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Genetic and Environmental Factors Affecting the Incidence of Coronary Artery Disease in Heterozygous Familial Hypercholesterolemia
J.S. Hill, M.R. Hayden, J. Frohlich, and P.H. Pritchard

This study explores the influence of selected genetic and environmental factors on the clinical expression of heterozygous familial hypercholesterolemia (FH). A detailed examination of the physical and biochemical features of FH was performed in a large cohort of 208 females and 156 males. Females with FH had higher levels of total, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol when compared with males, although the concentration of HDL cholesterol was significantly lower for both sexes when compared with normals. The reported incidence of coronary artery disease (CAD) was 31% for men and 13% for women, which was lower when compared with figures from previous studies. The average age of onset of coronary symptoms was delayed in females, with a mean age of 55 years compared with 48 years for males (/?<0.05). A greater risk of developing CAD in men was associated with lower levels of HDL cholesterol and a history of smoking. In women, however, CAD was associated with elevated triglycerides and the presence of hypertension. The frequencies of the e2, e3, and e4 alleles of apolipoprotein E in 125 unrelated FH subjects did not differ significantly from the normal population. In addition, there was no apparent relation between apo E4 and the concentration of any of the parameters in the plasma lipid profile; however, the presence of the E2 isoform was associated with significantly elevated triglycerides in both sexes. This study has allowed us to identify those factors, which, in addition to total cholesterol levels, are associated with the development of premature coronary atherosclerosis in heterozygous FH. {Arteriosclerosis and Thrombosis 1991;ll:290-297)

lipoprotein (LDL) receptor.1 Heterozygous FH is among the most common inborn errors of metabolism and occurs in approximately one in 500 persons; affected individuals can usually be identified from birth by elevated levels of plasma LDL cholesterol (LDL-C).1-2 The accumulation of this LDL-derived cholesterol frequently results in its deposition in tendons and skin, producing xanthomas, in addition to its contribution to premature coronary artery disease (CAD).1 In contrast, individuals who are homozygous for this genetic defect have a distinctly different clinical expression, which is considerably
From the Departments of Pathology (J.S.H., J.F., P.H.P.) and Medical Genetics (M.R.H.), University of British Columbia, Vancouver, Canada. Supported by grants from the British Columbia and Yukon Heart Foundation and by the British Columbia Health Care Research Foundation. Address for correspondence: Dr. Haydn Pritchard, Department of Pathology, Research Center, 950 West 28th Avenue, Vancouver, British Columbia, Canada V5Z 4H4. Received July 23, 1990; revision accepted November 5, 1990.

F

amilial hypercholesterolemia (FH) is an autosomal dominant disorder in which the primary defect is a mutation in the low density

more serious. They present with severe hypercholesterolemia at birth and develop cutaneous xanthomas in early childhood.3 The prognosis for homozygotes is poor, and they often die of coronary events before 30 years of age.3 Although all patients who are heterozygous for FH present with high serum cholesterol levels, the severity of the disease in terms of coronary symptoms is varied and not necessarily correlated with serum cholesterol levels. Even reports of single kindreds with FH have demonstrated considerable individual variation with respect to cholesterol levels and CAD.4-6 This phenotypic variation could be influenced by the variability of the underlying mutation; however, the effects of gender, obesity, hypertension, smoking, and possibly other forms of genetic polymorphism are likely to contribute to this poorly understood clinical heterogeneity. For example, a recent study of lipoprotein(a) (Lp[a]) levels and apolipoprotein (a) (apo[a]) phenotype in 115 FH patients indicated that this polymorphism was a significant independent risk factor for the development of coronary heart disease.7 In addition, the well-described polymorphisms of apolipoprotein E structure and function may be an-

