Presentation on theme: "The Identification of Genetic Hyperlipidemias Robert E.Ferrell, Ph.DRobert E.Ferrell Department of Human Genetics, Graduate School of Public Health, University."— Presentation transcript:
The Identification of Genetic Hyperlipidemias Robert E.Ferrell, Ph.DRobert E.Ferrell Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh
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% 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) 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 >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
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.