Lipopro. Class Syno nym Primary DisordersSecondary Disorders* Exogenous Hyperlipemia (VLDL) Type II Familial hypertriglyceridemia (mild form) Familial multiple lipoprotein- type hyperlipidemia Sporadic hypertriglyceridemia Tangier disease Dysglobulinemias Systemic lupus erythematosus Diabetic hyperlipemia+ Glycogenosis, typeI Lipodystrophies Uremia Hypopituitarism Nephrotic syndrome (Diabetes mellitus) (Alcoholism) (Estrogen use) (Glucocorticoid use) (Stress-induced) Mixed hyperlipemia (VLDL + chylomicrons) Type V Familial hypertriglyceridemia (severe form) Familial lipoprotein lipase deficiency C-II apolipoprotein deficiency

Generic Desig. and Elev. ipopro. Class SynonymPrimary DisordersSecondary Disorders* Hypercholest erolemia (LDL) Type II-aFamilial hypercholesterolesterolemia (LDL receptor defects) Familial multiple lipoprotein- type hyperlipidemia Polygenic hypercholestrolemia (include exogenous hypercholesterolemia) Nephrotic syndrome Hypothyroidism Dysglobulinemias Cushing syndrome Acute intermittent porphyria Combined hyperlipidem ia (LDL + VLDL) Type II-bFamilial multiple lipoprotein-type hyperlipidemia Unclassified Nephrotic syndrome Hypothyroidism Dysglobulinemias Cushing syndrome (Glucocorticoid use) (Stress-induced)

Table Hyperlipidemic Disorders (Cont.) Generic Desig. and Elev. Lipopro Class SynonmPrimary DisordersSecondary Disorders* Remnant Hyperlipidemia (beta-VLDL) Type IIIFamilial dysbetalipoproteinemia Unclassified Hypothyroidism Systemic lupus erythematosus Lamellar hyperlipoproteinemia (Vesicular and discoidal lipoproteins) Familial lecithin: cholesterol acyltransferase deficiency Cholestasis (with LP-X) Hepatic failure (with lamellar HDL)

Click for larger picture

Characteristics That May Identify An Individual with a Genetic Predisposition to Cardiovascular Disease Positive Family History Disease in a first-degree relative Parents, siblings Disease in female relatives Disease in the absence of other recognized risk factors Early age-at-onset Genetically determined risk often characterized by an earlier age-at onset Hyperlipidemia resistant to dietary intervention

Table Inbred populations with mutant LDL receptor alleles that account for >15% of the mutant alleles in that population Inbred Population Mutation Percent of FH Heterozygotes with mutation Christian Lebanon South African: Ashkenazi Jews Asian Indians Afrikaners FH Lebanese (C660X) FH Lithuania (G197del) FH Gujerat (P664L) FH Afrikaner-1 (D206E) FH Afrikaner-2 (V408M) >15*

Inbred Population Mutation Percent of FH Heterozygotes with mutation French Canada Iceland Finland Israel: Sephardic Jews Druze Ashkenazi Jews FH French Canadian-1 (del 5’ flanking region-intron 1) FH French Canadian-4 (W66G) FH Iceland (IVS4+2T>C) FH Helsinki (del exons 15-18) FH North Karelia (P288fs) FH Sephardic (D147H) FH Druze (Y167X) FH Lituania (G197del) >15* 35

Inbred Population Mutation Percent of FH Heterozygotes with mutation Norway Greece Spain Belgium (Sourthern) Denmark FH Elverum (IVS3+1G>A) FH Genoa (D528G) FH Afrikaner-2 (V408M) E10X C122X FH French Canadian-4 (W66X) FH Cincinnati-5 (W23X))

ENVIONMENT Individual & Shared POLYGENES MAJOR GENES CigarettesOral Contraceptives InactivityStress Diet ( Fat, calories, simple carbohydrates, Na, K, Cr, Mg, Ca, Folate, B6, B12, E, carotenoids, flavonoids, etc. ) Others LDL-C [APOE] HDL-C BP [AGT] Weight Others LDL-C [LDLR, APOB] FH FDB FCHL Dyslipidemia [LPL] Small Dense LDL Type III [APOE] HDL [APOAI] Apo A-1 [A-1 Milano] Lp(a) NIDDM IDDM H(e) [MTFHR, CS] Fibrinogen PAI-1 Platelet Glycoproteins Early HBP & CVA [GRA] [Liddle’s syndrome] [MEN-2] Figure 24.1 Overlapping domains represent combined (additive or multiplicative) effects of monogenic, polygenic, and environmental factors promoting atherosclerosis.

Figure 24.4 Coronary heart disease (CHD) incidence rates by family history and smoking status illustrate a multiplicative interaction, especially in the two younger age groups.

Click for larger picture