Triglycerides and HDL-cholesterol in pediatric patients

Progress in Pediatric Cardiology 17 (2003) 151–158

Triglycerides and HDL-cholesterol in pediatric patients Dennis L. Sprecher*, Melissa Stevens 9500 Euclid Avenue, Desk C51, Cleveland, Ohio 44195, USA Accepted 1 May 2003

Abstract Abnormalities in HDL-cholesterol and triglyceride values in adults increase the risk for cardiovascular disease, and the prevalence in children has advanced over the last two decades. These values track into adulthood, and already predict sub-clinical disease in adolescents. Pediatric screening and lifestyle changes such as nutrition and exercise are important considerations. HDL and triglyceride values are excellent markers of cardiovascular health and potential targets. 䊚 2003 Elsevier Ireland Ltd. All rights reserved. Keywords: Pediatrics; Triglycerides; HDL-cholesterol; Cardiovascular disease

1. Introduction HDLc has been proven to be a potent risk factor in the adult population (Framingham, PROCAM), while triglyceride values have now also been found to be independent predictors of cardiovascular risk w1,2x. This appears true even with adjustment for HDLc, a factor highly correlated with TG values. In addition, intervention trials suggest that modification in HDLc, and perhaps TG, influences CV outcomes. This has made some suggest abnormal HDL and TG values or perhaps most importantly low HDLyhigh TG, as triggers for therapy, and perhaps targets for change. TG and HDL abnormalities do not typically appear suddenly, but are the progressive aspects observed throughout a lifecycle. Such abnormalities are growing within the pediatric population, at least partially associated with the national pandemic of obesity. Adult cholesterol treatment guidelines have begun to address the cardiovascular risk exposure now understood from both low HDLc values and elevated TG. However, the pediatric lipid guidelines have made no further inroads into treatment associated with these risk parameters. In this brief review, we will examine the HDLyTG issues in published pediatric works, examine the tracking of such *Corresponding author. Present address: Director, Dyslipidemia, Discovery Medicine CVU CEDD. Tel.: q1-610-270-6007; fax: q1610-270-5250.. E-mail address: [email protected] (D.L. Sprecher).

values into adulthood, and describe the known CV risks resulting from these issues in adulthood. 2. Metabolism We are aware that there are two pathways (apoAIy HDL and apoByLDL:VLDL, Fig. 1) which interact to provide us the lipid profile seen in clinical practice. The apoB pathway originates with the hepatic organization of cholesteryl ester and triglyceride, brought together by the microsomal transfer protein (MTP) and developed into particles transported out into lymph and ultimately out into the vascular space. These initial very lowdensity lipoproteins (VLDL) are TG enriched (constitute a major component of the serum TG levels measured clinically), and are processed by lipoprotein lipase (LpL), which hydrolyses the fatty acids off of the glycerol backbone. Intermediate forms include products termed intermediate density lipoproteins (IDL). ApoCIII, often found on these particles appears to inhibit LpL activity. These remaining remnant particles can be removed through remnant receptors (e.g. LRP), or processed further by way of hepatic triglyceride lipase (HTgL) to the smaller LDL particle. This latter particle is removed through the high affinity LDL-receptor. For the second pathway, the extruded apoAI nascent disc (presumably from both liver and intestine) is matured into an HDL particle by way of membrane transfer of both free cholesterol and phospholipid. This

1058-9813/03/$ - see front matter 䊚 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/S1058-9813(03)00052-3

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D.L. Sprecher, M. Stevens / Progress in Pediatric Cardiology 17 (2003) 151–158

Fig. 1. Two lipoprotein pathways are depicted, including apoByVLDL from the liver, and apoAlyHDL from both the liver and intestine. The former illustrates processing of the TG-rich VLDL through both lipases, LpL and HTgL, with egress through the high affinity LDL-receptor, while the latter illustrates the LCAT-mediated maturation of the premature HDL form (pre-HDL) to dense spherical HDL (HDL3), further to lipid enriched HDL2 via transfer from apoB pathways (CETP) and ultimately depositing of HDL cholesteryl ester via the scavenger receptor (SRB1). Enriched TG in the system leads to denser LDL and lower HDL-cholesterol levels, a process catalyzed via CETP. Intermediate forms of apoB related lipoproteins can be removed through the LRP receptor. Abbreviations: Very low density lipoprotein (VLDL); intermediate density lipoprotein (IDL); lipoprotein lipase (LpL); hepatic triglyceride lipase (HTgL); lecil thin cholesterol acyl transferase (LCAT); cholesterol ester transfer protein (CETP); LDL-receptor like protein (LRP); apolipoprotein CIII (apoCIII).

