Stroke recurrence in patients with atrial fibrillation: concomitant carotid artery stenosis doubles the risk.

BACKGROUND AND PURPOSE: Atrial fibrillation (AF) and significant carotid artery stenosis (CAS) often coexist in patients with acute stroke but whether CAS affects the stroke recurrence rate in anticoagulated AF patients is largely unknown. The effect of concomitant CAS on both short- and long-term prognosis after stroke in patients with AF was evaluated. METHODS: The multicentre, retrospective FibStroke registry included AF patients with an ischaemic stroke or transient ischaemic attack (TIA) during 2003-2012. In this sub-study, 165 AF patients with ischaemic stroke or TIA with significant (>50%) CAS (CAS group) and 734 AF patients without CAS (non-CAS group) were identified. The median follow-up time after an index event was 3.5 (interquartile range 3.9) years. Long-term stroke recurrence rate, 30-day mortality, CHA2 DS2 -VASc score, other risk factors and the use and intensity of anticoagulation were assessed. RESULTS: The recurrence rate of ischaemic stroke (21.2% vs. 12.7%, P = 0.005, 8.1 vs. 3.6 events per100 follow-up years) was significantly higher in CAS patients compared to the non-CAS group despite similar anticoagulation/antithrombotic therapy. CAS patients had higher mean CHA2 DS2 -VASc scores than non-CAS patients (4.3 vs. 3.3, P < 0.001). However, in a multivariate analysis CAS was shown to be an independent risk factor for stroke recurrence (hazard ratio 2.02, 95% confidence interval 1.37-3.01, P = 0.001). The 30-day all-cause mortality was significantly higher in CAS patients (7.9% vs. 1.9%, P < 0.001) and CAS was an independent risk factor also for 30-day mortality (odds ratio 3.34, 95% confidence interval 1.51-7.38, P = 0.003). CONCLUSIONS: In patients with AF, concomitant CAS was an independent risk factor for both long-term stroke recurrence and 30-day mortality.

Underuse of anticoagulation in stroke patients with atrial fibrillation--the FibStroke Study.

BACKGROUND AND PURPOSE: Current guidelines recommend oral anticoagulation (OAC) for patients with atrial fibrillation (AF) and increased risk of thromboembolic events. The reasons for not using OAC in AF patients suffering stroke or transient ischaemic attack (TIA) were assessed. METHODS: This retrospective registry included 3404 patients with previously diagnosed AF who suffered a total of 2955 ischaemic strokes and 895 TIAs during 2003-2012. RESULTS: A CHA2DS2-VASc score ≥2 and a CHADS2 score ≥2 was observed in 3590 (93.2%) and in 2784 (72.3%) of the events, respectively. Of the high-risk patients (CHADS2 ≥2) only 55.1% were on OAC before the onset of stroke or TIA. The most frequently documented reasons for withholding OAC were infrequent paroxysms of AF (14%), previous bleeding episodes (13%) and the patient's decline/independent discontinuation of treatment (9%). Moreover, patients with paroxysmal AF (40% using OAC), previous bleeding (26% using OAC) and alcohol abuse (30% using OAC) were using OAC significantly less often than patients without these characteristics. A significant increase in the proportion of high-risk patients using OAC from 49% in 2003 to 65% in 2012 was seen. CONCLUSIONS: Underuse of anticoagulation is a common contributor to ischaemic strokes and TIA episodes in patients with AF. Infrequent AF episodes, previous bleeds, patient preference and alcohol abuse were the most common reasons for not using OAC.

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.

Serum C3 but not plasma acylation-stimulating protein is elevated in Finnish patients with familial combined hyperlipidemia.