Smoking was defined in both former and current smokers who had a history of smoking of at least 5 pack-years. Ontario. and E4. proven by electrocardiogram and/or serum enzyme changes) or angiographically proven disease or a history of coronary bypass surgery. A comparative analysis was made between males and females and between those with and without CAD through the investigation of lipids. LDL-C. many of these investigations differ with respect to size. After immunoblotting.2). The significance of difference between two means was determined by Student's t test. and apos as well as other potential risk factors. resulting in the expression of six apo E phenotypes. where 1 pack-year is equivalent to smoking 1 pack/ day for 1 year.10 In addition.12"15 The current clinical and biochemical features of heterozygous FH have been based on a number of different population studies. The ethnic origin of this cohort was very diverse. and focused in vertical polyacrylamide minigels.9.26 Apo E phenotypes were determined as previously described27 in plasma that was neuraminidase treated. E2. making it difficult to definitively describe the characteristics of FH.01) with a larger proportion of women identified between the ages of 50 and 69 years. e4). and apo B were greatly elevated in comparison with the . Laboratory Methods Venous blood was collected from all subjects after an overnight fast of 12-16 hours. This study has allowed us to identify those factors that. selection criteria. The EDTA/plasma was separated from cells by low-speed centrifugation (l. The body mass index (BMI) was calculated as body weight in kilograms Table 1 compares the lipid parameters between males and females with FH and contrasts this patient group with the randomly selected population. we have used specific selection criteria to perform a detailed examination of the physical and biochemical features of a large cohort of individuals with heterozygous FH. This age difference was statistically significant (/?<0. respectively. even if patients were currently on antihypertensive medication. are associated with the development of premature coronary atherosclerosis in heterozygous FH. lipoproteins. As expected. it has been shown that the incidence of the e2 and e4 alleles is greater in patients with ischemic heart disease.3±17 years and 45. in both sexes the levels of TC.4±17 years for women. including the polymorphism of apo E. Hypertension was indicated if clinically documented. The statistical significance of the differences in proportion between two groups was determined by the x2 t e st (employing Yates' correction for continuity). apo E4 and apo E2 have opposite effects on the concentrations of total cholesterol (TC) and LDL-C. Plasma Lipids.16"22 However. Methods Subjects 291 divided by the square of the height in meters. Lipoproteins. In addition. Beckman Instruments. The criteria for CAD were the presence of angina (history of typical exercise-associated chest pain) or myocardial infarction (MI.20Qt> 20 minutes) and was analyzed immediately or frozen at — 70°C. and genetic background.23-24 High density lipoprotein cholesterol (HDL-C) was determined as the amount of cholesterol remaining after precipitation of apo B-containing lipoproteins with heparin/MnQ2. The genetic locus for plasma apo E has three common alleles (e2.11 Although some previous reports have attempted to study the effects of coinheritance of these different apo E alleles on the phenotypic expression of FH.Hill et al Heterozygous Familial Hypercholesterolemia other factor that determines diversity in the clinical expression of FH. FH was diagnosed if subjects satisfied both of the following criteria: 1) a level of LDL-C greater than the 95th percentile corrected for both age and sex and 2) tendon xanthomas in the patient or a first-degree relative. where all values were measured in millimoles per liter. delipidated. The mean age for males was 40. In the present study. no clear pattern has been established. and Apoproteins A total of 364 patients from 283 families with heterozygous FH were identified among a population in the University Hospital Lipid Clinic. Plasma samples from 125 unrelated FH subjects from the larger patient population were randomly chosen for apo E phenorype determination. Canada. which encode for the three major apo E isoforms found in plasma. Plasma apo A-I and apo B were measured by rate nephelometry using a Beckman Immunochemistry System. where more than one of the CAD indicators may occur in a single patient.25 LDL-C was calculated from the formula [TC-(HDL-C)]-(TG/2. specimens from a randomly selected normal population of 203 subjects aged 18-78 years living in the Vancouver area were analyzed for lipids and apo E phenotype. Results Age and Sex Distribution A total of 364 patients (208 females and 156 males) with FH were identified from 283 families. e3. The frequency for each of these findings is indicated in Table 3. Data Analysis Statistical analysis was performed using data obtained on the patient's first visit to the lipid clinic to ensure that the lipid values represented were obtained before treatment. apo E was visualized with a polyclonal goat anti-apo E antibody followed by a protein G-peroxidase conjugate. in addition to TC levels.8 Several studies have established that in a normal population. with at least 38 different countries represented. The age distribution of this population is shown in Figure 1. TC and triglycerides (TGs) were measured by established enzymatic techniques. E3. Patients with hypothyroidism or poorly controlled diabetes and those on medication affecting lipoprotein metabolism were excluded from analysis.

