Apolipoprotein B and Cardiovascular Disease Risk: Position Statement from the AACC Lipoproteins and Vascular Diseases Division Working Group on Best Practices

John H. Contois; Joseph P. McConnell; Amar A. Sethi; Gyorgy Csako; Sridevi Devaraj; Daniel M. Hoefner; G. Russell Warnick

doi:10.1373/clinchem.2008.118356

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Figure 1.
Relative risk of CHD [adapted from Thompson and Danesh (37)].

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Table 1.

Prospective studies of apo B and LDL-P: comparison with LDL-C.

Study	Comparison	apo B	LDL-C	Matching and/or adjustment variables
Salonen et al. (48)		NS¹	No data	Sex, age, TC, smoking, CVD history, mean arterial BP
Stampfer et al. (49)	Quintile 5 vs 1	2.50 (1.31–4.75)	No LDL-C	Age, smoking
Sigurdsson et al. (50)	1 SD	1.32 (P < 0.001)	No LDL-C
Coleman et al. (51)	Tertile 3 vs 1	2.4 (1.0–4.7)	No LDL-C
Wald et al. (52)	Quintile 5 vs 1	7.02 (3.96–12.5)	No LDL-C
Lamarche et al. (39)	1 SD	1.44 (1.22–1.67)	No LDL-C	Age, SBP, diabetes, smoking, medications
Cremer et al. (53)	Quintile 5 vs 1	8.7 (5.2–14.5)	13.2 (7.4–23.6)	Age, smoking, alcohol use, family history
Sweetnam et al. (54)	1 SD	1.20 (1.05–1.37)	No data	DBP, smoking, BMI, ischemia at baseline
Gotto et al. (46)	Baseline 1 year treatment	P = 0.002	NS	Treatment group, age, sex, marital status, hypertension, smoking, family history
		P < 0.001	NS
Walldius et al. (38)	1 SD	M, 1.33 (1.17–1.51); W, 1.53 (1.25–1.88)	M, 1.14 (1.01–1.28); W, 0.85 (0.69–1.05)	Age, TC, TG, apo B, LDL-C
Simons et al. (55)	1 SD	1.28 (1.15–1.42)	1.28 (1.14–1.42)	Age, BMI, sex, family history, SBP, BP medications, smoking, diabetes, TC, HDL-C, TG
Sharrett et al. (45)	Quintile 5 vs 1	M, 2.4; W, 2.8	M, 2.5; W, 2.7	Smoking, BP, diabetes, medications
Talmud et al. (41)	1 SD	1.42 (1.19–1.70)	1.31 (1.12–1.52)	Age, clinic, HDL-C
Blake et al. (44)	Quartile 4 vs 1	2.43 (1.23–4.82)	2.06 (1.03–4.12)	Age, smoking, treatment group
Shai et al. (42)	1 SD, quintile 5 vs 1	1.8 (1.5–2.2); 4.7 (2.5–8.9)	1.4 (1.2–1.6); 2.7 (1.6–4.6)	Fasting status, age, smoking, month of blood draw
Jiang et al. (43)	Quartile 4 vs 1	2.31 (1.23–4.35)	1.74 (0.99–3.06)	Age, BMI, family history of MI, smoking, physical activity, alcohol intake, fasting status, hypertension, aspirin use, Hb A_1c
St-Pierre et al. (40)	Tertile 3 vs 1	7 years, 2.4 (1.5–3.8); 13 years, 1.6 (1.0–2.5)	No data	Age, BMI, SBP, diabetes, smoking, medications, TG, HDL-C
Ridker et al. (47)	Quintile 5 vs 1	2.50 (1.68–3.72)	1.62 (1.17–2.25)	Age, smoking, BP, diabetes, BMI
Meisinger et al. (56)	1 SD	M, 1.49 (1.25–1.78); W, 1.73 (1.32–2.27)	M, 1.49 (1.25–1.78); W, 1.79 (1.40–2.30)	Diabetes, smoking, BMI, hypertension, age, alcohol use
Pischon et al. (58)	Quintile 5 vs 1	2.98 (1.76–5.06)	2.07 (1.24–3.45)	Age, smoking, month of blood draw, BMI, family history of premature MI, diabetes, alcohol use, physical activity
					Continued on page 412

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Table 1A.

