Table 1.
Targets Genotyped by the CVD35 Assay
| Gene polymorphism: Reported implication, GenBank accession no., and references |
| Lipid metabolism |
| apolipoprotein B (apoB) on chr. 2p: component of plasma lipoproteins, particularly LDL; mediates binding to LDL receptor |
| Thr 71–Ile: possibly associated with increased plasma LDL cholesterol and apoB levels; Arg-3531-cys LDL receptor binding defect appears to segregate with Thr alleleHUMAPB03 (M19810); (Young and Hubl 1989; Pullinger et al. 1995) |
| Arg-3500–Gln mutation: disorder of hypercholesterolemia known as familial defectiveapoB-100, due to reduced binding to LDL receptor |
| HSLDL100 (X04506); (Soria et al. 1989; Humphries and Talmud 1995; Pullinger et al. 1995) |
| apolipoprotein CIII(apoCIII) on chr. 11q: component of plasma lipoproteins |
| T(−625)del, C(−482)T, T(−455)C: increased plasma triglyceride levels |
| HUMAPOCP (M60674), HSAPC3A (X01392); (Dammerman et al. 1993) |
| C3175G (Sst)I: increased plasma triglyceride levels |
| HSAPC3A (X01392); (Rees et al. 1985; Ordovas et al. 1991) |
| C1100T, T3206G: increased plasma triglyceride levels |
| HSAPC3A (X01392); (Xu et al. 1994) |
| apolipoprotein E (apoE) on chr. 19q: component of plasma lipoproteins; mediates binding to the LDL and remnant (apoE) receptors |
| e3/e2, e4: interindividual variation in plasma total and LDL cholesterol levels, atherosclerotic progression |
| HUMAPOE4 (M10065); (Mahley 1988; Hixson and Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group 1991; de Knijff et al. 1994) |
| cholesteryl ester transfer protein (CETP) on chr. 16q: reverse cholesterol transport pathway; possible proatherogenic role in presence of dyslipidemia (Tall 1995; Lassel et al. 1998) |
| Ile-405–Val: increased plasma HDL cholesterol and apoA-I levels |
| HUMCETP6 (M32997); Agellon et al. 1990; Funke et al. 1994;Gudnason et al. 1997) |
| Asp-442–Gly: increased HDL cholesterol levels, yet also disease risk |
| HUMCETP7 (M32998); (Takahashi et al. 1993; Zhong et al. 1996) |
| lipoprotein lipase (LPL) on chr. 8p: hydrolysis of plasma triglycerides |
| T(−93)G: increased LPL promoter activity, reduced plasma triglycerides |
| HUMLPLA (M29549); (Yang et al. 1995a,b; Ehrenborg et al. 1997; Hall et al. 1997) |
| T(−39)C: reduced LPL promoter activity |
| HUMLPLA (M29549); (Yang et al. 1995a,b) |
| Asp9–Asn: increased plasma triglycerides, increased atherosclerotic progression |
| HUMLPL (M15856); (Oka et al. 1990; Mailly et al. 1995; Jukema et al. 1996) |
| Asn-291–Ser: reduced plasma HDL cholesterol, increased triglyceride levels |
| HUMLPL (M15856): (Oka et al. 1990; Reymer et al. 1995; Zhang et al. 1995) |
| Ser-447–Ter: increased plasma HDL cholesterol, reduced plasma triglyceride levels; possible impact on responsiveness to β-blockers |
| HUMLPLF1 (M76722); (Hata et al. 1990; Groenemeijer et al. 1997; Kuivenhoven et al. 1997) |
| paraoxonase (PON) on chr. 7q: HDL-associated enzyme known to hydrolyze organophosphate poisons; possible contribution to HDL's protective capacity against LDL oxidation |
| Gln-192–Arg: increased enzymatic activity; in vitro, reduced protection against lipid peroxidation |
| HUMPONA (M63012); (Humbert et al. 1993;Hegele et al. 1995; Serrato and Marian 1995; Mackness et al. 1997;Sanghera et al. 1997) |
| Renin–angiotensin system |
| angiotensin-converting enzyme (ACE) on chr. 17q: proteolyzes angiotensin I to produce angiotensin II |
| Aluelement insertion/deletion in intron 16: increased plasma ACE levels; mixed evidence of association with myocardial infarction |
| HSATICE (X62855), HUMAICEB (J04144); (Cambien et al. 1992;Rigat et al. 1992; Evans et al. 1994; Lindpaintner et al. 1995; Ludwig et al. 1995) |
| angiotensin II receptor type 1 (ATIIR1 ) on chr. 3q: one of two receptors for angiotensin II, particularly in vascular smooth muscle cells |