transfer is mediated by way of an ATP-binding cassette transporter (ABC1) enzyme which resides at the membrane interface w3x. Further maturation of this early form proceeds via transfer of the free cholesterol and phopholipid resulting from LpL hydrolysis of apoB particles noted above, which the HDL particle scavenges. The denser form of HDL (HDL3) can be subsequently enriched with CE and TG, producing HDL2, while hepatic lipase can hydrolyze the HDL2 back to HDL3. Removal of HDL can be mediated through the SR-B1 receptor, which accepts the CE, and allows the apoAI to remain in the serum. Such apoAI could either be degraded and cleared through the kidney, or returned to the original nascent HDL pool w4x. Generally in the setting where an increase in serum free fatty acids persists, e.g. diabetes and obesity, hepatic cells increase the synthetic rate of VLDL and there is a down-regulation of LpL activity. These mechanistic changes appear to be the result of a lack of repression or activation exerted by insulin. This condition leads to an enhanced population of TG enriched particles, both due to the saturation of sites of egress from the plasma space, as well as less effective LpL-mediated hydrolysis. Such conditions provide for more time to allow Cholesterol ester transfer protein (CETP) to interchange CE for TG in both LDL as well as HDL. Both LDL and

HDL, therefore, become TG enriched, and HDL-c decreases. LDL becomes more amenable for HTgL processing which leads to denser LDL, while HDL again processed by HTgL decreases its TG and CE concentration and evolves towards HDL3. Affinity between apoAI and lipid moieties in TG enriched HDL is reduced leading to HDL degradation and catabolism. Therefore, the hyperTG state is often associated with dense LDL and low HDL-c levels. This paradigm is first observed when plasma TG levels are greater than approximately 130 mgydl, potentially due to an improved substrate for CETP activity w5x. The associated risk cluster progressively worsens with higher TG values. Unique in-born errors of metabolism are noteworthy in producing low HDLc and often elevation in TG levels (Table 1). Such defects would be clinically transmitted as recessive traits, and have been recognized as rare features associated with HDLyTG changes in our pediatric population. However, more subtle alterations in these genes may impose a far more frequent distributional shift in the HDL and TG serum values. For example, heterozygous LpL deficiency w6x and modest point mutations in the ABC A1 gene, w7x leads to low HDLc and, at times high TG.

D.L. Sprecher, M. Stevens / Progress in Pediatric Cardiology 17 (2003) 151–158 Table 1 HDL

TG

PROCESSING Lipoprotein lipase deficiency ApoCII deficiency Lecithin cholesterol acetyl-transferase deficiency Fish eye disease *Cholesterol-ester transfer protein deficiency

x x x x ≠

≠ ≠ –y≠ ≠ –

STRUCTURAL ApoAI deficiency

x

xy≠

x

–y≠

UPTAKEy SYNTHESIS Tangier disease (ABCAI deficiency) *Potential dominant autosomal transmission

3. HDLyTG transmissibility HDLc correlation between monozygotic twins average approximately 0.7, compared to 0.4 in dizygotic twins w8x. Further, using path analyses among nuclear families, a heritability of 0.55 has been was noted w8x. While it is clear that HDLc is the product both of genetics and environment, it appears to be particularly related to the former. TG and HDLc are inversely correlated (as suggested above), and thus the heritability of one may partially define the heritability of the other. Among 748 white probands in the LRC study, bottom decile HDL, upper decile Tg andyor both were identified in 110 (14.7%) individuals, who were in turn associated with 496 first degree family members. While the elevation of TG alone did not markedly increase the percentage of associated family members with HDLy TG abnormalities, low HDLc alone in the proband resulted in approximately one-third of family members having some HDLyTG changes. However, for probands with both low HDLc and high TG (a conjoint presentation), nearly one-half of first degree family members also had abnormal HDL or TG changes. A mathematical analysis of the same concept in a different family data set revealed the transmissibility to be at least 25% conjoint (i.e. the transmissible factor was the HDLyTG interaction) while the rest was accounted through independent features of HDL and TG alone w9,10x. 4. Tracking The relatively frequent LpL Serine-447 mutation has been noted to enhance the tracking of HDLc (perhaps twice what it might be otherwise) w11x. ApoE isoforms also suggest the tracking of the HDLyTG values (e2) e4), particularly with increased adiposity w12x. In a recent work related to tracking of 76 males and 76 females, subjects were followed an average of 12 years, beginning at 8–18 years of age w13x. Follow-up was specifically focused on metabolic risk factors. The partial interage correlations were HDL; 0.51 and 0.57 and

