Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23.

More than half of the patients with angiographically confirmed premature coronary heart disease (CHD) have a familial lipoprotein disorder. Familial combined hyperlipidaemia (FCHL) represents the most common genetic dyslipidemia with a prevalence of 1.0-2.0%. FCHL is estimated to cause 10-20% of premature CHD and is characterized by elevated levels of cholesterol, triglycerides, or both. Attempts to characterize genes predisposing to FCHL have been hampered by its equivocal phenotype definition, unknown mode of inheritance and genetic heterogeneity. In order to minimize genetic heterogeneity, we chose 31 extended FCHL families from the isolated Finnish population that fulfilled strictly defined criteria for the phenotype status. We performed linkage analyses with markers from ten chromosomal regions that contain lipid-metabolism candidate genes. One marker, D1S104, adjacent to the apolipoprotein A-II (APOA2) gene on chromosome 1, revealed a lod score of Z = 3.50 assuming a dominant mode of inheritance. Multipoint analysis combining information from D1S104 and the neighbouring marker D1S1677 resulted in a lod score of 5.93. Physical positioning of known genes in the area (APOA2 and three selectin genes) outside the linked region suggests a novel locus for FCHL on 1q21-q23. A second paper in this issue (Castellani et al.) reports the identification of a mouse combined hyperlipidaemia locus in the syntenic region of the mouse genome, thus further implicating a gene in this region in the aetiology of FCHL.

Relations of life-style with lipids, blood pressure and insulin in adolescents and young adults. The Cardiovascular Risk in Young Finns Study.

The associations of life-style variables, namely type of dietary fat, alcohol use, smoking, obesity, physical activity and oral contraceptive use with serum lipids, insulin and blood pressure were studied in 1398 adolescents and young adults aged 15-24 years. Smokers were more often physically inactive and regular users of alcohol compared to non-smokers. In females, smoking and alcohol use were more prevalent among oral contraceptive users. Independent effects of life-style variables on lipids, blood pressure and insulin were assessed with multiple linear regression models. In both sexes, body mass index was positively related to low density lipoprotein cholesterol (LDL-C), triglycerides (TG), systolic (SBP) and diastolic (DBP) blood pressure and insulin, and negatively with high density lipoprotein cholesterol (HDL-C). Leisure time physical activity was associated with lower levels of insulin among males. Smoking was related with 0.07 mmol/l lower HDL-C levels and about 0.09 mmol/l higher TG levels in males. In both sexes, smoking was related with lower levels of SBP. In males, alcohol use was associated with 0.05 mmol/l higher level of HDL-C (P = 0.06). In females, alcohol use was associated with lower levels of LDL-C and TG. Oral contraceptive use was associated with approximately 0.15 mmol/l higher levels of TG and about 4.0 mmHg higher SBP. Preferring butter over margarine as dietary fat was associated with 0.26 and 0.19 mmol/l higher levels of LDL-C in males and females, respectively. Accumulation of adverse life-habits contributed to the clustering of an atherogenic lipid profile and high blood pressure. In males, those with 4 selected life-habits present, namely obesity, smoking, inactivity and the use of butter, had 5.5 times greater risk (95% confidence interval 1.4-20.7) of belonging to the group with high LDL-C, low HDL-C and high DBP compared to those with zero or one life-habits present. These data demonstrate that life-habits show clustering in adolescents and young adults. Individuals with many adverse life-style risk factors present are at increased risk of having an atherogenic lipid and blood pressure profile.

Short-term intra-individual variation and long-term tracking of serum lipid levels in children: the Cardiovascular Risk in Young Finns Study.

