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2025 Familial Lipoprotein Disorders in Patients With Premature Coronary Artery Disease Jacques J. Genest Jr., MD; Sarah S. Martin-Munley, PhD; Judith R. McNamara, MT; Jose M. Ordovas, PhD; Jennifer Jenner, BsC; Richard H. Myers, PhD; Steven R. Silberman, PhD; Peter W.F. Wilson, MD; Deeb N. Salem, MD; and Ernst J. Schaefer, MD Background. Genetic lipoprotein disorders have been associated with premature coronary artery disease (CAD). Methods and Results. The prevalence of such disorders was determined in 102 kindreds (n=603 subjects) in whom the proband had significant CAD documented by angiography before the age of 60 years. Fasting plasma cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, apolipoprotein (apo) B, and lipoprotein (a) [Lp(a)] values above the 90th percentile and high density lipoprotein (HDL) cholesterol and apo A-I below the 10th percentile of age- and sex-specific norms were defined as abnormal. An abnormality was noted in 73.5% of probands compared with 38.2% in age-matched controls (p<0.001), with a low HDL cholesterol level (hypoalphalipoproteinemia) being the most common abnormality (39.2% of cases). In these kindreds, 54% had a defined phenotypic familial lipoprotein or apolipoprotein disorder. The following frequencies were observed: Lp(a) excess, 18.6% (includes 12.7% with no other dyslipi- demias); hypertriglyceridemia with hypoalphalipoproteinemia, 14.7%; combined hyperlipidemia, 13.7% (11.7% with and 2.0%o without hypoalphalipoproteinemia); hyperapobetalipoproteinemia (elevated apo B only), 5%; hypoalphalipoproteinemia, 4%; hypercholesterolemia (elevated LDL only), 3%; hypertriglycer- idemia, 1%; decreased apo A-I only, 1%. Overall, 54% of the probands had a familial dyslipidemia; unclassifiable lipid disorders (spouse also affected) were found in 3%. No identifiable familial dyslipi- demia was noted in 43% of kindreds of those; nearly half (45%) had a sporadic lipid disorder. Parent-offspring and proband-spouse correlations for these biochemical variables revealed that lipopro- tein and apolipoprotein levels are in part genetically determined, with Lp(a) showing the highest degree of parent-offspring correlation. Conclusions. Our data indicate that more than half of patients with premature CAD have a familial lipoprotein disorder, with Lp(a) excess, hypertriglyceridemia with hypoalphalipoproteinemia, and com- bined hyperlipidemia with hypoalphalipoproteinemia being the most common abnormalities. (Circulation 1992;85:2025-2033) KEY WoRDs * coronary artery disease * lipids * lipoproteins * genetics F amily history of myocardial infarction or sudden death is a frequent finding in patients with premature coronary artery disease (CAD) and is considered a risk factor for the development of CAD.1 Several familial lipid disorders, including familial hyper- From the Lipid Metabolism Laboratory (J.J.G., S.S.M.-M., J.R.M., J.M.O., J.J., E.J.S.), U.S.D.A. Human Nutrition Research Center on Aging at Tufts University and Cardiology Division (D.N.S.), Department of Medicine, New England Medical Center Hospital, Boston; Department of Neurology (R.H.M.), Boston University School of Medicine, Boston; Terumo Medical Corpo- ration (S.R.S.), Elkton, Md.; and the Framingham Heart Study (P.W.F.W.), Framingham, Mass. Supported by grant HL-35243 and subcontract HV-83-03 from the National Heart, Lung, and Blood Institute, National Institutes of Health, and by contract 53-3K06-5-10 from the U.S. Department of Agriculture Research Service. J.J.G. was supported by a Centen- nial Fellowship of the Medical Research Council of Canada. Presented in part at the 62nd Scientific Sessions of the Ameri- can Heart Association, New Orleans, November 1989. Address for correspondence: Ernst J. Schaefer, MD, Lipid Metabolism Laboratory, U.S.D.A. Human Nutrition Research Center on Aging, Tufts University, 711 Washington St., Boston, MA 02111. cholesterolemia (FH),2 familial combined hyperlipid- emia (FCH),3-5 and familial hypoalphalipoproteinemia (FHA),6 have been associated with an increased risk of premature CAD. The role of plasma lipids and lipopro- teins in the development of CAD has been shown in large prospective7-8 and case-control studies.9-10 The protein content of low density lipoproteins (LDL) and the main apolipoproteins of high density lipoproteins (HDL), i.e., apolipoprotein (apo) B and apo A-I,1-14 as well as lipoprotein (a) [Lp(a)] and apo (a)15"6 have been shown in some studies, but not all, to be better markers for the presence of CAD than elevated LDL cholesterol or decreased HDL cholesterol levels. Elevation of LDL apo B with normal (or near-normal) lipid values (hyper- apobetalipoproteinemia) is associated with premature CAD and has been shown to segregate in family mem- bers." Lp(a) excess also is associated with premature CAD and is present in families of affected individuals. The modes of inheritance for many of these disorders is thought to be autosomal dominant or polygenic, with varying degrees of penetrance and/or expression in adulthood. With the exception of FH,2 familial defective apo B-100,17 familial dysbetalipoproteinemia (type III by guest on October 5, 2017 http://circ.ahajournals.org/ Downloaded from