| A1166C: hypertension; possible synergism with ACE conferring risk of myocardial infarction HSANTENII (Z11162); (Bonnardeaux et al. 1994;Tiret et al. 1994) |
| angiotensinogen (AGT) on chr. 1q: substrate for renin, yielding angiotensin I |
| Met-235–Thr: increased plasma AGT levels; hypertension |
| HUMAGT02 (M24686); (Jeunemaitre et al. 1992; Morgan et al. 1996) |
| Homocysteine metabolism |
| cystathionine β-synthase (CBS) on chr. 21q: transulfuration pathway, converting homocysteine to cystathioine, with pyridoxine as cofactor |
| Ala-114–Val: pyridoxine-responsive homocystinuria |
| HUMCYSTATH (L19501); (Kozich et al. 1993) |
| Arg-125–Gln, glu131asp: pyridoxine-unresponsive homocystinuria |
| HUMCYSTATH (L19501); (Marble et al. 1994) |
| Ile-278–Thr: pyridoxine-responsive homocystinuria |
| HUMCYSTATH (L19501); (Kozich and Kraus 1992; Hu et al. 1993) |
| 68-bp insertion: linkage disequilibrium with 278thr; (Sebastio et al. 1995; Sperandeo et al. 1996; Tsai et al. 1996) |
| Gly-307–Ser: pyridoxine-unresponsive homocystinuria |
| HUMCYSTATH (L19501); (Hu et al. 1993) |
| methylene tetrahydrofolate reductase (MTHFR) on chr. 1p: remethylation pathway, generating the 5-methyltetrahydrofolate that serves as the methyl group donor |
| C677T (Ala/Val) increased thermolability; associated with hyperhomocysteinemia given low dietary folate; increased risk for deep-vein thrombosis in carriers of factor V Leiden HSU09806 (U09806); (Frosst et al. 1995; Goyette et al. 1995; Kluijtmans et al. 1996; Cattaneo et al. 1997; Christensen et al. 1997) |
| C692T: absence of enzyme activity |
| HSU09806 (U09806); (Goyette et al. 1995) |
| Thrombosis |
| glycoprotein IIIa (GPIIIa) on chr. 17q: component of GPIIb/IIIa platelet adhesion receptor, binding fibrinogen, fibronectin, and von Willebrand factor; (Nurden 1996) |
| Leu-33–Pro: interindividual variation in platelet adhesion and/or adhesion; mixed evidence of association with risk of coronary thrombosis |
| HUMGPP3A07 (M32672); (Newman et al. 1989; Jin et al. 1993; Weiss et al. 1996; Ridker et al. 1997) |
| fibrinogen on chr. 4q: determinant of plasma viscosity, cofactor for platelet aggregation, precursor of fibrin (component of plaques); (Cook and Ubben 1990; Mannucci 1995) |
| β chain G(−455)A: increased plasma fibrinogen levels and progression of atherosclerosis |
| HSFIBBR1 (X05018); (Green et al. 1993;Humphries et al. 1995; Humphries et al. 1997) |
| factor Von chr. 1q: activated form is procoagulant cofactor in prothrombin activation, inactivated through cleavage by activated protein C |
| Arg-506–Gln (Leiden mutation): resistance to activated protein C; hypercoagulability |
| HUMF510 (L32764); (Bertina et al. 1994;Ridker et al. 1995; Kalafatis and Mann 1997) |
| Leukocyte adhesion |
| endothelial leukocyte adhesion molecule-1 (ELAM) on chr. 1q: adhesion of leukocytes to activated arterial endothelium (Carlos and Harlan 1990); also known asE-selectin |
| G98T, Ser-128–Arg, Leu-554–Phe: increased risk for severe atherosclerosis |
| HUMELAM1 (M61895), HUMELAM3 (M61888), HUMELAM7 (M61892); (Wenzel et al. 1994; 1996) |
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Markers are grouped by gene within broad categories based upon biological function. Chromosomal locations of each gene are given; among these genes, no two are known to be in strong linkage disequilibrium. For each target, with wild-type or most frequent allele is listed to the left, and the variant to the right, of the numerical nucleotide or codon position. Single letters indicate nucleotide variations; three-letter codes designate amino acid variations. For each target, a possible role for the variant allele, the GenBank sequence used for primer and probe selection, and references for the sequence variations are listed. Review articles are cited in the interest of space.