5 mmol/1 (/?<0.2 330±l.99±1. . there was a significantly greater concentration of apo B and apo A-I in females compared with males (p<0. ^Significance of difference between males and females in the normal population (p<0. Also.8t 1.48±0.5t 6.8 0. of patients/age group).2t Normal (n = 101) 41.26±0.81 ±0.20+0. The concentration of lipids and apos was also analyzed for each age group within each sex (Table 2). The concentration of HDL-C after age 30 years appeared to decline for men but to increase for women.05).50±0.001).7 mmol/1 and for males.292 Arteriosclerosis and Thrombosis 30-.7*t 6. 8. the concentration of TGs increased with age and peaked between the ages of 30 and 49 years and then TABLE 1.3 1.53±0. and HDL-C were all significantly elevated in FH females compared with FH males. 434035302320131030 30-| 434033302320151050 Vol 11.55±0.99 ±1. low density lipoprotein.48±1. tSignificance of difference between normal and FH groups (/><0.001). differences could be detected when the separate age groups were analyzed. No 2 March/April 1991 FEMALES (n-208) 0-t 10-1* SO-tt 30-90 40-40 SO-M M-M 70-71 FIGURE 1.24±0.34 FH (n=208) 45. familial hypercholesterolemia.3 FH Females (n = 156) 4O.20±0.24 1. In addition.3* 1. 'Significance of difference between males and females with FH (p<0.26±1.89±0.05). MALES (n-136) 0-1 10-it 10-M 30-3i 40-M SO-W 7O-7t Age in Years normal population. The levels of TC.09±0.001).48±1.35±0. The magnitude of this difference was reflected in LDL-C.40±0.9 1.5t 1.6*t 1. 6.001). Lipoprotein.5f 1.005) although the concentration within the FH population did not differ significantly between the sexes.09±0.001). However. 1.05). LDL-C. the levels of HDL-C and apo A-I were consistently lower in all FH patients when compared with normals (/?<0. For males. The values of TC and LDL-C increased steadily with age in both sexes. and Apoprotein Levels in Familial Hypercholesterolemia Patients Males Variable Age (yr) Total cholesterol (mmol/1) LDL cholesterol (mmol/1) HDL cholesterol (mmol/1) Triglycerides (mmol/1) Apoprotein B (g/1) Apoprotein A-I (g/1) Normal («=97) 44.9 1.3*t FH.2 mmol/1 for males (/><0. with lower values found in males for the remaining age groups.63 ±1. Higher levels of TC were observed in females for each age group. and HDL-C. Lipid. Bar graphs showing age distribution (years) of familial hypercholesterolemia patients for each sex (No. The mean cholesterol value for females was 9.84 0.05±1. LDL.45±0.63 ±1.05+1. high density lipoprotein. Also.26±0.4*t 1.2t 1.2 1. Values are given as mean±SD. Although there was no significant difference between TG values between the sexes in the whole group.3 mmol/1 for females and 1.l 1. HDL. Table 1 shows several differences among other variables between males and females with FH.42±0.5±18 5.6 mmol/1 for females and 6.5 mmol/1 for males (p<0.8±17 5. the levels of plasma TGs were elevated in FH females compared with normals (p<0.4±17* 9.52±0.3±17 8.3*t 1.1 3.36±0.37±1.