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Familial Lipoprotein Disorders in Patients WithPremature Coronary Artery Disease

Jacques J. Genest Jr., MD; Sarah S. Martin-Munley, PhD; Judith R. McNamara, MT;Jose M. Ordovas, PhD; Jennifer Jenner, BsC; Richard H. Myers, PhD; Steven R. Silberman, PhD;

Peter W.F. Wilson, MD; Deeb N. Salem, MD; and Ernst J. Schaefer, MD

Background. Genetic lipoprotein disorders have been associated with premature coronary artery disease(CAD).

Methods and Results. The prevalence of such disorders was determined in 102 kindreds (n=603 subjects)in whom the proband had significant CAD documented by angiography before the age of 60 years. Fastingplasma cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, apolipoprotein (apo) B, andlipoprotein (a) [Lp(a)] values above the 90th percentile and high density lipoprotein (HDL) cholesteroland apo A-I below the 10th percentile of age- and sex-specific norms were defined as abnormal. Anabnormality was noted in 73.5% of probands compared with 38.2% in age-matched controls (p

2026 Circulation Vol 85, No 6 June 1992

hyperlipoproteinemia),18 and rare disorders of the apoAI-CIII-AIV gene cluster,'9'20 the molecular defects ofmost familial lipoprotein disorders associated with pre-mature CAD are unknown. In FH, multiple disorders ofthe LDL receptor gene have been identified, and thedisease is transmitted in a Mendelian dominantfashion.21,22The prevalence of lipid disorders is increased in

patients with premature CAD. However, the type andprevalence of familial dyslipidemias have not been wellcharacterized since the description of FCH in CADpatients,3-5 which was based on measurements of totalcholesterol and triglyceride concentrations and the li-poprotein electrophoresis pattern.The purpose of the present study was to determine

the type and prevalence of dyslipidemias in patientswith premature coronary disease. The genetic contribu-tion of lipoprotein and apolipoprotein levels was as-sessed by comparing parental with offspring plasmalevels of various lipid parameters.


From July 1986 through December 1987, 259 consec-utive patients referred to our hospital for coronaryangiography were included in the study if they wereCaucasian and less than 60 years of age at the time ofangiography and had significant CAD, defined as >50%stenosis of one or more epicardial coronary artery.Patients with

