Ilpo Nuotio

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.

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.

Combined analysis of genome scans of dutch and finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q

Several genomewide screens have been performed to identify novel loci predisposing to unfavorable serum lipid levels and coronary heart disease (CHD). We hypothesized that the accumulating data of these screens in different study populations could be combined to verify which of the identified loci truly harbor susceptibility genes. The power of this strategy has recently been demonstrated with other complex diseases, such as inflammatory bowel disease and asthma. We assessed the largely unknown genetic background of CHD by investigating the most common dyslipidemia predisposing to CHD, familial combined hyperlipidemia (FCHL), affecting 1%-2% of Western populations and 10%-20% of families with premature CHD. To be able to perform a combined data analysis, we unified the diagnostic criteria for FCHL and its component traits and combined the data from two genomewide scans performed in two populations, the Finns and the Dutch. As a result of our pooled data analysis, we identified three chromosomal regions, on chromosomes 2p25.1, 9p23, and 16q24.1, exceeding the statistical significance level of a LOD score >2.0. The 2p25.1 region was detected for the FCHL trait, and the 9p23 and 16q24.1 regions were detected for the low high-density lipoprotein cholesterol (HDL-C) trait. In addition, the previously recognized 1q21 region also obtained additional support in the other study sample, when the triglyceride trait was used. Analysis of the 16q24.1 region resulted in a statistically significant LOD score of 3.6 when the data from Finnish families with low HDL-C were included in the analysis. To search for the underlying gene in the 16q24.1 region, we investigated a novel functional and positional candidate gene, helix/forkhead transcription factor (FOXC2), by sequencing and by genotyping of two single-nucleotide polymorphisms in the families.

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.

Thromboembolic complications after cardioversion of acute atrial fibrillation: the FinCV (Finnish CardioVersion) study.

OBJECTIVES This study sought to explore the incidence and risk factors of thromboembolic complications after cardioversion of acute atrial fibrillation. BACKGROUND Anticoagulation therapy is currently recommended after cardioversion of acute atrial fibrillation in patients with risk factors for stroke, but the implementation of these new consensus-based guidelines has been slow. METHODS A total of 7,660 cardioversions were performed in 3,143 consecutive patients with atrial fibrillation lasting <48 h in 3 hospitals. For this analysis, embolic complications were evaluated during the 30 days after 5,116 successful cardioversions in 2,481 patients with neither oral anticoagulation nor peri-procedural heparin therapy. RESULTS There were 38 (0.7%; 95% confidence interval [CI]: 0.5% to 1.0%) definite thromboembolic events (31 strokes) within 30 days (median 2 days, mean 4.6 days) after cardioversion. In addition, 4 patients suffered transient ischemic attack after cardioversion. Age (odds ratio [OR]: 1.05; 95% CI: 1.02 to 1.08), female sex (OR: 2.1; 95% CI: 1.1 to 4.0), heart failure (OR: 2.9; 95% CI: 1.1 to 7.2), and diabetes (OR: 2.3; 95% CI: 1.1 to 4.9) were the independent predictors of definite embolic events. Classification tree analysis showed that the highest risk of thromboembolism (9.8%) was observed among patients with heart failure and diabetes, whereas patients with no heart failure and age <60 years had the lowest risk of thromboembolism (0.2%). CONCLUSIONS The incidence of post-cardioversion thromboembolic complications is high in certain subgroups of patients when no anticoagulation is used after cardioversion of acute atrial fibrillation. (Safety of Cardioversion of Acute Atrial Fibrillation [FinCV]; NCT01380574).

Association Between Carotid Intima-Media Thickness and Low-Density Lipoprotein Size and Susceptibility of Low-Density Lipoprotein to Oxidation in Asymptomatic Members of Familial Combined Hyperlipidemia Families

Background and Purpose— In addition to low-density lipoprotein (LDL) cholesterol, small, dense LDL particles and oxidative modification of LDL have been linked to the pathogenesis of atherosclerosis. The present study was aimed at investigating the association between carotid artery intima-media thickness (IMT) and LDL particle size and susceptibility of LDL to oxidation in vitro in asymptomatic members of familial combined hyperlipidemia (FCHL) families. Methods— LDL particle size, susceptibility of LDL to oxidation in vitro, and carotid IMT were measured in 148 asymptomatic FCHL family members. Results— LDL particle size and lag time for LDL oxidation were reduced in hyperlipidemic compared with normolipidemic family members. LDL particle size, serum total cholesterol, and &agr;-tocopherol in LDL were independently associated with lag time for LDL oxidation in multivariate analysis. LDL particle size was associated with carotid mean IMT independently of clinical, lipid, and antioxidant variables in multivariate analysis. Although the susceptibility of LDL to oxidation in vitro was correlated with mean IMT, it did not have a significant independent contribution to variation in mean IMT in the multivariate model. Conclusions— We conclude that LDL particle size but not susceptibility of LDL to oxidation in vitro is independently associated with carotid IMT in asymptomatic FCHL family members. These results imply that small, dense LDL as an inherent feature of FCHL is an important diagnostic indicator for coronary artery disease risk in FCHL.

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.

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.

Time to cardioversion for acute atrial fibrillation and thromboembolic complications.

Methods | In the retrospective Finnish CardioVersion study,4 all patients with a primary diagnosis of AF, aged 18 years or older, with successful cardioversion in the emergency department within the first 48 hours of AF, and residence in the catchment areas of Turku and Kuopio university hospitals from 2003 to 2010 and Pori central hospital during 2010 were included. Clinical details and the occurrence of thromboembolic complications within 30 days after cardioversion were retrospectively collected from medical reports. The primary outcome, a thromboembolic event, was defined as a clinical stroke or systemic embolism confirmed by computerized tomography or magnetic resonance imaging, surgery, or autopsy. Time to cardioversion was determined as the difference between the beginning of arrhythmic symptoms to the exact time of cardioversion. If the duration of arrhythmia was uncertain, the cardioversion

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.