2 1.75 ±0.15±0.3 70-79 («=9) 9.7 1.4 6.50±0J 1.53±0.7 1.5 5.2 135±0.28±0. females generally showed a steady increase in the concentration of TGs with age. at which point they increased significantly in women (p<0.20+0. declined after age 50.41 ±0.8 1J7±O.2 1.0 6.39±0.90±2.5 5.42±0.16±0.09±0.1 10-19 («=8) 8i6±1.30±0.7 1.0 1.6 1. apo A-I levels were similar for both sexes until the age of 40 years.3 50-59 ("=45) 9.4 1.2 1.47 ±0. for which data are expressed as mean±Vi the range.1 30-39 (n=28) 8.4 1. men had significantly higher TG levels than did women.ll±0. Between the ages of 30 and 49.2 40-49 (n=35) 8.4 1.4 1.11 ±0.63 ±1.39 ±2.57±0.86±1.01 + 1.39±0.61 ±0.2 6.22±03 1.4 1.25±0.39±1.4 1.1 1.63 ±1.0 1.20±0.2 0.3 1.77±1.45 ±0.16±0.92±0.2 0.3 30-39 (n=44) 8.6 1.29+1. Tendon xanthomas begin to appear most commonly after age 20. and their frequency increases with age.2 1.28±0.7 1.00±U 6.24±0.2 1.8 1.001).3 1.7 1.3 Total cholesterol (mmol/1) LDL cholesterol (mmol/1) HDL cholesterol (mmol/1) Triglycerides (mmol/1) Apoprotein B (g/1) Apoprotein A-I (g/1) Values are given as mean±SD except for the male age group of 70-79 years. In contrast.3 1. division (yr) (7i=208) Clinical finding Tendon xanthoma Corneal arcus Myocardial infarction Angina Bypass surgery Angiographically documented disease Stroke 0-19 (" = 17) 3 (18%) 1(6%) 0 0 0 0 0 20-29 (71 = 18) 30-39 (n=44) 40 (91%) 16 (36%) 2(5%) 1(2%) 1(2%) 2(5%) 0 40-49 ("=30) 29 (97%) 13 (43%) 1(3%) 1(3%) 2(7%) 2(7%) 0 50-59 (T.14±0.002).3 1.25±0.0 6.9 mmol/1 (/><0. The values of apo B for all ages were consistently higher in females.4 1.4 1.2 1.48±l-5 7.52±0.4 6.91 + 1.85 ±1.4 1.=35) 50-59 (n=32) 31 (97%) 25 (78%) 11 (34%) 6 (19%) 9(28%) 5 (16%) 1 (3%) 2(7%) 0 32 (91%) 31 (89%) 6(17%) 6(17%) 7(20%) 11(31%) 0 60-69 (" = 19) 18 (95%) 17 (89%) 8 (42%) 5 (26%) 3 (16%) 3 (16%) 0 70-79 ("=2) 2(100%) 2 (100%) 1(50%) 2 (100%) 1 (50%) 2(100%) 0 Female agi.3 6.7 1.48±0.4 1.85 ±1.97±1.19±0.Hill et al Heterozygous Familial Hyperchoiesterolemia 293 TABLE 2.3 6. Mean Values for LJpids.3 40-49 (n=30) 9.3 1.59±0.4 1.24+0.2 20-29 (« = 18) 8.18±03 50-59 ("=32) 8.21±2.3 2.7 1.33±1. .24±0.15±0.28±0.41±0. and Apoproteins for Each Age Division in Familial Hyperchoiesterolemia Male age division (yr) (n = 156) Variable Total cholesterol (mmol/1) LDL cholesterol (mmol/1) HDL cholesterol (mmol/1) Triglycerides (mmol/1) Apoprotein B (g/1) Apoprotein A-I (g/1) 0-9 (" = 12) 7.41±0.84±0.34±0.4 1.85 + 1. 1.31 ±0.9 7.4 1.91 ±0.6 1.06±0.0 mmol/1 compared with 1. Clinical Data for Each Age Division in Familial Hyperchoiesterolemia Male age division (yr) (in = 156) Clinical finding Tendon xanthoma Corneal arcus Myocardial infarction Angina Bypass surgery Angiographically documented disease Stroke 0-19 ("=21) 0 1 (5%) 0 0 0 0 0 20-29 (" = 19) 12 (63%) 7 (37%) 0 0 0 0 0 30-39 (n=28) 25(89%) 11(39%) 5 (18%) 2(7%) 0 40-49 (T.88+1.57±1.4 1.84±1.96±1.2 1.03 Female age division (yr) (n=208) 0-9 (/i =9) 7. The total TABLE 3.2 20-29 (" = 19) 8.86±0.96+1.65±0.3 1.0 1.2 70-79 ("=2) 6.54±1.1 5.4 0.05±0.9 6.66±1.2 60-69 (" = 19) 8.43 ±0.24±0.38±0. Clinical Features of Familial Hyperchoiesterolemia The frequency of specific clinical findings in FH for each age group is listed in Table 3.48±0_5 1.2 130±0.9 1.7 6. LJpoproteins.07±0.24 ±1. In contrast.1 1.5 1.09±0.41 ±0.8 1.2 1.26±0.2 1.04±0.1 10-19 («=9) 7.7 1.61 ±0.22±0.4 1.2 1.09±0.40 ±0.49+1.4 1.6 6.90±O l.88±1.20±1. =45) 60-69 ( n =45) 45 (100%) 27(60%) 4 (9%) 8(18%) 2(4%) 2(4%) 2 (4%) 70-79 ("=9) 9(100%) 5 (56%) 14 (78%) 3 (17%) 0 0 0 0 0 45 (100%) 31 (69%) 5(11%) 2(4%) 3(7%) 0 0 3 (33%) 4(9%) 0 0 0 Values are given as absolute numbers (and as percentages in parentheses) of the total number for each age group.4 1.99±0.81 + 1.44±0J 60-69 ("=45) 9.04±0.