Genest et al Genetic Lipoprotein Disorders and CAD 2027

precipitation.24'25 Our laboratory meets the perfor-mance criteria of the Centers for Disease Control-National Heart, Lung, and Blood Institute Lipid Stan-dardization program. In most subjects, LDL cholesterolwas estimated with the Friedewald formula.24-26 How-ever, in cases where the plasma triglyceride levels were>400 mg/dl, cholesterol was measured in the density> 1.006 g/ml infranate plasma after ultracentrifugation;LDL cholesterol was then calculated by subtractingHDL cholesterol from infranate cholesterol.23 Apo A-Iand apo B were determined by noncompetitive ELI-SAs.2728 These assays were standardized using aminoacid analysis of purified protein standards. Lp(a) wasmeasured using a commercially available ELISA (Ter-umo Medical Corp., Elkton, Md.), which uses twoantisera, one monoclonal antibody that does not cross-react with plasminogen, and a polyclonal antibody thatis specific for the apo (a) protein of Lp(a). The assay isstandardized with respect to the total Lp(a) particle.Results are expressed in milligrams per deciliter ofLp(a). Coefficients of variance for this assay were 2.46%for intrarun and 3.33% for interrun variations, respec-tively, and 90th percentilevalue of age- and sex-matched control subjects. Simi-larly, hypercholesterolemia was defined as a plasmalevel of LDL cholesterol >90th percentile, and hypoal-phalipoproteinemia was defined as a plasma level ofHDL cholesterol 39 mg/dl for men, >39.5 mg/dl for women) in theproband and at least one first-degree relative. Familialhyperapo B was defined as apo B >90th percentile in

normal lipid and lipoprotein levels. Familial apo A-Ideficiency was defined as apo A-I levels < 10th percentilewith normal lipid values, including HDL cholesterol.FCH was defined as the finding of an elevated triglycer-ide level and/or an elevated LDL cholesterol level(>90th percentile) in the proband and at least onefirst-degree relative, with the stipulation that both abnor-malities had to be present in the kindred. Familialhypertriglyceridemia with hypoalphalipoproteinemia wasdefined as an elevated triglyceride level and/or a lowHDL cholesterol level (< 10th percentile) in the probandand at least one first-degree relative, with the stipulationthat both abnormalities had to be present within thekindred. We call this entity familial dyslipidemia.

Statistical AnalysisData were stored on a VAX 11/780 (Digital Equip-

ment Corp., Maynard, Mass.) on the data base RS/1(BBN Software, Cambridge, Mass.). The RPL languagewas used for all programming (BBN software); Z scoreswere determined by using a built-in subroutine. Tocalculate correlation coefficients between parents andoffspring for biochemical variables, the Z score wasdetermined for each lipoprotein and apolipoproteinvariable to correct for age and sex differences. Pearson'smultiple regression analysis, using the SAS statisticalpackage (SAS Institute, Cary, N.C.) was used to deter-mine correlation coefficients between lipoprotein andapolipoprotein levels in proband-spouse, midparent-midoffspring, and proband (or spouse)-offspring com-binations. Because we did not observe age and sexdifferences for Lp(a) levels in this study, we useduncorrected Lp(a) data for these correlation analyses.Differences in lipids, lipoproteins, and apolipoproteinswere analyzed by t tests, and differences in the fre-quency of lipid disorders were assessed by x2 analysis.Covariate analysis between cases and controls was per-formed using a general linear model (GLM) procedure.The data were adjusted for body mass index, sex, age,use of ,8-blockers, cigarette smoking, and hypertension.

ResultsThe mean age of the probands was 516 years (age

range, 34-59 years). When the CAD cases were com-pared with Framingham controls, prevalence rates forsmoking (within the past 2 years; 44% versus 28%,p

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TABLE 1. LApid, Lipoprotein, and Apolipoprotein Levels in ProbandsMen Women

CAD FHS controls CAD FHS controlsLevels (mg/dl) (n=87) (n=901) (n=15) (n=1,125)Cholesterol 20055 21436t 24196 21543*Triglycerides 177+107 141+ 104t 219225 110144*LDL cholesterol 13955* 13835 152+58 13438HDL cholesterol 358 45+12t 41+7 57+15tApo B 126+37 10833t 14653 96+31tApo A-I 11223 13632t 13728 16039*Lp(a) 1918 1517t 1919 14+14

CAD, coronary artery disease; FHS, Framingham Heart Study; LDL, low density lipoprotein; HDL, high densitylipoprotein; apo, apolipoprotein; Lp(a), lipoprotein (a).Values are given as meanSD.*LDL cholesterol is estimated at 14758 mg/dl in CAD patients once corrected for f-blocker use and diet effects.tp