A trapping defect of fatty acids due to impaired function of acylation-stimulating protein (ASP) has been suggested as one mechanism underlying the metabolic abnormalities in familial combined hyperlipidemia (FCHL). The study aimed at defining the role of ASP and complement C3 in 35 Finnish FCHL families. There was no difference in plasma ASP levels between the 66 hypertriglyceridemic FCHL patients and their 84 normotriglyceridemic relatives. No response in plasma ASP could be observed after a fatty meal in 10 FCHL patients or in 10 control subjects. In familial correlation analyses, C3 exhibited a significant sibling-sibling correlation. The FCHL patients had higher serum C3 levels than their unaffected relatives (P<0.001). Furthermore, serum C3 levels correlated significantly with several lipid parameters. The correlations between ASP and lipid variables were weaker than those of C3. These analyses suggest that common genes might contribute to the regulation of serum C3, triglycerides, HDL-C, free fatty acids, and insulin. The present data do not support the hypothesis that defects of the ASP pathway are reflected in plasma lipoproteins or in impaired plasma lipid clearance postprandially.

A 1-year prospective study on the relationship between physical activity, markers of bone metabolism, and bone acquisition in peripubertal girls.

We conducted a 1-yr prospective study to evaluate the association between physical activity and biochemical markers of bone formation and resorption with bone mineral acquisition in 155 peripubertal Caucasian girls (51 gymnasts, 50 runners, and 54 nonathletic controls). The bone mineral density (BMD) of the femoral neck, the greater trochanter, and the lumbar spine were measured by dual energy x-ray absorptiometry. Serum biochemical markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, amino-terminal propeptide of type I procollagen) and bone resorption (degradation product of C-terminal telopeptide of type I collagen) were measured. The 1-yr increase in BMD (adjusted for age, height, Tanner stage, BMD at baseline, and increases in height and weight) of the femoral neck was 0.037 g/cm2 x yr [95% confidence interval (CI), 0.019-0.051 g/cm2 x yr), and that of the greater trochanter was 0.020 g/cm2 x yr (95% CI, 0.003-0.039 g/cm2 x yr) greater in gymnasts than in controls. The corresponding figures for gymnasts compared with runners were 0.038 g/cm2 x yr (95% CI, 0.009-0.041 g/cm2 x yr) and 0.033 g/cm2 x yr (95% CI, 0.006 to 0.043 g/cm2 x yr). The figures for the lumbar spine did not differ significantly between study groups. The baseline serum concentrations of formation markers and resorption marker accounted for 2.3-12.8% (P < 0.05) of the variation in the 1-yr increase in BMD at the femoral neck and lumbar spine. However, there was no significant difference between the levels of adjusted baseline bone turnover markers of the gymnasts, runners, and controls. The present data add considerable support to the argument that high impact mechanical loading is extremely important and beneficial for the acquisition of BMD of the hip during peripubertal years. Our results indicate also that a high rate of bone turnover, reflected as elevated bone markers, is only weakly associated with the 1-yr bone gain in peripubertal girls.

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.

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.

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.

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.

The effect of conventional vitamin D(2) supplementation on serum 25(OH)D concentration is weak among peripubertal Finnish girls: a 3-y prospective study.