01).0 1.05. The values for HDL-C for CAD-positive men (0.7±12 years for females (p<0.40±0. tp<0.6 1.005) but not in women. Angina was also more frequent in men (18%) than in women (9%) for this age group (p<0. the only difference between CAD-positive and -negative women was the level of TGs.05). Table 4 divides the male and female populations into two groups and compares the same lipid parameters for those with or without CAD.2 1.5 ±10 8. For males. The concentration of LDL-C was higher in men with CAD. TABLE 4. . 20FEMALES | 10-1 o 0-1 » 6 10 20 30 40 50 Age in Years 6070 FIGURE 2.2 48.6 7. a higher frequency of hypertension was observed in women with CAD but not among men (p<0.4 1.294 Arteriosclerosis and Thrombosis 40-i Vol 11.7 1. and Apoproteln Levels in Familial Hypercholesterolemia Patients With and Without Coronary Artery Disease Males Variable n Females CAD+ 47 CAD68 CAD147 CAD + 26 Age (yr) Total cholesterol (mmol/1) LDL cholesterol (mmol/1) HDL cholesterol (mmol/1) Triglycerides (mmol/1) Apoprotein B (g/1) Apoprotein A-I (g/l) 45.96±1. There was no difference in BMI between those with and without CAD for both sexes.25 ±2. The frequency of corneal arcus also increased with age but was more common in males (60%) than in females (46%) (p<0. Lipid. In contrast.13±1.33 ±0.001). with a frequency of 31% for the total male population as compared with 13% for females (p<0. when the frequency of disease was greater than 50%. 2. high density lipoprotein. but the most common age of onset was between the ages of 40 and 49. incidence of tendon xanthomas was greater in females (89%) compared with males (77%) Q?<0.13±0.7 mmol/1 (/?<0. Males had a much higher incidence of disease.05).7±12 9.01.10±1.70±0. No 2 March/April 1991 o 30-1 o MALES males the earliest symptoms of CAD occurred between the ages of 30 and 39 years after which the incidence of disease increased with age. as compared with 1.6 1.2±9 years for males and 54.01 ±1. 7.025). The occurrence of MI was much greater in men over 30 (27%) than in women of the same age (7%) (p< 0. compared with 6. and Apoproteins for Those With and Without Coronary Artery Disease £ U. Lipoproteins. 1p<0.09±1.99±0.5* 0. the clinical findings related to CAD first appeared and became more prevalent with increasing age. However.3 1.3 6. LDL. Plasma Lipids. After age 30. Frequency of Risk Factors for Coronary Artery Disease-Positive and -Negative Groups The frequencies of common risk factors for the CAD-positive and -negative groups are compared in Table 5. Stroke or cerebrovascular disease occurred in only one man and six women between the ages of 50 and 69.4 1. low density lipoprotein. The cumulative frequency of CAD in FH as a function of age is shown in Figure 2.18±0.7±12 9.51±1. Significance of difference between CAD+ and CAD.025).28±0. Conversely.53±0. Line plot showing cumulativefrequency(%) of coronary artery disease in male (•) and female (•) familial hypercholesterolemia patients as a function of age (years).70±1.6 7.99±0.2 mmol/1) (p<0.001).1 7.4 mmol/1. Lipoprotein.groups for males and females is */><0.31±0J CAD.46+0. for fe- To assess differences associated with the presence or absence of CAD.22 ±0. only those FH patients at least 30 years of age were analyzed.2t 1.05). HDL.3 54.0 1.4 mmol/1 for those without (p<0. Similar trends were observed for women. which were elevated in women with CAD.47 ±1.29±0. In contrast.13±1.00l.7 1J1±O.5 mmol/1.46±0. Smoking was associated with the presence of CAD in men (p<0.5* 1.4 2.00l). but these differences were not statistically significant.59 ±0.001).025).05). Figure 3 depicts the distribution of the age of onset of symptoms of CAD in FH.09±1.4t 1.24 49. Values are given as mean±SD.4 1.13±0.2±9 8. A higher percentage of men with CAD had HDL-C levels in the lower quartile of this population (/7<0. symptoms occurred from as early as ages 20-29.68±2. The mean age of onset was 48.2 mmol/1) were significantly lower than those in the CAD-negative group (1. coronary artery disease. significantly fewer men with HDL-C levels in the upper quartile were positive for CAD (/?<0. The difference observed for these values was also reflected in significantly higher apo B and lower apo A-I levels for men with CAD.51±1.