Genest et al Genetic Lipoprotein Disorders and CAD 2029

TABLE 4. Prevalence of Familial Lipid Disorders in 102 Familiesin Which the Proband Has Premature Coronary Artery Disease

Familial lipid disorder No. of families (%)Lp(a) (includes 5.9% with

dyslipidemias) 19 (18.6)Combined hyperlipidemia 14 (13.7)Hyper-apo B 5 (5.0)Hypertriglyceridemia with

hypoalphalipoproteinemia* 15* (14.7)Hypoalphalipoproteinemia 4 (4.0)Apo A-I deficiency 1 (1.0)Hypercholesterolemia* 3 (3.0)Hypertriglyceridemia 1 (1.0)Genetic dyslipidemiat 55 (53.9)Unclassified* 3 (3.0)Normal 44 (43.1)

*One patient has both familial hypercholesterolemia (LDLreceptor gene defect) and familial dyslipidemia (hypertriglyceri-demia with hypoalphalipoproteinemia).tOf the kindreds, 6.9% had two abnormalities; however, each

case was counted only once, and the overlaps are indicated.tBoth proband and spouse were dyslipidemic and children were

affected; therefore, the type of lipid disorder could not unequiv-ocally be assigned to the proband.

tendinous xanthomas. On Southern blot analysis, a10-kilobase (kb) deletion of the 5' end of the LDLreceptor was detected in one of the patients (French-Canadian mutation, H. Hobbs, Dallas, Tex., personalcommunication).2' This patient also had familial hyper-triglyceridemia combined with FHA. Another familyhad hypercholesterolemia without tendinous xantho-mas. One family had isolated familial hypertriglyceri-demia (1%).

< t$>~~~~~~L(a) Exc7ess

II 3 ~~~~~~~~~~~Lp(a)mgtdL

1 2 3 4 5 6





xv TI T H1 2 3 4 5 6 7 a 9

Levels of apo A-I and apo B further refined theanalysis; five kindreds (4.9%) had elevated apo B as thesole abnormality, and one kindred (1%) had decreasedapo A-I only. An additional three (3%) had an unclassi-fiable lipoprotein disorder. When Lp(a), apo B, and apoA-I were included in the analysis, 55 kindreds (53.9%)manifested a familial lipoprotein disorder, and 6.9% of allkindreds had more than one disorder (Table 4).There were 20 patients (19.6%) with dyslipidemia in

whom no familial segregation was observed; these caseswere defined as "sporadic" dyslipidemias. In 24 patients(23.5%), no lipid disorder was identified. Thus, of 44probands with no familial lipoprotein disorder, 20(43%) had a sporadic dyslipidemia. Ten of these indexcases were diabetic. In two, a pattern consistent withFCH was found; in two other subjects, Lp(a) excess wasidentified; in two additional subjects, a sporadic hyper-lipoproteinemia was found (both with low HDL choles-terol); and in the remaining four subjects, no lipopro-tein abnormality was identified.The lipoprotein and apolipoprotein levels in male

probands with the most common disorders are shown inTable 5 (there were too few women in each category formeaningful comparison). It is noteworthy that patientswith FHA as well as those with familial hypertriglycer-idemia with hypoalphalipoproteinemia and familialLp(a) excess had mean total cholesterol levels below200 mg/dl. Familial Lp(a) excess without other lipopro-tein abnormalities occurred in 13 kindreds. In thosefamilies, lipoprotein cholesterol levels were not signifi-cantly different from those of the control group.The genetic relations of the various lipid and apolipo-

protein parameters were assessed by calculating corre-lation coefficients for lipid, lipoprotein cholesterol, andapolipoprotein levels in proband-offspring, midparent-


iii *



FAM 060

Familial dyslipidemia

2 3 4 5

10 IV

1 2 3 4 5 6

FIGURE 1. Men are indicated by a square; women are indicated by a circle. Subjects sampled are shown in thick symbols.Deceased subjects are marked with a diagonal line. An asterisk indicates premature coronary artery disease. T, triglycerides >90thpercentile; L, low density lipoprotein cholesterol >90th percentile; H, high density lipoprotein cholesterol

