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

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Table 114 -9 Hyperlipidemic Disorders Generic Designation and Elevated Lipoprotein Class Exogenous Hyperlipemi a Table 114 -9 Hyperlipidemic Disorders Generic Designation and Elevated Lipoprotein Class Exogenous Hyperlipemi a (chylomicron s Syno Primary Disorders nym Secondary Disorders* Type Familial lipoprotein lipase Dysglobuline deficiency mias I C-II apolipoprotein deficiency Unclassified Systemic lupus erythematosu s

Table 114 -9 Hyperlipidemic Disorders (Cont. ) Generic Desig. Syno Primary Disorders and Elev. Table 114 -9 Hyperlipidemic Disorders (Cont. ) Generic Desig. Syno Primary Disorders and Elev. nym Lipopro. Class Secondary Disorders* Exogenous Hyperlipemia (VLDL) Dysglobulinemias Systemic lupus erythematosus Diabetic hyperlipemia+ Glycogenosis, type. I Lipodystrophies Uremia Hypopituitarism Nephrotic syndrome (Diabetes mellitus) (Alcoholism) (Estrogen use) (Glucocorticoid use) (Stress-induced) Type Familial hypertriglyceridemia II (mild form) Familial multiple lipoproteintype hyperlipidemia Sporadic hypertriglyceridemia Tangier disease Mixed Type Familial hypertriglyceridemia hyperlipemia V (severe form) (VLDL + Familial lipoprotein lipase chylomicrons) deficiency C-II apolipoprotein deficiency

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

Table 114 -9 Hyperlipidemic Disorders (Cont. ) Generic Desig. and Elev. Lipopro Class Synonm Table 114 -9 Hyperlipidemic Disorders (Cont. ) Generic Desig. and Elev. Lipopro Class Synonm Primary Disorders Remnant Hyperlipidemia (beta-VLDL) Type III Lamellar hyperlipoproteinemia (Vesicular and discoidal lipoproteins) Secondary Disorders* Familial Hypothyroidism dysbetalipoproteinemia Systemic lupus Unclassified erythematosus Familial lecithin: cholesterol acyltransferase deficiency Cholestasis (with LP-X) Hepatic failure (with lamellar HDL)

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Characteristics That May Identify An Individual with a Genetic Predisposition to Cardiovascular Disease Positive 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 120 -4 Inbred populations with mutant LDL receptor alleles that account for >15% Table 120 -4 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 FH Lebanese (C 660 X) 100 South African: Ashkenazi Jews FH Lithuania (G 197 del) Asian Indians FH Gujerat (P 664 L) >15* Afrikaners FH Afrikaner-1 (D 206 E) 60 -70 FH Afrikaner-2 (V 408 M) 20 -30 80

Inbred Population Mutation French Canada Percent of FH Heterozygotes with mutation FH French Canadian-1 Inbred Population Mutation French Canada Percent of FH Heterozygotes with mutation FH French Canadian-1 60 (del 5’ flanking region-intron 1) Iceland Finland FH French Canadian-4 (W 66 G) FH Iceland (IVS 4+2 T>C) FH Helsinki (del exons 15 -18) FH North Karelia (P 288 fs) Israel: Sephardic Jews FH Sephardic (D 147 H) FH Druze (Y 167 X) Druze Ashkenazi Jews FH Lituania (G 197 del) 18 60 34 34 >15* 35

Inbred Population Mutation Percent of FH Heterozygotes with mutation FH Elverum (IVS 3+1 G>A) Inbred Population Mutation Percent of FH Heterozygotes with mutation FH Elverum (IVS 3+1 G>A) FH Genoa (D 528 G) FH Afrikaner-2 (V 408 M) E 10 X Spain Belgium (Sourthern) C 122 X FH French Canadian-4 (W 66 X) Denmark FH Cincinnati-5 (W 23 X)) Norway Greece 28 23 15 20 16 15 15

LDL-C [LDLR, APOB] FH MAJOR GENES FDB FCHL LDL-C [APOE] POLYGENES Dyslipidemia [LPL] HDL-C LDL-C [LDLR, APOB] FH MAJOR GENES FDB FCHL LDL-C [APOE] POLYGENES Dyslipidemia [LPL] HDL-C Small Dense LDL BP [AGT] Type III [APOE] Weight HDL [APOAI] Others Apo A-1 [A-1 Milano] Lp(a) NIDDM Individual IDDM ENVIONMENT & Shared H(e) [MTFHR, CS] Fibrinogen Cigarettes Oral Contraceptives PAI-1 Inactivity Stress Platelet Glycoproteins Diet (Fat, calories, simple carbohydrates, Early HBP & CVA [GRA] Na, K, Cr, Mg, Ca, Folate, B 6, B 12, [Liddle’s syndrome] E, carotenoids, flavonoids, etc. ) [MEN-2] Others 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 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.

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