Discussion The detailed analysis of this large population of subjects with heterozygous FH has revealed a relatively low incidence of CAD in the presence of a gender-specific response to selected risk factors.200 for e4. Significance of difference between CAD+ and CAD.5 CAD.056 0. In FH. or frequency of smoking and hypertension (data not shown). smoking. Bar graph showing distribution (%) of age of onset of coronary artery disease in male (•) and female ( • ) familial hypercholesterolemia patients. Hypertension. When the lipid and lipoprotein data of males and females with FH were analyzed. The only observable difference was found in the frequency of CAD. and no significant difference was observed for the incidence of tendon xanthomas. It should be recognized that the ratio of males to females in each group was similar.0 57. this finding was well correlated with the higher frequency of tendon xanTABLE 6. Clinical data for these patients were compared between these two groups.153 0.05. 0. 0. and Body Mass Index on Coronary Artery Disease in Familial Hypercholesterolemia Males Variable n Females CAD+ 47 CAD68 CAD147 CAD + 26 Smoking Hypertension HDL cholesterol in lower quartile HDL cholesterol in upper quartile Body mass index 26 (38%) 7 (10%) 11 (16%) 23 (34%) 24.200 0.0 0-19 tO-3» 30-X «O-4« 80-SO tO-M 70-7S Age in Years FIGURE 3.groups for males and females is */?<0.4 100- n \ 1 PI 33.761 0. while the E3/2 incidence was lower. corneal arcus. where the only significant difference found was a distinct elevation of TGs associated with the E2 isofonn (/7<0. as the TC levels were higher in every age group (Table 2). These differences were also reflected for the individual allele frequencies.6 8.056 for e2.31±3. High Density Lipoprotein Cholesterol Levels.086 .2 24. 8. Apolipoprotein E and Familial Hypercholesterolemia The apo E phenotype distribution and allele frequency for both FH and normal populations are shown in Table 6.744 for e3.761 for e3. Although not statistically significant. sex distribution. Assessment of Effects of Smoking. and that a separate analysis for males and females revealed the same relations observed in Table 7 (data not shown). several differences were observed. tp<0.086 for e2. For the first time. and 0. or hypertension.153 for e4. 0. high density lipoprotein. the frequency of the E4/3 phenotype was higher in FH patients (33. This FH population was separated into two sets of two groups: those who had a phenotype containing the apo E4 or the apo E2 isoform and those who did not. and in normals.01.0 9 (35%) 9 (35%)t 9 (35%) 5 (19%) 25.6 3. they were 0. coronary artery disease.6 12.3%. In addition.0 53.75±3.6 Population (%) Normal (n=2O3) 1. but this difference did not reach statistical significance. Table 7 displays the lipid and lipoprotein data for the same categories. This observation did not appear to be influenced by an age difference alone. we have shown that females with FH have significantly higher mean levels of TC and LDL-C than males.6 3.6%) compared with normals (24. 29% for those with E4 and 19% for those without. It should be noted that there was no difference between these patient groups with CAD with respect to mean age. 0. Apoprotein E Phenotype Distribution and Allele Frequency in Familial Hypercholesterolemia 50- IZZ1 MALES C23 FEMALES 5 30- Phenotype/ allele Apo E phenotype E4/4 E4/3 E4/2 E3/3 E3/2 E2/2 Apo E allele e4 e3 c2 FH (n = 125) 1.0% compared with 12. HDL.744 0.Hill et al Heterozygous Familial Hypercholesterolemia 295 TABLE 5.0 0.8 58 (39%) 18(12%) 34 (23%) 38(26%) 24. and 0.15±2.10±4.001).0 33 (70%)' 3(6%) 18 (38%)t 6(13%)t 25.6%).3 1.