We have studied the short-term intra-individual variation and long-term tracking until early adulthood of serum total cholesterol, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglyceride levels in 9-year-old Finnish boys. The study was based on two different cohorts; one to study short-term tracking and another to study long-term tracking. The short-term tracking cohort consisted of 57 healthy Finnish 9-year-old boys with serum lipid determinations 2 and 7 days apart in 1984. The other cohort consisted of 40 healthy Finnish 9-year-old boys and the serum lipid determinations were made in 3-year intervals from 1980 to 1989. Tracking was expressed as Spearman's rank order correlation coefficients between subsequent measurements. Tracking was weaker as the time between measurements became longer. For serum total cholesterol the correlation coefficients were 0.92, 0.77, 0.70, 0.73, and 0.59 for measurements made 2 days, 7 days, 3 years, 6 years, and 9 years apart, respectively. Other lipid variables behaved quantitatively in a similar manner. The dependence of tracking on time was not linear. The greatest relative decrease in correlations took place during the determination periods of 2 and 7 days, whereafter the decline was only moderate. In conclusion, short-term intra-individual variation of serum lipid levels in children, which is mainly due to biological variation, has a major influence on their long-term tracking. Our findings emphasize the need for several independent serum lipid determinations, performed at least one week apart, in the assessment of a child's true serum lipid level.

Reduced hormone-sensitive lipase activity is not a major metabolic defect in Finnish FCHL families.

The pathogenetic mechanisms behind familial combined hyperlipidemia (FCHL) are unknown. However, exaggerated postprandial lipemia and excessive serum free fatty acid (FFA) concentrations have drawn attention to altered lipid storage and lipolysis in peripheral adipose tissue. Hormone-sensitive lipase (HSL) is the enzyme responsible for intracellular lipolysis in adipocytes and a decrease of adipocyte HSL activity has been demonstrated in Swedish FCHL subjects. The aim of the study was to investigate if adipose tissue HSL activity had any effect on lipid phenotype and if low HSL activity and FCHL were linked in Finnish FCHL families. A total of 48 family members from 13 well-characterized Finnish FCHL families and 12 unrelated spouses participated in the study. FCHL patients with different lipid phenotypes (IIA, IIB, IV) did not differ in adipose tissue HSL activity from each other or from the 12 normolipidemic spouses (P = 0.752). In parametric linkage analysis using an affecteds-only strategy the low adipose tissue HSL activity was not significantly linked with FCHL phenotype. However, we found a significant sibling-sibling correlation for the HSL trait (0.51, P < 0.01). Thus, a modifying or interacting role of HSL in the pathogenesis of FCHL could not be excluded.

Serum complement and familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is one of the most common inherited lipid disorders. Resistance of adipocytes to the effects of acylation stimulating protein (ASP) may contribute to ineffective triglyceride synthesis and thereby prolonged postprandial lipemia and increased fatty acid flux to the liver seen in FCHL patients. Interestingly, ASP is identical to C3a-desArg, fragment of the third component of complement. We examined the relationships between serum levels of complement components C3 and C4 and markers of lipid and glucose metabolism in 11 large FCHL families (n = 53). Median serum C3 levels were 38% higher in affected compared to non-affected male FCHL family members (1.90 g/l vs. 1.38, P = 0.0027). The strongest correlations were observed between serum complement C3 and apolipoprotein B levels, reaching 0.77 in males. These relations were not confounded by obesity or impaired glucose tolerance. In conclusion, serum levels of the main complement components C3 and C4 correlated significantly with serum lipid levels. Further studies are needed to clarify the importance of disturbances in the complement system on the pathogenesis of FCHL and other lipid disorders.

Prevalence of hyperapobetalipoproteinemia and factors affecting the phenotype expression in children and young adults. The Cardiovascular Risk in Young Finns Study.

Hyperapobetalipoproteinemia (hyperapoB) is one of the most common phenotypes in patients with premature coronary heart disease. In this study the factors that affect the expression of the hyperapoB phenotype were evaluated in young individuals. A cohort of 1125 children and young adults aged 9-24 years was classified into three groups by sex: (1) normal serum apolipoprotein B (apoB), (2) high apoB (> or = 90th percentile) and normal low density lipoprotein cholesterol (LDL-C < 90th), (3) high apoB and high LDL-C (> or = 90th percentile). In females, alcohol use (11, 33, 0%, in groups 1-3, P < 0.05) and oral contraceptive use (35, 83, 47%, P < 0.01) were significantly different between the groups and the highest frequencies were seen in the hyperapoB group (group 2). In both sexes smoking tended to be more common in the hyperapoB group (29, 43, 18%, P < 0.14). The two hyperapoB definition criteria (high apoB and low LDL-C/apoB ratio) were studied with multiple linear regression analyses. Oral contraceptive use correlated positively with apoB values (coefficient beta = 0.101, R2 = 2.1%, P < 0.01) and negatively with LDL-C/apoB ratio (beta = -0.134, R2 = 3.3%, P < 0.001). Alcohol use (beta = -0.072, R2 = 2.9%, P < 0.001) and smoking (beta = -0.050, R2 = 1.0%, P < 0.05) correlated negatively with LDL-C/apoB ratio. Prevalence of the hyperapoB phenotype was 4.4%. According to the results, the expression of the hyperapoB phenotype may be influenced by common lifestyle habits. This should be considered if high risk young individuals are identified through the expression of the hyperapoB phenotype.