OBJECTIVES: To study the effect of vitamin D supplementation and the impact of summer season on serum 25-hydroxyvitamin D (S-25(OH)D) in Finnish 9-15-y-old girls. DESIGN: Three-year follow-up study with vitamin D(2) supplementation using D(2) 10 microg daily from October to January for the first and from October to February for the second winter as well as 20 microg daily from October to March for the third winter. SETTING: Paavo Nurmi Centre, University of Turku, Turku, Finland. SUBJECTS: A total of 171 female volunteers aged 9-15 y. METHODS: Vitamin D and calcium intakes were estimated by a semi-quantitative food frequency questionnaire (FFQ). S-25(OH)D was measured by radioimmunoassay. RESULTS: The median daily dietary intakes of vitamin D and calcium were 3.8 microg (interquartile range (IQR) 2.7-5.0) and 1451 mg (IQR 1196-1812), respectively, over 3 y. The prevalence of severe hypovitaminosis D (S-25(OH)D<20 nmol/l) was 14% and of moderate hypovitaminosis D (20 nmol/l < or = S-25(OH)D < or = 37.5 nmol/l) 75% at baseline in winter. None of the participants had severe hypovitaminosis D in summer. The effect of 10 microg of D(2) daily was insufficient to raise S-25(OH)D from baseline. The daily supplementation of 20 microg of D(2) increased S-25(OH)D significantly in wintertime compared with the non-supplement users (to 45.5 vs 31.8 nmol/l; P<0.001). None of the subjects with vitamin D(2) supplementation approximately 20 microg daily had severe hypovitaminosis D; however, 38% of those participants had moderate hypovitaminosis D at 36 months. Sun exposure in summer raised mean S-25(OH)D to 62.0 nmol/l. Both the daily supplementation of approximately 20 microg of D(2) and summer sunlight exposure had more effect on those who had severe hypovitaminosis than those who had a normal vitamin D status (increase of 24.2 vs 0.9 nmol/l (P<0.001), and 38.8 vs 18.2 nmol/l (P<0.001), respectively). CONCLUSION: Vitamin D supplementation daily with 20 microg is needed to prevent hypovitaminosis D in peripubertal Finnish girls in winter. Sunlight exposure in summer is more effective than approximately 20 microg of D(2) supplementation daily in winter to raise S-25(OH)D. Both the daily supplementation with 20 microg of D(2) and summertime sunlight exposure had more effect on those who had severe hypovitaminosis D than those who had a normal vitamin D status. SPONSORSHIP: Supported by the Yrjö Jahnsson Foundation and the Medical Research Foundation of the Turku University Central Hospital.

Expression of common familial dyslipidemias in early childhood.

Early identification of common familial dyslipidemias may prevent premature atherosclerotic disease. This study estimated the diagnostic values of few early childhood repeatedly deviant lipid samples by the knowledge of the parent's dyslipidemia. The first 7 years of age data of 353 children with their parents were evaluated from atherosclerosis risk-factor intervention study controls. Parents' low high-density-lipoprotein-cholesterol concentration (hypo-HDL-C), and high total cholesterol concentration-HDL-C (hyper-non-HDL-C) were defined. True hypo-HDL-C and hyper-non-HDL-C children were defined when their respective individual longitudinal means were beyond the appropriate lipid quintiles. Sensitivities, specificities, positive and negative predictive values of the early lipid samples were estimated with individual standard deviation models and bootstrap confidence. Hypo-HDL-C children proportions were 15.3% of all, and 20.9% of the children from the hypo-HDL-C parents (p=0.26). Hyper-non-HDL-C children were 16.7% of all and 31.8% of the children from the hyper-non-HDL-C parents (p=0.008). One early non-HDL-C sample in the highest quintile predicted 56% of the hyper-non-HDL-C children from healthy parents, but 83% of the hyper-non-HDL-C children from the hyper-non-HDL-C parents. Mean of three samples improved the latter prediction to 91%. This showed that if hypercholesterolemic parent's child expressed repeatedly hyper-non-HDL-C, it predicts true dyslipidemia of the child.

Influence of physical activity on ultrasound and dual-energy X-ray absorptiometry bone measurements in peripubertal girls: a cross-sectional study.