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TABLE 5. Lipoprotein Levels in Probands (Men Only) With Common Dyslipidemias (mg/dl)

Totaln cholesterol Triglycerides LDL cholesterol HDL cholesterol Apo B Apo A-I Lp(a)

T+H 12 178+32* 225+128* 107+42* 29+6* 130+34t 99+20* 9+12tT+LH 11 21329 233+104* 135+31 32+6* 14028* 113+17t 24+20tLp(a) 12 18932t 168142 11737t 39+ 10t 105 18 12120t 479*Apo B 4 222+23 226+135t 14130 36+4 17632* 12012 1115HDL 4 196+28 130+61 141+16 28+3* 12728 90+11* 2026Control 901 21436 141104 138+35 4512 10833 13632 1517

T, triglycerides >9Oth percentile; H, high density lipoprotein (HDL) cholesterol 90th percentile; Lp(a), lipoprotein(a) >38 mg/dl.


Genest et al Genetic Lipoprotein Disorders and CAD 2031

alence of hypertriglyceridemia without low HDL cho-lesterol did not differ significantly between CADpatients and control subjects. This suggests that ele-vated triglyceride levels are important as a risk factoronly when associated with another lipoprotein abnor-mality (elevated LDL cholesterol or decreased HDLcholesterol). The etiology of FTgH is unknown. As inFCH, apo B levels were increased and HDL cholesterollevels were decreased (Table 5). Whether FTgH andFCH share a common metabolic etiology is uncertain;in FTg, hyperproduction of triglycerides has been doc-umented, whereas in FCH (or in familial hyperapobeta-lipoproteinemia), there is overproduction of apo B.34-36The importance of this disorder is its association with anormal total cholesterol. We suggest that this entity becalled familial dyslipidemia to distinguish it from FCH.

FCHFCH, as defined by elevated triglycerides, LDL cho-

lesterol, or both, was one of the most common dyslipi-demias found in the present study. This disorder wasseen in 13.7% of probands (2% with normal HDLcholesterol and 11.7% with decreased HDL cholesterollevels). In affected family members, increased hepaticapo B production rates have been reported.37 The apo Blevels were elevated (Table 5). A closely related disor-der, hyperapobetalipoproteinemia (elevated apo B lev-els in the presence of normal lipid levels), is probably avariant of FCH. In this study, five families (5%) hadelevated apo B without abnormal lipoprotein choles-terol levels. We did not, however, determine the prev-alence of hyperapobetalipoproteinemia as described bySniderman et a32 because our assay for apo B measurestotal plasma apo B but not LDL apo B."

FHAOnce thought to be a common lipid disorder, FHA is

most often associated with hypertriglyceridemia, includ-ing FCH. Patients with rare disorders of the apo A-I-C-III-A-IV gene cluster and those with Tangier diseaseand other unusual disorders of HDL metabolism38exhibit severely depressed HDL cholesterol levels.These cases are extremely rare. In this study, 4% of thefamilies had hypoalphalipoproteinemia, and 1% had adecreased apo A-I as the sole abnormality.

FHFH may be due to a variety of mechanisms. Although

LDL receptor defects underlie many severe hypercho-lesterolemic subjects, defective apo B-100 and disordersof hepatic overproduction of LDL particles may accountfor a substantial number of cases.39 The prevalence ofhypercholesterolemia was lower than that found byGoldstein et al.3 In one of our cases, hypertriglyceri-demia with hypoalphalipoproteinemia also was present.The prevalence of LDL receptor defects in this cohortwith CAD appears to be on the order of 3%. Othermechanisms may play a role in FH, such as defectswithin the apo B gene, which decrease binding to theLDL receptor'7 or overproduction of LDL particles.