Phenotype expression in familial combined hyperlipidemia.

Familial combined hyperlipidaemia (FCHL) is one of the most common hereditary disorders predisposing to early coronary death. The affected family members have elevations of serum total cholesterol, triglycerides or both. Despite intensive research efforts the genetic and metabolic defects underlying this complex disorder are still unknown. To dissect the metabolism and genetics of FCHL the phenotype of an individual must be precisely defined. We assessed the influence of different diagnostic criteria on the phenotype definition and studied factors affecting the phenotype expression in 16 large Finnish families (n = 255) with FCHL. The fractile cut-points used to define abnormal lipid values had a profound influence on the diagnosis of FCHL. If the 90th percentile cut-point was used, approximately 45% of the family members were affected, in concord with the presumed dominant mode of transmission for FCHL. If the 95th percentile was used only 22% of study subjects were affected. To characterize the metabolic differences or similarities between the different lipid phenotypes, we determined very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) particles separated by ultracentrifugation. In linkage analysis no single ultracentrifugation variable could discriminate reliably affected family members from non-affected family members. Our data emphasizes the need for re-evaluation of FCHL diagnostic criteria. Preferably, the diagnosis should be based on a single, reliable metabolic marker.

Tracking of serum lipids in children; association with the absolute lipid level--the cardiovascular risk in young Finns study.

We studied tracking of serum lipids in children and young adults (n = 248) during a 12-year follow-up. A novel method was developed for assessing tracking. It was based on the calculation of the absolute width of the individual track consisting of 5 serum lipid determinations. The total cholesterol (TC) track width tended to be broader in females compared to males (1.33 versus 1.24 standard deviation (SD) units). Approximately 35, 39, 24 and 13% of subjects had all 5 measurements within 1 SD (of the cohort mean) from serum TC, low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglycerides, respectively. However, variations in excess of 2.5 SDs were not rare. We also assessed the dependence of tracking on the absolute lipid level by calculating the SD of the standardized 6-year change in a cohort of 2236 children. In each serum lipid variable studied, lowest degree of tracking was found in highest lipid values. The mean changes were also largest in extreme values due to regression toward mean phenomenon. Our findings indicate that the width of longitudinal track of serum lipids may be two wide to reliably detect high risk children. Further, the track width was even broader in subjects with extreme serum lipid values.

Clustering and six year cluster-tracking of serum total cholesterol, HDL-cholesterol and diastolic blood pressure in children and young adults. The Cardiovascular Risk in Young Finns Study.

Clustering and tracking of serum total cholesterol, high-density lipoprotein cholesterol (HDL-C) and diastolic blood pressure were studied in children and young adults. "High-risk" individuals were defined as those having these risk factors at the age and sex specific upper tertile (lowest tertile for HDL-C). Among older boys risk factors occurred at adverse levels more often than expected by chance. Cluster-tracking was assessed as the probability of remaining in the extreme tertiles during follow-up. Approximately 25% of subjects initially at "risk" remained there for 6 years. Subjects who became high-risk individuals during the follow-up expressed greater increase in obesity indices, started to consume more saturated fat and cholesterol and became physically active less often compared to those subjects who were initially at risk, but no longer at the follow-up.

Influence of parental occupation on coronary heart disease risk factors in children. The Cardiovascular Risk in Young Finns Study.