2 E2111 46.32±1. When HDL-C levels were divided into quartiles. low density lipoprotein. Instead.29 their distant locations would not indicate a functional relation.97 ±1.30 It is likely that in most cases.5 1. However. No 2 March/April 1991 TABLE 7. The reported incidence of CAD of 31% for males and 13% for females was lower when compared with those of other studies16-18.5 1.3 E4+ 48 47. In this study.15 One genetic factor that has not been assessed by the present study is the influence of Lp(a) levels and apo(a) phenotype. As previously mentioned. the only difference seen for females was higher concentrations of TG for those positive for CAD. hypertension.7 1. has been shown to be a remarkably consistent feature in several different FH populations. the concentration of both LDL-C and HDL-C had a greater predictive value.9 1.3 1. The analysis of the apo E polymorphism in 125 unrelated FH subjects revealed several similarities to the study of Eto et al12 of 50 Japanese patients with FH. This observation was also confirmed in the measurement of apo concentration. where as much as 70% of the CAD-positive males were smokers.001.296 Arteriosclerosis and Thrombosis Vol 11.81 + 1. for males.53±0.16+0.3 E2+ 14 44. Smoking was found to have a profound effect in males. This observation. high density lipoprotein. Having been reported in other studies. compared with 48 years for men. However.08±0.7 6.5±12 9.16±1. the relation between low values and CAD was confirmed in males.18-28 our study found that it was a good indicator for males only. HDL. An increased risk of CAD has been associated with smoking in other FH studies. and Apoprotein Levels in Familial Hrpercbolesterolemia Patients With and Without Apolipoprotein E4 and E2 Variable n Age(yr) Total cholesterol (mmol/1) LDL cholesterol (mmol/1) HDL cholesterol (mmol/1) Triglycerides (mmol/1) Apoprotein B (g/l) Apoprotein A-I (g/l) E477 45.64±0.4 1.groups for each apolipoprotein E isoform is */?<0. In addition.75+0.9 1.70±1.9 1. however.9 7. Significance of difference between the + and .19 but it remains unclear why female smokers are not similarly affected.28±0. the levels of Lp(a) have been found to be independent risk factors for the development of coronary heart disease in FH. In their study.13-15 was the lack of a relation between apo E4 and the concentration of any of the parameters in the plasma lipid profile.47±0.4 1.7±14 8. a mutation in the LDL receptor gene would affect cholesterol metabolism to such an extent that the influence of the different apo E alleles on cholesterol concentration seen in the normal population would not be evident in those with FH.2 LDL.3 1. there was also a tendency of the e4 allele to have a higher frequency in FH compared with the normal population. especially those aged less than 30 years (Table 3).7 6.3 1.5* 1. The differences between the sexes still remained after additional risk factors were assessed. while the frequency of other risk factors did not differ between the two groups.18 This elevation in TGs was independent of BMI values. We have established that the dissimilarity in clinical expression between .7 The analysis of Lp(a) levels and apo(a) phenotype has been initiated in our laboratory. also reported by Hirobe et al.31-32 Yet.7 1. LJpoprotein. Lipid.46±0.35 ±0.6±17 9.18+0.5 1. Although other reports have shown that low HDL-C in FH is associated with CAD in both sexes.2 2.79+1. 55 years.5 6. The age of onset of coronary symptoms and its delay for women. it appears that the TG-raising effect associated with the E2 isoform is more dramatic in FH.18 suggests that higher levels of HDL-C offer a degree of protection against CAD even in the presence of hypercholesterolemia. which was seen with greater frequency in females. This was particularly evident in females who had higher plasma cholesterol levels than males but who still had a very low incidence of CAD. and the data are currently being collected to be presented in a subsequent manuscript. Values are given as mean±SD.619 especially for males.6±16 9.07 ±1. In contrast. we have assessed the influence of selected genetic and environmental factors on the phenotypic expression of FH. an important difference in our study.50±0.19-21 this observation confirms that hypertension is an independent risk factor for females with FH. thomas in females. which were similar in all groups (Table 5). Since the locus for both the apo E and LDL receptor genes is found on chromosome 19. with lower values of apo A-I and higher values of apo B being more often associated with CAD. However. as well as others. it was interesting to note that a higher percentage of patients with an HDL-C value in the upper quartile were negative for CAD. the prevalence of ischemic heart disease was greater in those patients who were positive for apo E4.16'19-21 The levels of TC in either sex did not distinguish between those patients with and those without CAD. an observation sometimes seen in the normal population. was associated with CAD.28±0.52±2. Also.56+2. this may have been affected by the lower mean age of this population compared with the mean age associated with the first symptoms of CAD.13±0.54±1. it is of interest that those patients who have phenotypes containing the E2 isoform have elevated TGs.2 1.31±0. an observation also made by Hirobe et al.

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