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for TG; 0.37 and 0.20 for males and females, respectively. This compares with sum of skin folds, which was the highest correlation at 0.7 and 0.5. The HDL tracking has been well demonstrated, even including such data from the Lipid Research Clinics. However, more recently, it does appear that the HDL and TG values track with their clustered metabolic mates including blood pressure, diabetes and body mass w13x. Berenson has demonstrated (n)5000) that such clustering continues throughout the ages particularly high in whites compared to blacks, and with obesity accounting for approximately 50% of the clustering w14x. Variables evaluated include insulin resistance index, BMI, TGy HDL and mean BP. These were all within age-genderrace specific groupings. The central theme of body mass in childhood and adulthood perhaps most characterizes the literature for HDL and TG values. Siervogel reveals in 1304 examinations w15x of subjects prior to age of 45 years, body mass and adiposity changes correspond to HDL and TG levels (r values of 0.2–0.35), while beyond 45 years HDL is the primary correlate among the two (rs0.1– 0.2). The correlation is with fat, not lean body mass, utilizing total body fat, percent body fat (by hydrodensitometry), and body mass index. All correlates examined in women were less than those with men. This correlation between childhood body mass and future lipoprotein values was corroborated by Wright et al. w16x. They re-evaluated 1142 children born in the United Kingdom in 1947. Nearly 700 children were analyzed at age 9 and 13 years, while approximately 529 subjects were reviewed at age 50 years. Again, the relation between childhood BMI and age 50 BMI was good (rs0.39, P-0.001), yet not with age 50 year% body fat (rs0.10, Ps0.07). Therefore, the BMI relationship most likely reveals a continuum of body build rather than fat content. The conclusions of this report indicate that most of those found to be in the top quarter for body fat at the age of 50 years were not typically above the 90th percentile for BMI in childhood (94% below at age 9). TG values (age 50 years) were associated with age 9 and 13 year BMI in both men and women, which remained modestly correlated only in women when adjustment was made for adult percentage fat. These data would further suggest that many if not most overweight adults come from the thinner childhood cohort. Only at the extremes does the tracking of body fat stay robust. The concordance of HDL and TG changes with the overweight status remains intact, and thus would suggest that the body mass measure would be at least a surrogate marker for the HDLyTG values. 5. Vascular changes and HDLyTG levels It is most fortunate that clinically manifest cardiovascular disease is fairly rare in our pediatric populations.

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However, subclinical disease is, in contrast, recognized and progressive, based on necropsy studies as well as new non-interventional testing strategies. Berenson evaluated 204 individuals w17x (age 2–39 years) who had died due to variable causes, and found aortic and coronary plaque associated with HDL and TG values. The combined presence of elevated LDL, TG, BMI and SBP was particularly relevant to enhanced atherogenesis. This suggests the importance of the metabolic syndrome, which includes the latter three variables. The PDAY study w18x separated the combined value of VLDL and LDLc into three intervals (low, medium and high), and determined that raised lesions in the RCA and abdomen were correlated to these apoB related particles (Ps 0.04). This was more apparent in the age group 25–34 years, than in those of age 15–24 years. Low HDLc is more significantly associated with raised lesions, observed both in abdomen (Ps0.0001) and RCA (Ps 0.0015). In childhood follow-up study (Muscatine) (ages 8– 18 years), over 300 adult men and 300 women were evaluated for carotid internal medial thickness (IMT) w19x. Childhood values of HDL and TG were correlated to these carotid measurements, approximately y0.13 and 0.14, respectively (P-0.05). In multivariate analyses, outside of LDL and DBP, HDL was associated with IMT measurements with an odds ratio of 0.66, while in women (outside of LDL, DBP and BMI) only TG was relevant, OR 1.49. A recent report reviewed the IMT measurements in subjects with defects in the ABCA1 gene, compared to non-defective family members. These individuals who are known to present with low HDLc serum values have thicker IMT recordings at any particular age than those without the defects. These data strongly recommend HDL as relevant to intimal thickening and atherosclerotic disease at an early age w20x. Recent CT calcium measurements made in a longitudinal study (Muscatine) reveals body mass in childhood to be mostly related to future calcium positivity. Such calcium scores do strongly suggest the presence of vascular plaque w19x. HDL again was another strong predictor, but not childhood TG levels. 6. Adult disease and HDLyTG levels Epidemiologically, HDL has been demonstrated to be a striking risk factor for future cardiac events w1,21,22x TG has continued to be more controversial, however, a recent meta-analyses indicated the independent prediction of TG for CHD (1.30 odds ratio), even after adjustment for the highly correlated HDL serum level. HDL continues to be viewed as a powerful risk trigger contributing to the overall risk score, utilized by national guideline committees, and promoted by the Framingham data. Information gleaned from the VA-