BACKGROUND: The influence of parental occupation on selected coronary heart disease risk factors was studied in a cohort of Finnish children aged 9, 12 and 15 years (n = 1211) as part of the Cardiovascular Risk in Young Finns Study in 1986. METHODS: The relationships of parental occupation to serum lipid and apolipoprotein concentrations, blood pressure, obesity, smoking, physical activity, diet and birthweight were examined. The occupation of the parents was obtained by a questionnaire and classified as I: upper non-manual (22%), II: lower non-manual (26%), III: upper manual (32%), IV: lower manual (5%) and F: farmers (15%). RESULTS: Highest serum total and how density lipoprotein cholesterol concentrations were found in classes IV and F. Boys from class IV had 7.1% higher total cholesterol concentrations compared to class I (4.98 mmol/l versus 4.65 mmol/l, P = 0.0033), whereas farmers' girls had 10.4% higher concentrations than girls from class III (5.31 mmol/l versus 4.81 mmol/l, P = 0.0057). Blood pressure was related to parental occupation only in boys, and the values were highest in class F. Boys from class IV smoked most often, and they also had lowest values for physical activity index and highest obesity indices. Farmers' children consumed significantly more saturated fat and cholesterol than children from other classes. In boys, the percentage of subjects with a low birthweight (< or = 10th percentile) was smallest in class I and greatest in class IV (7.1% versus 20.7%, P = 0.0330). CONCLUSIONS: Socioeconomic status based on parental occupation is associated with several coronary heart disease risk factors already present in children. These differences should be taken into account in prevention programmes aimed at children at an increased risk for developing coronary heart disease as adults.

Associations of education with cardiovascular risk factors in young adults: the Cardiovascular Risk in Young Finns Study.

BACKGROUND: Low educational level is associated with an increased risk of coronary heart disease. The aim of the present study was to examine the relationships between education and common cardiovascular risk factors in young adults. METHODS: Trends in conventional risk factors of young adults aged 21, 24, 27 and 30 years in 1992 (n = 443) were examined across the educational groups as part of a 12-year follow-up study, the Cardiovascular Risk in Young Finns Study. Education was determined as participants' own educational level and as parental years of schooling. RESULTS: In males, subject's own education was related inversely and independently of parental school years to serum total and low density lipoprotein (LDL) cholesterol concentration, smoking and body mass index. In females, participant's own educational level associated inversely with smoking and physical inactivity. Parental school years was associated inversely and independently of one's own educational level with serum total and LDL cholesterol values and waist-hip ratio in females. In both genders, parental education was a stronger determinant of diet (butter use) than one's own educational level. CONCLUSIONS: The least educated young adults have adopted a more adverse lifestyle than the more educated. The risk factor profile in young adulthood, especially in females, is still affected by parental education. The influences of one's own and parental educational level on vascular risk profile should be taken into consideration when planning public health campaigns among young adults.

The effect of physical activity on serum total and low-density lipoprotein cholesterol concentrations varies with apolipoprotein E phenotype in male children and young adults: The Cardiovascular Risk in Young Finns Study.

Apolipoprotein E (apo E) determines serum total (TC) and low-density lipoprotein (LDL-C) cholesterol concentrations and is thus associated with coronary heart disease (CHD) risk. We studied if the effect of physical activity (PA) on serum TC and LDL-C concentrations varies with apo E phenotype in a population-based sample of children and young adults with regular PA. The study cohort consisted of subjects aged 9, 12, 15, 18, 21, and 24 years in 1986 (N = 1,498) participating in a large multicenter study of cardiovascular risk factors in children and young adults. Serum lipid concentrations were determined enzymatically, and apo E phenotypes by isoelectric focusing and immunoblotting. The composition of the diet was determined by a 48-hour recall method, and a PA index was calculated on the basis of frequency, intensity, and duration of activity assessed by a questionnaire. LDL-C (P = .0082), TC (P = .014), and the high-density lipoprotein cholesterol (HDL-C)/TC ratio (P = .0004) responses to exercise varied with apo E phenotype. The effect of PA on LDL-C, TC, or HDL/TC was not found in apo E phenotype E4/4. A moderate inverse effect of PA on TC and LDL-C and a positive effect on HDL/TC was found in subjects with E4/3 and E3/3 phenotypes. Similar but stronger associations were found between these variables within the group of E3/2 males. The effect of PA on serum lipid levels was strongest within the phenotype E3/2. These associations were not explained by dietary habits. Apo E phenotype partly determines the effect of PA on serum TC and LDL-C in Finnish male children and young adults with regular PA.