The aim of this cross-sectional study was to investigate whether two types of physical exercise affect the growing skeleton differently. We used calcaneal quantitative ultrasound measurements (QUS) and dual-energy X-ray absorptiometry (DXA) for measurement of bone mineral density (BMD), and to test how QUS values reflect the axial DXA values in these various study groups. A total of 184 peripubertal Caucasian girls aged 11-17 years (65 gymnasts, 63 runners, and 56 nonathletic controls) were studied. Weight, height, stage of puberty, years of training, and the amount of leisure-time physical activity were recorded. Broadband ultrasound attenuation (BUA) and sound of speed (SOS) through the calcaneus were measured. The BMD of the femoral neck and the lumbar spine were measured by DXA. The differences in mean values of bone measurements among each exercise group were more evident in pubertal than prepubertal girls. The mean BUA and SOS values of the pubertal gymnasts were 13.7% (77.8 dB/MHz versus 68.4 dB/MHz, P < 0.05) and 2.2% (1607.7 m/s versus 1572.4 m/s, P < 0.001) higher than of the controls, respectively. The mean BMD of the femoral neck in the pubertal gymnasts and runners was 20% (0.989 g/cm2 versus 0.824 g/cm2, P < 0.001) and 9.0% (0.901 g/cm2 versus 0.824 g/cm2, P < 0.05) higher than in the controls, respectively. The amount of physical activity correlated weakly but statistically significantly with all measured BMD and ultrasonographic values in the pubertal group (r = 0.19-0.35). The correlation between ultrasonographic parameters and BMD were weak, but significant among pubertal runners (r = 0.47-0.55) and controls (r = 0.39-0.42), whereas the DXA values of the femoral neck and the ultrasonographic parameters of the calcaneus did not correlate among highly physically active gymnasts. By stepwise regression analysis, physical activity accounted for much more of the variation in the DXA values than the ultrasonographic values. We conclude that the beneficial influence of exercise on bone status as measured by ultrasound and DXA was evident in these peripubertal girls. In highly active gymnasts the increase of the calcaneal ultrasonographic values did not reflect statistically significantly the BMD values of the femoral neck.

Associations between diet and the hyperapobetalipoproteinemia phenotype expression in children and young adults: the Cardiovascular Risk in Young Finns Study.

The effect of diet on blood lipids has been under intensive study during recent decades. However, diet in the context of the hyperapobetalipoproteinemia (hyperapoB) phenotype has received less attention. The hyperapoB phenotype is commonly encountered in patients with premature coronary heart disease. It is defined as a combination of an increased concentration of apolipoprotein B (apo B), a normal concentration of LDL cholesterol (LDL-C), and as a result, a low LDL-C/apo B ratio. We studied the associations between diet and blood lipids in a cohort of 534 children and young adults 9 to 24 years old. The ratio of polyunsaturated to saturated fats (P/S ratio) correlated (r=-0.19, P<.001) with the LDL-C/apo B ratio. This association was also found when the model was adjusted with triglycerides (r=-0.24, P<.001). A change in the P/S ratio from 0.10 to 0.60 corresponded to a decrease of 0.12 in the LDL-C/apo B ratio, and in the highest apo B decile, the P/S value was higher in hyperapoB individuals (0.33) than in others (0.28, P=.019). Our results imply that the fatty acid composition of the diet may be one of the environmental factors that influence the hyperapoB phenotype expression.

Glucose intolerance in familial combined hyperlipidaemia. EUFAM study group.

BACKGROUND: Familial combined hyperlipidaemia (FCHL) is a common hereditary disorder. Hypertriglyceridaemia is associated with glucose intolerance and insulin resistance. METHODS: To study glucose tolerance in FCHL patients with different lipid phenotypes [hypercholesterolaemia (IIA), mixed hyperlipidaemia (IIB), hypertriglyceridaemia (IV)], we investigated 253 family members and 92 spouses arising from 33 well-defined Finnish FCHL pedigrees. RESULTS: In oral glucose tolerance tests the affected family members had higher values for glucose area under the curve than did non-affected family members [673+/-127 min mmolL(-1), 754+/-145 min mmol L(-1), 846+/-180 min mmol L(-1) and 838+/-183 min mmol L(-1) for phenotypes normal, IIA, IIB and IV respectively; P < 0.001 after adjustment for body mass index, waist circumference and age]. Impaired glucose tolerance and diabetes were more common among affected than non-affected family members (prevalences of normal glucose tolerance 94.0%, 80.0%, 54.3% and 58.5% for phenotypes normal, IIA, IIB and IV). CONCLUSION: Affected FCHL family members were more glucose intolerant than non-affected family members. In men, this disturbance was not related to lipid phenotype nor was it explained by obesity.