HIT study, w23x in which veterans with CHD were treated with a fibrate and outcome benefit correlated with HDL change paralleled the findings in angiographic studies. These included FATS (niacin and statin separately, with HDL proving to be relevant to luminal modification), w24x HATS (revealing the value of a statin:niacin combination in altering HDL and TG), w25x along with the LOCAT (gemfibrozil in post-CABG patients), w26x BECAIT (bezafibrate in premature CHD patients), w27x and DIAS w28x (fenofibrate in Type II diabetics). Each revealed the use of a fibrate or niacin, resulting in modification in HDL and TG with clinical benefit. The association between vascular disease and intermediate particle metabolism (reviewed at the front part of this section) has been most supportive towards the use of either TG levels, or non-HDLc, as surrogate markers. The tracking of HDL and TG during the lifecycle, regardless of companion factors such as body mass provides an early signal recommending real cardiovascular danger in the adulthood years. 7. Nutrition 7.1. Low HDL-C and high triglycerides in children Lifestyle factors that aggravate hypertriglyceridemia and low HDL include obesity and excessive calories from dietary carbohydrate. Today, 1 in 5 children is overweight or obese and an additional 14% have a body mass index between the 85th and 95th percentiles w29x. If childhood obesity persists until adulthood, it will likely place the child at future increased risk of heart disease, diabetes and hypertension. In childhood, eating and lifestyle habits such as physical activity are formed. Yet fewer than 25% of children participate in physical education classes w30x and fast food kiosks and vending machines continue to infiltrate schools and after-school events. Now more than ever should health care providers and the government intervene to reverse this obesity epidemic. American Heart Association dietary guidelines have focused on low-fat (-30% of total energy), high carbohydrate (up to 60% total energy) dietary patterns to optimize LDL-cholesterol lowering w31x. This mainly emphasized the utilization of carbohydrate-rich foods for fat in the diet. As a result of following these guidelines, rates of obesity and enrichment in TG levels have developed, leading to a host of additional cardiovascular risk factors to emerge. It has been shown that in the absence of weight loss, low fat (15–20% fat), high-carbohydrate (G55%) diets lead to elevations in TG and reductions in HDL w32–36x. While this is an adaptability issue, w37x most would agree weight loss is needed to preclude elevations in TG when a low-fat, high-carbohydrate diet is administered w36,38–40x.