Associations between physical activity and risk factors for coronary heart disease: the Cardiovascular Risk in Young Finns Study.

Risk factors such as high serum cholesterol concentration measured in young adulthood predict premature coronary heart disease (CHD) in the middle-aged. The objective of this study was to analyze the associations between physical activity and CHD risk factors--body composition, blood pressure, serum lipids, apolipoproteins, and insulin--in children and young adults. The design was a cross-sectional study of atherosclerosis precursors in children and young adults using a cohort of children and young adults (N = 2,358) aged 9 to 24 years to determine indices of physical activity, measurements of anthropometric characteristics, blood pressure, serum lipids, apolipoproteins A-I and B, and insulin. The results show that a high level of physical activity was associated with high serum high density lipoprotein cholesterol (HDL-C) and HDL2-C concentrations, and low levels of serum triglycerides (TG), apolipoprotein B and insulin in males. However, in females, the influence of physical activity was evident only on TG level. In both genders, physical activity was inversely associated with obesity. In all these associations, a significant dose-related relationship was observed. We found no association between physical activity and blood pressure. In conclusion, physical activity is associated with a favorable serum lipid profile already during childhood and early adulthood in a dose-related manner, particularly in males. The promotion of physical activity is important in childhood in preventing obesity and premature cardiovascular disease.

Genetics of familial combined hyperlipidemia.

Complex disorders are caused by several environmental factors that interact with multiple genes. These diseases are common at the population level and constitute a major health problem in Western societies. Familial combined hyperlipidemia (FCHL) is characterized by elevated levels of serum total cholesterol, triglycerides, or both. This disorder is estimated to be common in Western populations with a prevalence of 1% to 2%. In addition, 14% of patients with premature coronary heart disease (CHD) have FCHL, making this disorder one of the most common genetic dyslipidemias underlying premature CHD. Both genetic and environmental factors are suggested to affect the complex FCHL phenotype, but no specific susceptibility genes to FCHL have been identified. It is hoped that further analysis of the first FCHL locus and other new loci obtained in genome-wide scans will guide us to genes predisposing to this complex disorder.

Should children or young adults be screened for serum lipid levels to prevent adult coronary heart disease? Experience from the Cardiovascular Risk in Young Finns study.

Coronary heart disease (CHD) has its origin in childhood. High cholesterol levels measured in children and adolescents are indicative of concurrent atherosclerotic changes and probably predict adult coronary heart disease. We review here the relevance of screening children, adolescents or young adults for serum lipid levels in order to efficiently prevent premature adult coronary heart disease. Data is presented in the light of the large Cardiovascular Risk in Young Finns study and other studies. The authors do not recommend universal screening strategies because of (i) the limited predictive power of serum lipid levels on an individual level, (ii) the limited knowledge on the safety of interventive measures on the growing child, and (iii) the limited knowledge on the ethical aspects of screening (labelling). However, the importance of measuring serum lipids to detect familial dyslipidaemic disorders such as familial hypercholesterolaemia, is stressed. The selection of children or adolescents for serum lipid measurements should be made on the basis of family history of early CHD or dyslipidaemia.

Smoking, alcohol and lipoprotein metabolism.

Daily smoking and use of alcohol have a many-fold influence on lipid metabolism. The relations between HDL-cholesterol, alcohol use and smoking are well known. During recent years, the influence of smoking on postprandial lipid and glucose metabolism, and on insulin sensitivity in particular, has gained increasing attention. In addition, new data have emerged about the oxidative properties of alcohol use and smoking. As life habits tend to show clustering, isolating mechanisms responsible for the lipid changes induced by smoking or alcohol per se is difficult and is one factor causing contradiction in this study area.

Serum lipoproteins in children and young adults: determinants and treatment strategies.

Serum lipoproteins are related to vascular atherosclerotic changes as seen in necropsy studies of child fatal accident victims; therefore, efforts have been made to reveal the determinants of lipoprotein metabolism in children and young adults. Recent data emphasize the adverse effects of obesity, insulin resistance and high fat intake on lipid profiles of children, and currently many lifestyle and dietary intervention studies are in progress. Detection of hereditary dyslipidemias in childhood is presently hampered by diagnostic problems. However, with the advent of efficient tools for genetic mapping, early diagnosis of common genetic dyslipidemias will probably be possible in the near future.

