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