D.L. Sprecher, M. Stevens / Progress in Pediatric Cardiology 17 (2003) 151–158

However, carbohydrate-induced high TG may not correlate with CV disease w41x. In contrast, weight loss appears to reduce HDL w36,40x. A meta-analysis of weight loss studies indicates that in the active weight-loss phase HDL decreases, but after stabilization it increases for every kilogram of weight that is not regained w42x. The hypertriglyceridemic response to a low-fat, highcarbohydrate diet is also contingent upon carbohydrate source. Hypertriglyceridemia is most pronounced when monosaccharides (simple sugars) are administered w43,44x. Hirsch w35x speculates that consumption of large amounts of simple sugar causes rapid intestinal absorption that overloads the normal pathways of carbohydrate metabolism, increasing lipogenesis and production of very-low-density-lipoprotein cholesterol (VLDL). Others find the TG-raising affects of simple sugars are mainly attributed to its content of fructose w45x. Large amounts of fructose have been shown to increase hepatic TG synthesis and release from plasma in VLDL w46x. This occurs through inhibition of insulin suppression of non-esterified fatty acid release from adipose tissue w45x. Acheson w47x suggests these metabolic responses can be prevented when glucose is absorbed slowly and proposes mixed meals and complex carbohydrate intakes delay glucose absorption. Simple sugar intake is a significant health concern in America as calorie-dense beverages such as sodas and fruit drinks are a substantial source of calories in the diet contributing up to 40% of children’s total added sugar intake. Sugar consumption rose 28% from 1983 to 1999 and is expected to continue w48x. Additional dietary interventions thought to reduce the hypertriglyceridemic response include the substitution of carbohydrates with monounsaturated fats w49,50x and omega-3 fatty acids w51x. A high-fiber diet derived from unprocessed whole foods can prevent the hypertriglyceridemic response w44,52x. A meta-analysis of 67 controlled trials indicated that high carbohydrate diets rich in soluble fiber (from oats, psyllium, pectin and guar gum) decrease total and LDL-cholesterol with insignificant effects on HDL and TG w53x. In persons with diabetes, increases in TG and reductions in HDL resulted when comparing a highcarbohydrate, low-fiber (16 gyday) dietary regimen to one high in soluble fiber food sources (54 gyday) w54x. It is proposed that soluble fiber’s gel-forming capabilities delays digestion and absorption of nutrients leading to prevention of hyperinsulinemia and hypertriglycerdemia. Insoluble fiber, mainly from cereal may reveal similar outcomes, but has not been as well studied. It is also suspected that consumption of fiber-rich carbohydrates are associated with body weight loss as a result of decreased food intake, w36x attributed to the early satiety derived from fiber-rich foods w55x and thus may be an additional driving force that prevents elevated TG.

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The Dietary Intervention Study in Children (DISC) trial w56,57x (initiated by the National Heart, Lung and Blood Institute (NHLBI), 1987) measured the safety and efficacy of long-term dietary intervention on reduction of LDL in more than 600 hypercholesterolemic children (8–10 years). While the focus of this study was to look at dietary effects on LDL, it allows the clinician to understand how dietary intervention and adolescence affects TG and HDL as well. Children were divided into a usual care group or intervention group (Step I dietary guidelines) w56,58x. The children in the intervention group consumed significantly less total fat (28.6% total calories in intervention vs. 33% total calories in usual care, P-001) and more total carbohydrate (56.2% total calories in intervention vs. 52.9% total calories in usual care, P-001) than the usual care group w56x. The incremental contrast of carbohydrate and fat between the two groups did not result in a difference in TG values. The increase in TG and decrease in HDL noted in both groups concurrently from baseline to year 7.5 more likely was the result of pubertal changes, such as weight gain and hormonal maturation. 8. Physical activity Wood and associates w59x showed that the addition of aerobic exercise to a prudent weight-reducing diet (Step I diet) increased HDL levels in men by 13% and prevented a reduction of HDL in women. Yet, women who did not participate in exercise but lost weight showed a 10% reduction in HDL. Sung et al. w60x evaluated the effects of low-energy diet (20–25% total fat, 50–60% total carbohydrate) with or without strength training on 82 obese children and found significant decreases in HDL in the non-training group. Exercise in the adult offspring andyor pediatric period is associated with influences on HDL and TG and decreases particularly in the TG level w61–63x. However, the data are generally inconsistent w64x with a study in Greece revealing increasing HDLc with exercise w65x in contrast to no observed change in US study w66x nor an Australian study (ns2000), ages 7–15 years w67x. It is suspected that regular physical activity preserves andy or increases HDL when added to a prudent cholesterollowering dietary pattern. In addition, aerobic exercise may exert TG-lowering benefits as it aids in weight loss and uses glucose as fuel for activity. 9. Recommendations Twenty-five percent of the obese adult population has insulin resistance, which significantly increases risk of hypertriglyceridemia w68x. Because obesity results from chronic consumption of calories in excess of that expended by the body, the primary preventive measure in children should balance the energy they consume

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Table 2 Recommended dietary guidelines for the hypertriglyceridemic child Nutrient