Tracking of serum HDL-cholesterol and other lipids in children and adolescents: the Cardiovascular Risk in Young Finns Study.

BACKGROUND: We have studied the tracking (i.e., the correlation between subsequent measurements) of serum lipids in a cohort of 2,236 children and adolescents (ages initially 3-18 years). METHODS: Determinations of the serum variables were made 3 and 6 years apart. Six-year tracking values (Spearman's r) were 0.63, 0.66, 0.58, and 0.36 for serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides, respectively. Boys were found to track better than girls. Subjects who remained persistently in the highest (total cholesterol, low-density lipoprotein cholesterol, and triglycerides) or lowest (high-density lipoprotein cholesterol and high-density lipoprotein ratio) quintile tended to become obese and smoked cigarettes more frequently than the others. CONCLUSION: The tracking of high-density lipoprotein cholesterol was higher than in previous studies, but differences in methodology may account for this. We conclude that total cholesterol and low-density as well as high-density lipoprotein cholesterol measurements in childhood and adolescence are predictive of adult values.

Why don't all heavy snorers have obstructive sleep apnea?

Patients with obstructive sleep apnea (OSA) and heavy snorers without apnea both show intrathoracic suction pressures during sleep that exceed their static upper airway closing pressures. Complete airway occlusion, however, occurs only in the former patient group. We hypothesized that the kinetic properties of the airflow would be different in these two types of patients because of differences in upper airway morphology. The pharyngeal computed tomography (CT) was used to measure the cross-sectional areas of the upper airways in 15 patients with OSA, 25 nonapneic heavy snorers, and 14 control subjects while they were awake. Nocturnal breathing was monitored with the static charge-sensitive bed (SCSB). The patients with OSA had a narrower airspace at the velopharyngeal (VP) level than the controls (p less than 0.01); the nonapneic snorers did not differ from the other groups. At the tongue base (TB) and the hyoid bone (HB) levels there was no difference between the OSA and the control groups, but the nonapneic snorers had narrower airways at both of these levels compared with control subjects (p less than 0.01) and at the hyoid bone level compared with the OSA group (p less than 0.05). The VP/HB ratio was the parameter that best distinguished the patients with OSA from the nonapneic snorers (lower in the OSA group, p less than 0.001). We suggest that airway collapse during sleep is favored by a narrow velopharynx associated with large hypopharynx. Some heavy snorers may not have an oropharyngeal collapse because the peak inspiratory suction pressure could already be damped down at the level of the relatively narrow hypopharyngeal airways.

Cardiovascular risk factors of young adults in relation to parental socioeconomic status: the Cardiovascular Risk in Young Finns Study.

The socioeconomic status (SES) of the family influences the cardiovascular risk status of children and adolescents; however, it is not as well known whether parental SES has any effect on the risk factor profile of young adults. The aim of the present study was to investigate the relations of different aspects of parental SES, namely occupation, education, income and living area, to the common cardiovascular risk factors of their offspring (n = 919) aged 18, 21 and 24 years as a part of the Cardiovascular Risk in Young Finns Study in 1986. Subjects from farming families and rural areas had the highest serum total and low-density lipoprotein cholesterol values, and the lowest diastolic blood pressure compared with subjects from other occupational groups and subjects from urban regions. The diet of young adults from farming families and from rural areas contained more saturated fatty acids and less monounsaturated and polyunsaturated fatty acids. In addition, the body mass index was lower in subjects from urban regions compared with rural regions, and physical inactivity was less common in the urban group. Subjects with the highest parental occupational status smoked less compared with those with the lowest status. Parental education related inversely to physical inactivity and directly to dietary polyunsaturated fatty acids. The income level of the family associated positively with frequent inebriation by alcoholic beverages and inversely with the percentage of dietary energy from fat. In conclusion, there were modest inverse associations between different indicators of the SES of parents and some of the traditional risk factors of their offspring in young adulthood, which may contribute to the future risk of cardiovascular diseases.