Haplotypes of the ApoA-I/C-III/A-IV gene cluster and familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is the most frequent familial lipoprotein disorder associated with premature coronary heart disease. However, no genetic defect(s) underlying FCHL has been identified. A linkage between FCHL and the apoA-I/C-III/A-IV gene cluster has been reported but not verified in other populations. A recent study identified FCHL susceptibility haplotypes at this gene cluster. To study whether such haplotypes are also associated with FCHL susceptibility in Finns, we studied 600 well-defined Finnish FCHL patients and their relatives belonging to 28 extended FCHL families by using haplotype, linkage, sib-pair, and linkage disequilibrium analyses. The genotypes of the MspI polymorphisms were associated with total serum cholesterol (P<0.01) and apoB (P<0.05) levels in spouses, which represent the general Finnish population. However, no evidence of direct involvement of any of these loci or their specific haplotypes in the expression of FCHL in the Finnish FCHL families was found.

Coronary flow reserve in young men with familial combined hyperlipidemia.

BACKGROUND: Familial combined hyperlipidemia (FCHL) is a common hereditary disorder of lipoprotein metabolism estimated to cause 10% to 20% of premature coronary heart disease. We investigated whether functional abnormalities exist in coronary reactivity in asymptomatic patients with FCHL. METHODS AND RESULTS: We studied 21 male FCHL patients (age, 34.8+/-5.4 years) and a matched group of 21 healthy control subjects. Myocardial blood flow (MBF) was measured at baseline and during dipyridamole-induced hyperemia with PET and 15O-labeled water. The baseline MBF was similar in patients and control subjects (0.79+/-0.19 versus 0.88+/-0.20 mL. g-1. min-1, P=NS). An increase in MBF was seen in both groups after dipyridamole infusion, but MBF at maximal vasodilation was lower in FCHL patients (3.54+/-1.59 versus 4.54+/-1.17 mL. g-1. min-1, P=0.025). The difference in coronary flow reserve (CFR) was not statistically significant (4.7+/-2.2 versus 5.3+/-1.6, P=NS, patients versus control subjects). Considerable variability in CFR values was detected within the FCHL group. Patients with phenotype IIB (n=8) had lower flow during hyperemia (2.5+/-1.2 versus 4.2+/-1.5 mL. g-1. min-1, P<0.05) and lower CFR (3.4+/-2.1 versus 5.4+/-2.0, P<0.05) compared with phenotype IIA (n=13). CONCLUSIONS: Abnormalities in coronary flow regulation exist in young asymptomatic FCHL patients expressing phenotype IIB (characterized by abnormalities in both serum cholesterol and triglyceride concentrations). This is in line with previous observations suggesting that the metabolic abnormalities related to the pathophysiology of FCHL are associated with the phenotype IIB.

No evidence of linkage between familial combined hyperlipidemia and genes encoding lipolytic enzymes in Finnish families.