Recommended intake in children 2 years and older

Total calories

Balance energy intake with expenditure to maintain desirable body weight or prevent weight gain 25–35% of total calories Less than 7% of total calories Up to 20% of total calories Up to 10% of total calories Keep to a minimum Include at least 2 servings of fish per week; include other omega-3 rich foods like canola oil, walnuts, and flaxseeds Less than 200 mg daily Approximately 50–55% of total calories derived mainly from unprocessed whole foods. Limit simple sugar intake to approximately 5% of total calories 15–20% of total calories Age in yearsq5 g (after age 18, 25 or more grams daily) Emphasis should be placed on soluble fiber food sources (e.g. psyllium, guar gum, oats, pectin and legumes)

Total fat Saturated fat Monounsaturated fat Polyunsaturated fat Trans fat Omega-3 rich fatty acids Cholesterol Total carbohydrate

Total protein Total fiber

from food and drinks to that expended in metabolic and physical activities. Many overweight children who are still growing have no need to lose weight, but can reduce their rate of weight gain so that they can ‘grow into’ their weight. Educating children on appropriate portion sizes and emphasis on reduction of calories from simple sugar food sources is essential. Public health organizations w31,69,70x agree on very basic, well-accepted dietary patterns for good health, which are clearly applicable to the pediatric population. The foundation of a child’s diet, irrespective of elevated TG should emphasize whole unrefined food sources of carbohydrate from legumes, vegetables, fruits, starches and whole grains and be limited in simple carbohydrates from beverages, fast foods, desserts and snack foods (see Table 2). Adequate carbohydrate levels for children should minimally be set at 50% of total calories, however, high fructose and sucrose-containing foods should be limited to approximately 5% of total caloric intake w70x. Total fat should not exceed 35% of total calories yet not dip below 20% for children over the age of 2 years w70x. Limitation of saturated fat to 7% of calories and minimizing trans fats (e.g. partially hydrogenated or hydrogenated oils) is essential. Diet and lifestyle patterns initiated early on in life have a tremendous potential public health impact, including lower lipid levels, reduced incidence of obesity and avoidance of premature cardiovascular disease w71x. Guidelines presented in 1991, ‘Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents’ provide screening approaches, dietaryy exercise strategies and potential pharmacalogic practices to alter risk. The central theme is LDL, consistent with that of adult guidelines then and now. However, the level of HDL and VLDL are also viewed as relevant to vascular disease.

We will be hard pressed to target the change in HDL and TG when this remains highly controversial in the adult treatment guidelines. However, we can reason that such alterations would impose some nutritional and exercise boundaries around which health is defined. References w1x Jeppesen J, Hein HO, Suadicani P, Gyntelberg F. Relation of high TG-low HDL cholesterol and LDL cholesterol to the incidence of ischemic heart disease. An 8-year follow-up in the Copenhagen male study. Arterioscler Thromb Vasc Biol 1997;17:1114 –1120. w2x Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of populationbased prospective studies. J Cardiovasc Risk 1996;3:213 –219. w3x Marcil M, Brooks-Wilson A, Clee SM, Roomp K, Zhang LH, Yu L, et al. Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux. Lancet 1999;354:1341 –1346. w4x Breslow J. Familial disorders of high-density lipoprotein metabolism. In: Scriver C, Beaudet A, Sly W, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 1995. w5x Freeman DJ, Packard CJ, Shepherd J, Gaffney D. Polymorphisms in the gene coding for cholesteryl ester transfer protein are related to plasma high-density lipoprotein cholesterol and transfer protein activity. Clin Sci 1990;79:575 –581. w6x Sprecher DL, Kobayashi J, Rymaszewski M, Goldberg IJ, Harris BV, Bellet PS, et al. Trp64—nonsense mutation in the lipoprotein lipase gene. J Lipid Res 1992;33:859 –866. w7x Clee SM, Kastelein JJ, van Dam M, Marcil M, Roomp K, Zwarts KY, et al. Age and residual cholesterol efflux affect HDL cholesterol levels and coronary artery disease in ABCA1 heterozygotes. J Clin Inves 2000;106:1263 –1270. w8x McGue M, Rao DC, Iselius L, Russell JM. Resolution of genetic and cultural inheritance in twin families by path analysis: application to HDL-cholesterol. Am J Hum Genet 1985;37:998 –1014.

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