Prospective studies of apo B and LDL-P: comparison with LDL-C. (Continued from page 411)

Study	Comparison	apo B	LDL-C	Matching and/or adjustment variables
Ingelsson et al. (57)	1 SD	M, 1.35 (1.18–1.55); W, 1.42 (1.18–1.73)	M, 1.10 (0.96–1.27); W, 1.19 (0.98–1.45)	Age, SBP, antihypertension medications, diabetes, smoking
Benn et al. (60)	Tertile 3 vs 1	M, 1.4 (1.1–1.8); W, 1.5 (1.1–2.1)	“less predictive”	Age, TC, LDL-C, HDL-C, TG, BMI, hypertension, diabetes, smoking
Mora et al. (59)	Quintile 5 vs 1	2.57 (1.98–3.33)	1.74 (1.40–2.16)	Age, treatment group, smoking, menopausal hormone use, BP, BMI, diabetes
Pedersen et al. (61)	–10 mg/dL	−5.3% risk (placebo)	−3.3% risk (placebo)	Sex, age, qualifying MI, smoking, hypertension
		−5.1% risk (baseline)	2.9% risk (baseline)
		−8.8% risk (on-trial)	−7.2% risk (on-trial)
Moss et al. (62)	Quartile 4 vs 1–3	1.82 (1.10–3.00)	No data	Diabetes, MI, electrocardiogram infarct type, pulmonary congestion, sex, ejection fraction
van Lennep et al. (63)	On-trial, 1 unit	3.21 (1.10–9.35)	1.16 (0.80–1.67)	Age [LDL-C, mmol/L; apo B, g/L]
Simes et al. (64)	Baseline, 1 unit	2.07 (1.32–3.22)	1.28 (1.10–1.46)	Age, sex, hypertension, diabetes, smoking, stroke or TIA, PVD, previous revascularization, stable angina, and qualifying event. [LDL-C, mmol/L; apo B, g/L]
	On-trial, 1 unit	2.10 (1.21–3.64)	1.20 (1.00–1.45)
Corsetti et al. (65)	1 unit	2.02 (1.10–3.69)	No data	Calcium channel blockers
Otvos et al. (66)	Baseline, 1 SD	1.12 (0.99–1.27)	1.10 (0.97–1.25)	Treatment group, age, hypertension, smoking, BMI, diabetes
	On-trial, 1 SD	1.07 (0.94–1.23)	1.08 (0.95–1.23)

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Table 2.

Prospective studies of LDL-P in comparison with LDL-C.

Study	Comparison	LDL-P	LDL-C	Matching and/or adjustment variables
Blake et al. (44)	Quartile 4 vs 1	4.17 (1.96–8.87)	2.06 (1.03–4.12)	Age, smoking, treatment group
Kuller et al. (67)	Quartile 4 vs 1	M, NS; W, 2.59	M, NS¹; W, 3.34	Age, race
Rosenson et al. (68)	Above vs below median	2.1 (0.7–5.8)	1.4 (0.5–3.9)	Age, race, baseline lumen diameter
El Harchaoui et al. (69)	Quartile 4 vs 1	1.78 (1.34–2.37)	1.22 (0.92–1.61)	Smoking, SBP, LDL-C or LDL-P
Otvos et al. (66)	Baseline, 1 SD	1.20 (1.05–1.37)	1.10 (0.97–1.25)	Treatment group, age, hypertension, smoking, BMI, diabetes
	On-trial, 1 SD	1.28 (1.12–1.47)	1.08 (0.95–1.23)
Cromwell et al. (70)	1 SD	M, 1.24 (1.10–1.39); W, 1.33 (1.17–1.50)	M, 1.06 (0.94–1.20); W, 1.18 (1.02–1.37)	Age, SBP, DBP, smoking, medications
Mora et al. (59)	Quintile 5 vs 1	2.51 (1.91–3.30)	1.74 (1.40–2.16)

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Table 3.

