PIDEMIOLOGICAL STUDIES CONSIStently demonstrate that a low plasma level of high-density lipoprotein (HDL) cholesterol is associated with increased risk of ischemic heart disease (IHD). 1 However, whether HDL cholesterol is a primary causal factor in the pathogenesis of IHD is unclear. Data from observational studies are potentially confounded by other factors related to low HDL cholesterol levels that may contribute independently to increases in cardiovascular events. One such factor is plasma triglycerides, 2 a marker for the presence of atherogenic remnant lipoproteins. 3-5 Mendelian randomization, which is the random assortment of genes from parents to offspring that occurs during gamete formation, provides a method of assessing whether modifiable exposures are causally related to increased risk of IHD. 6 Thus, studies of genetic disorders that lower HDL cholesterol without increases in plasma triglycerides and remnant lipoproteins provide an ideal system in which to assess the consequences of isolated, lifelong low HDL cholesterol levels. A genetic disorder that fulfills such a criterion is Tangier disease, which is due to loss-of-function mutations in the adenosine triphosphatebinding cassette transporter A1 (ABCA1; GenBank No. AF275948) gene and results in unmeasurable HDL cholesterol levels in homozygotes and half-normal HDL cholesterol levels in heterozygotes. Family studies of homozygotes or heterozygotes for these severe HDL de-Author Affiliations are listed at the end of this article.

IMPORTANCE Low-density lipoprotein cholesterol (LDL-C), a key cardiovascular disease marker, is often estimated by the Friedewald or Martin equation, but calculating LDL-C is less accurate in patients with a low LDL-C level or hypertriglyceridemia (triglyceride [TG] levels Ն400 mg/dL). OBJECTIVE To design a more accurate LDL-C equation for patients with a low LDL-C level and/or hypertriglyceridemia. DESIGN, SETTING, AND PARTICIPANTS Data on LDL-C levels and other lipid measures from 8656 patients seen at the National Institutes of Health Clinical Center between January 1, 1976, and June 2, 1999, were analyzed by the β-quantification reference method (18 715 LDL-C test results) and were randomly divided into equally sized training and validation data sets. Using TG and non-high-density lipoprotein cholesterol as independent variables, multiple least squares regression was used to develop an equation for very low-density lipoprotein cholesterol, which was then used in a second equation for LDL-C. Equations were tested against the internal validation data set and multiple external data sets of either β-quantification LDL-C results (n = 28 891) or direct LDL-C test results (n = 252 888). Statistical analysis was performed from August 7, 2018, to July 18, 2019. MAIN OUTCOMES AND MEASURES Concordance between calculated and measured LDL-C levels by β-quantification, as assessed by various measures of test accuracy (correlation coefficient [R 2 ], root mean square error [RMSE], mean absolute difference [MAD]), and percentage of patients misclassified at LDL-C treatment thresholds of 70, 100, and 190 mg/dL. RESULTSCompared with β-quantification, the new equation was more accurate than other LDL-C equations (slope, 0.964; RMSE = 15.2 mg/dL; R 2 = 0.9648; vs Friedewald equation: slope, 1.056; RMSE = 32 mg/dL; R 2 = 0.8808; vs Martin equation: slope, 0.945; RMSE = 25.7 mg/dL; R 2 = 0.9022), particularly for patients with hypertriglyceridemia (MAD = 24.9 mg/dL; vs Friedewald equation: MAD = 56.4 mg/dL; vs Martin equation: MAD = 44.8 mg/dL). The new equation calculates the LDL-C level in patients with TG levels up to 800 mg/dL as accurately as the Friedewald equation does for TG levels less than 400 mg/dL and was associated with 35% fewer misclassifications when patients with hypertriglyceridemia (TG levels, 400-800 mg/dL) were categorized into different LDL-C treatment groups. CONCLUSIONS AND RELEVANCEThe new equation can be readily implemented by clinical laboratories with no additional costs compared with the standard lipid panel. It will allow for more accurate calculation of LDL-C level in patients with low LDL-C levels and/or hypertriglyceridemia (TG levels, Յ800 mg/dL) and thus should improve the use of LDL-C level in cardiovascular disease risk management.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) has been the cornerstone measurement for assessing cardiovascular risk for nearly 20 years.CONTENT: Recent data demonstrate that apolipoprotein B (apo B) is a better measure of circulating LDL particle number (LDL-P) concentration and is a more reliable indicator of risk than LDL-C, and there is growing support for the idea that addition of apo B measurement to the routine lipid panel for assessing and monitoring patients at risk for cardiovascular disease (CVD) would enhance patient management. In this report, we review the studies of apo B and LDL-P reported to date, discuss potential advantages of their measurement over that of LDL-C, and present information related to standardization.

Objective-The aim of this study was to investigate whether the M235T polymorphism in the angiotensinogen gene was associated with angiotensinogen levels, systolic and diastolic blood pressure, hypertension, and risk of ischemic cardiovascular disease in different ethnic populations. Methods and Results-One hundred twenty-seven studies published between January 1992 and March 2002 examining the association of angiotensinogen gene polymorphisms with the above-mentioned end points were selected. Pooled effect sizes and Mantel-Haenszel odds ratios were calculated using Review Manager. In white subjects, genotype was associated with a stepwise increase in plasma angiotensinogen levels of 5% (95% CI, 2% to 8%; Pϭ0.0004) in MT heterozygotes and 11% (7% to 15%; PϽ0.00001) in TT homozygotes compared with MM individuals. Correspondingly, genotype was associated with a stepwise increase in aggregated odds ratio for hypertension of 1.08 (95% CI, 1.01 to 1.15) in MT individuals and 1.19 (1.10 to 1.30) in TT individuals in white subjects and of 1.29 (95% CI, 0.96 to 1.74) and 1.60 (1.19 to 2.15) in Asian subjects. M235T genotype did not predict systolic or diastolic blood pressure or risk of ischemic heart disease or myocardial infarction in either ethnic group. Conclusions-Angiotensinogen M235T genotype was associated with a stepwise increase in angiotensinogen levels in white subjects and a corresponding increase in risk of hypertension in both white and Asian subjects. Key Words: meta-analysis Ⅲ blood pressure Ⅲ genetics Ⅲ hypertension Ⅲ cardiovascular disease H ypertension is a multifactorial disorder because of the interaction of many risk genes and environmental factors such as obesity, dietary salt intake, alcohol consumption, and stress. Approximately 20% to 60% of the population variability in blood pressure is genetically determined. 1 In the first report linking a gene to hypertension, Jeunemaitre et al 2 suggested that the M235T polymorphism in the angiotensinogen gene in the homozygous TT state was associated with an approximate 20% increase in plasma angiotensinogen and an odds ratio for hypertension of 1.95 compared with the MM wild type. The mechanistic explanation behind this was that a higher throughput in the renin-angiotensin system might increase blood pressure by the actions of angiotensin II on sodium reabsorption in the kidneys and by vessel constriction. Apart from hypertension, which is a well-established risk factor for ischemic cardiovascular disease, many researchers were also prompted to investigate whether polymorphisms in the angiotensinogen gene were independent risk factors for ischemic cardiovascular disease. 3,4 In the last decade, hundreds of studies either supporting or rejecting the findings of the initial study 2 have been published. In the late 1990s, 3 independent meta-analyses 5-7 suggested a 22% to 32% increase in risk of hypertension in Japanese and white individuals carrying the TT genotype. The largest of these meta-analyses included 20 397 individuals. 6 With the publication...