Familial Lp(a) ExcessFamilial Lp(a) excess was seen in 18.6% of our

families. Elevated levels of Lp(a) appear to be inversely

correlated with the molecular weight of apo (a) and thenumber of kringlelike domains in the protein.40 Thepathogenic mechanisms by which Lp(a) enhances ath-erosclerosis may be related to its cholesterol estercontent or the antithrombolytic effects of the particle.40Lp(a) appears to be a highly heritable trait. Parent-offspring correlations indicate that this may be thelipoprotein disorder that has the strongest geneticdeterminant.The molecular basis for most of these disorders is

unknown. One approach in finding a genetic basis hasbeen the candidate gene approach, in which the genesfor the apolipoproteins found in abnormal amounts inthese disorders were investigated for genetic polymor-phisms.4' Thus, genetic variability within the apo B- andapo A-I-C-III-A-IV genes has been investigated byrestriction fragment-length polymorphisms (RFLP)analysis in patients with a variety of lipid disorders orvascular problems. Some RFLPs have been associatedwith altered lipid values in some but not all studies;these associations have, for the most part, not beenconsistent in various populations. In the present study,no RFLP of the apo B gene42 or the apo A-I-C-III-A-IV gene complex43 appeared to segregate with thelipoprotein disorders outlined above. A few rare disor-ders, including hypobetalipoproteinemia, familial defec-tive apo B-100,17 and defects of the apo A-I-C-III-A-IVgene complex,'1920 have been documented in the apo-lipoprotein genes; these have a profound effect onplasma lipid levels but do not contribute to any signifi-cant extent to plasma lipoprotein levels within a popu-lation because of their low frequency.44The cutoff points used in the present study, in which

we assumed that the 90th or 10th percentile of avariable constituted an abnormal level, may have led toan overestimation of familial lipoprotein disorders.There was no control for environmental influenceswithin individual families. The effect of diet was notcontrolled for, nor were other environmental variablessuch as exercise, body mass index, and cigarette smok-ing. Because most of our patients were referred fromcommunity hospitals, the sampling may be biased to-ward patients with more severe CAD. Therefore, theseresults may not be representative of the population atlarge. However, plasma lipoprotein cholesterol, apo A-Iand apo B, and Lp(a) were not significantly different inthese probands than in 321 men with premature CADon whom we reported previously.45 46Sampling patientswith cardiovascular events during the acute episode maylead to misclassification of lipid disorders. Waiting 6weeks after acute myocardial infarction is necessary tobest approximate lipoprotein cholesterol levels presentbefore the event (reviewed in Reference 47).The phenotypic assignment of individual families may

not precisely reflect accurate genotypes. Furthermore,it is likely that the disorders discussed above have apolygenic etiology, in which case the chance associationof several genetic variations will have an effect onplasma lipoprotein levels. This may explain in part thepatterns of inheritance of these disorders in which anaffected offspring may have inherited only one anomalyand thus may reveal a different lipid disorder than theproband. Phenotypic expression has been explained byincomplete penetrance, expression of the disorder inadults but not in children, or coexisting environmental

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2032 Circulation Vol 85, No 6 June 1992

variables such as diet, exercise, hormonal status, orponderosity. One also must consider the inheritance ofseveral unlinked genetic disorders, each with an effecton plasma lipoprotein levels. Despite these caveats,familial dyslipidemias were identified in more than halfof the probands with premature CAD. Most of thesedisorders were associated with normal total cholesterolor LDL cholesterol levels.No single lipoprotein parameter will identify all pa-

tients at risk for CAD. From the data presented here, itappears that triglyceride, HDL cholesterol, apo B, andLp(a) levels are useful markers for the detection offamilial lipid disorders. LDL cholesterol elevation, al-though strongly associated with the development of CAD,is an infrequent finding in CAD probands. The highprevalence of lipid disorders in offspring and first-degreerelatives makes it mandatory to sample children of dyslip-idemic probands with premature CAD.

AcknowledgmentsThe authors wish to thank Pamella Miller, BSc, for her

computer programming skills; Lindsay A. Farrer, PhD, andDan Kiely, PhD, for their advice on statistical analysis ofgenetic traits; and Leah Zanotti, RN, and the nurses of theMetabolic Research Unit for their help in conducting thisstudy.

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Silberman, P W Wilson, D N Salem and E J SchaeferJ J Genest, Jr, S S Martin-Munley, J R McNamara, J M Ordovas, J Jenner, R H Myers, S R

Familial lipoprotein disorders in patients with premature coronary artery disease.

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