Effectiveness of statin treatment at reducing LDL-C, non–HDL-C, apo B, and LDL-P.¹

	Reduction on therapy, %	Mean on-treatment concentration	Mean on-treatment percentile
ApoB studies (n = 17 035)
LDL-C	42.1	99.2 mg/dL	21
Non–HDL-C	39.6	127.0 mg/dL	29
apo B	33.1	101.6 mg/dL	55
LDL-P Studies (n = 889)
LDL-C	35.9	105.2 mg/dL	27
LDL-P	30.6	1459 nmol/L	51

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Table 4.

Population distributions of LDL-C, non–HDL-C, apo B, and LDL-P in the Framingham Offspring Study.

Percentile	LDL-C, mg/dL	Non–HDL-C, mg/dL	LDL-P, nmol/L	apo B, mg/dL
2	70	83	720	54
5	78	94	850	62
10	88	104	940	69
20	100	119	1100	78
30	111	132	1220	85
40	120	143	1330	91
50	130	153	1440	97
60	139	163	1540	103
70	149	175	1670	110
80	160	187	1820	118
90	176	205	2020	130
95	191	224	2210	140

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Table 5.
Suggested treatment goal for apo B and non–HDL-P with “equivalent” cutoffs for LDL-C.
apo B, mg/dL LDL-C, mg/dL Non–HDL-C, mg/dL LDL-P, nmol/L
<70 <80
<80 <100 <120 <1100
<100 <130 <150 <1400

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Table 6.

Comparison of LDL-C and apo B.

Parameter	LDL-C	apo B
Nature of target analyte	LDL is not a unique molecular species but a heterogeneous and polydisperse population of particles with varying chemical composition and physicochemical properties. Therefore, LDL is defined functionally in terms of the method used to separate it from other lipoproteins.	apo B is well defined as a molecular species (apo B-100 and apo B-48). Although methods for measuring apo B-48 are available, routine “apo B” methods measure either apo B-100 or total apo B.
Reference material	Standard Reference Material (SRM) 1951b (frozen human serum preparations) certified by the National Institute of Standards and Technology (NIST), Gaithersburg, MD. LDL-C determined by β-quantification (see below) at CDC, USA. Level I, 113.2 (3.1) mg/dL or 2.93 (0.08) mmol/L; level II, 152.6 (3.0) mg/dL. Note: Direct comparison with the “reference method” β-quantification (see below) is considered the only reliable accuracy test for an LDL-C method at present.¹	International Reference Material SP3–07 (a human serum preparation in liquid-stabilized form) developed by IFCC Standardization Project and endorsed by WHO.² Accuracy-based mass value of 1.22 g/L [3.95 (0.08) mmol/L] assigned to apo B.²
Comparison methods	Various ultracentrifugation methods sometimes combined with chemical precipitation agents [e.g., dextran sulfate or phosphotungstate with MgCl₂, heparin with MnCl₂, and polyethylene glycol (PEG) 6000].¹³	Behring (now Siemens) Nephelometer at the Northwest Lipid Research Laboratories (NWLRL), University of Washington, Seattle, WA.⁴
Reference method	β-Quantification.¹³ Widely accepted (including CDC in USA) but not formally credentialed.¹³ Defines LDL as a population of particles with hydrated density ≥1.006 kg/L and precipitation by polyanion-metal ions.	Not defined.
Definitive method	Not defined.	Not defined.
Principle of analytical methods for quantitation	Different methodologies are based on different physicochemical properties of LDL particles	All methodologies are based on the antigenicity of apo B and involve the use of specific anti-apo B antibodies.