Familial combined hyperlipidemia (FCHL) is characterized by different lipid phenotypes (IIa, IIb, IV) and elevated apolipoprotein B (apo B) levels in affected family members. Despite intensive research, the genes involved in the expression of this complex disorder have not been identified, probably because of problems associated with phenotype definition, unknown mode of inheritance, and most probably genetic heterogeneity. To explore the genetics of FCHL in the genetically homogeneous Finnish population, we collected 14 well-documented Finnish pedigrees with premature coronary heart disease and FCHL-like dyslipidemia. The lipolytic enzymes lipoprotein lipase (LPL), hepatic lipase (HL), and hormone-sensitive lipase (HSL) were selected as initial candidate genes because of their central roles in apo B and triglyceride metabolism. On the basis of the pedigree structures, a dominant mode of inheritance was adopted for linkage analyses, and serum total cholesterol and/or triglyceride levels exceeding the 90th percentile level were set as diagnostic criteria (criterion 1). In pairwise linkage analyses with intragenic markers, no evidence for linkage was found. Instead, the significantly negative LOD scores suggested exclusion of all three loci for single major gene effect. LOD scores were -14.63, -5.03, and -5.70 for the three LPL polymorphisms (theta=0.00); -9.40, -6.30, and -4.74 for the three HL polymorphisms (theta=0.00); and -15.29 for the HSL polymorphism (theta=0.00). The results were very similar when apo B levels over the 90th percentile were used as criteria for affected status (criterion 2). Also, when linkage calculations were carried out using an intermediate or recessive mode of inheritance, the results of pairwise linkage analysis remained negative. Furthermore, when haplotypes were constructed from multiple polymorphisms of the LPL and HL genes, no segregation with the FCHL phenotype could be observed in the 14 Finnish families. Data obtained by the affected sib-pair method supported these findings, suggesting that the LPL, HL, or HSL genes do not represent major loci influencing the expression of the FCHL phenotype.

Genomewide scan for familial combined hyperlipidemia genes in finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol, and apolipoprotein B levels.

Familial combined hyperlipidemia (FCHL) is a common dyslipidemia predisposing to premature coronary heart disease (CHD). The disease is characterized by increased levels of serum total cholesterol (TC), triglycerides (TGs), or both. We recently localized the first locus for FCHL, on chromosome 1q21-q23. In the present study, a genomewide screen for additional FCHL loci was performed. In stage 1, we genotyped 368 polymorphic markers in 35 carefully characterized Finnish FCHL families. We identified six chromosomal regions with markers showing LOD score (Z) values >1.0, by using a dominant mode of inheritance for the FCHL trait. In addition, two more regions emerged showing Z>2.0 with a TG trait. In stage 2, we genotyped 26 more markers and seven additional FCHL families for these interesting regions. Two chromosomal regions revealed Z>2.0 in the linkage analysis: 10p11.2, Z=3.20 (theta=.00), with the TG trait; and 21q21, Z=2.24 (theta=.10), with the apoB trait. Furthermore, two more chromosomal regions produced Z>2.0 in the affected-sib-pair analysis: 10q11.2-10qter produced Z=2.59 with the TC trait and Z=2.29 with FCHL, and 2q31 produced Z=2.25 with the TG trait. Our results suggest additional putative loci influencing FCHL in Finnish families, some potentially affecting TG levels and some potentially affecting TC or apoB levels.

Two loci on chromosomes 2 and X for premature coronary heart disease identified in early- and late-settlement populations of Finland.

Coronary heart disease (CHD) is a complex disorder constituting a major health problem in Western societies. To assess the genetic background of CHD, we performed a genomewide linkage scan in two study samples from the genetically isolated population of Finland. An initial study sample consisted of family material from the northeastern part of Finland, settled by a small number of founders approximately 300 years ago. A second study sample originated from the southwestern region of Finland, settled approximately 2,000 years ago. Families were ascertained through probands exhibiting premature CHD, defined as >50% stenosis of at least two coronary arteries at a young age, as verified by coronary angiography. Both study samples and the pooled data set provided evidence for linkage in two chromosomal regions. A region on chromosome 2q21.1-22 yielded two-point LOD scores of 3.2, 1.9, and 3.7, in the affected sib-pair (ASP) analyses of the northeastern, southwestern, and pooled study samples. The corresponding multipoint maximum-likelihood scores (MLSs) for these three study samples were 2.4, 1.3, and 3.0. In addition, a region on chromosome Xq23-26 resulted in two-point LOD scores of 1.9, 3.5, and 2.9 and in multipoint MLSs of 3.4, 3.1, and 2.5, respectively. In conclusion, this study identifies two loci likely to contribute to premature CHD: one on chromosome 2q21.1-22 and another on chromosome Xq23-26.