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

Synonym

Primary Disorders Secondary Disorders*

Exogenous Hyperlipemia (chylomicrons

Type I Familial lipoprotein lipase deficiency

C-II apolipoprotein deficiency

Unclassified

Dysglobulinemias

Systemic lupus erythematosus

Table 114-9 Hyperlipidemic Disorders (Cont.)

Generic Desig. and Elev. Lipopro. Class

Synonym

Primary Disorders Secondary 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

Synonym Primary Disorders Secondary Disorders*

Hypercholesterolemia (LDL)

Type II-a Familial hypercholesterolesterolemia (LDL receptor defects)

Familial multiple lipoprotein-type hyperlipidemia

Polygenic

hypercholestrolemia (include exogenous hypercholesterolemia)

Nephrotic syndrome

Hypothyroidism

Dysglobulinemias

Cushing syndrome

Acute intermittent porphyria

Combined hyperlipidemia (LDL + VLDL)

Type II-b Familial multiple lipoprotein-type hyperlipidemia

Unclassified

Nephrotic syndrome

Hypothyroidism

Dysglobulinemias

Cushing syndrome

(Glucocorticoid use)

(Stress-induced)

Table 114-9 Hyperlipidemic Disorders (Cont.)

Generic Desig. and Elev. Lipopro Class

Synonm Primary Disorders Secondary Disorders*

Remnant Hyperlipidemia (beta-VLDL)

Type III Familial 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)

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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 Table 120-4 Inbred populations with mutant LDL receptor alleles that account for >15% of the receptor alleles that account for >15% of the

mutant alleles in that populationmutant 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)

100

80

>15*

60-70

20-30

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)

60

18

60

34

34

>15*

>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))

28

23

15

20

16

15

15

ENVIONMENT Individual& Shared

POLYGENES

MAJOR GENES

Cigarettes Oral ContraceptivesInactivity StressDiet (Fat, calories, simple carbohydrates, Na, K, Cr, Mg, Ca, Folate, B6, B12, E, carotenoids, flavonoids, etc. )Others

LDL-C [APOE]HDL-CBP [AGT]WeightOthers

LDL-C [LDLR, APOB] FH FDBFCHLDyslipidemia [LPL]Small Dense LDLType III [APOE]HDL [APOAI]Apo A-1 [A-1 Milano]Lp(a)NIDDMIDDMH(e) [MTFHR, CS]FibrinogenPAI-1Platelet GlycoproteinsEarly 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.

05

101520253035404550

30-39 40-49 50-59 60-69

Age (years)

CH

D I

ncid

ence

Smokers with +FHx

Non-smokers with +FHx

Smokers in Controls

Non-smokers in Controls

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.

Xba I Apo B

14%

Non-Genetic

37%

Apo E7%

FH1%

Residual Plygenes

40%

Gm, Hp, Se, ABO

1%

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