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.

T he protective effect of HDL cholesterol and apolipoprotein A1 [apo(a1)] on the risk of coronary heart disease (CHD) is mediated mainly through the promotion of cholesterol efflux from peripheral cells (1). In addition, both HDL cholesterol and apo(a1) may have antioxidant, antithrombotic, and anti-inflammatory properties, which could have important antiatherogenic effects (1). The level of circulating HDL cholesterol and apo(a1) is dependent on sex, BMI, age (2), smoking (3), alcohol intake, and lipid-lowering medication (4). In addition, different variants in the apo(a1) gene can modify its expression and affect HDL cholesterol and apo(a1) levels (5,6).Restriction site polymorphisms have been identified at Ϫ75 bp in the promoter region and ϩ37 and ϩ83 bp in intron 1 of the apo(a1) gene. Polymorphisms at Ϫ75 and ϩ83 bp of the apo(a1) gene have been related to elevated levels of HDL cholesterol and apo(a1) in nondiabetic subjects (5-7), although not confirmed in all studies (8,9). Association of the ϩ83-bp polymorphism with elevated levels of HDL cholesterol has been stronger than that with the Ϫ75-bp polymorphism (6). The genotype effect on circulating apo(a1) and HDL cholesterol levels is modulated by sex and environmental factors such as smoking (3,7,10). The differences in HDL cholesterol and apo(a1) levels among various genotypes of the apo(a1) gene are not modified by different diets, suggesting that the possible benefit is independent of fat and cholesterol intake (11).So far, no studies have been published on the impact of the Ϫ75-and/or ϩ83-bp polymorphisms of the apo(a1) gene on HDL cholesterol and apo(a1) levels in patients with type 2 diabetes. To this aim, we screened nondiabetic and type 2 diabetic subjects with CHD for the Ϫ75-and ϩ83-bp polymorphisms of the apo(a1) gene. RESEARCH DESIGN AND METHODS SubjectsAll unrelated subjects (n = 641: 469 men, 172 women) participating in this study were R I G I N A L A R T I C L EOBJECTIVE -Elevated HDL cholesterol and its principal carrier protein apolipoprotein A1 [apo(a1)] are associated with reduced risk of coronary heart disease (CHD). No studies are available on the impact of the Ϫ75-bp and/or ϩ83-bp polymorphisms of the apo(a1) gene on HDL cholesterol and apo(a1) levels in patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -We determined the prevalence of the Ϫ75-bp and ϩ83-bp polymorphisms of the apo(a1) gene by restriction fragment length polymorphism analysis among 308 unrelated nondiabetic subjects with CHD and among 251 unrelated patients with type 2 diabetes with CHD and in randomly selected 82 healthy men (CHD Ϫ ). RESULTS-The rare M1 Ϫ and M2 Ϫ allele frequencies of the apo(a1) gene were 23 and 1.8%, respectively, among control subjects; 20 and 1.5%, respectively, among nondiabetic subjects with CHD; and 22 and 2.6%, respectively, among patients with type 2 diabetes and CHD (NS). Nonsmoking nondiabetic subjects with CHD having the M2 ϩϪ genotype had higher HDL cholesterol (1.48 ± 0.19 vs. 1.23 ± 0.02 mmol/l, P Ͻ 0.01) and apo(a1) (1.43...

The endothelial nitric oxide synthase (eNOS) gene is responsible for constitutive nitric oxide synthesis and arterial vasodilatation. Recently two polymorphisms, the 27-bp repeat sequence in intron 4 and the Glu298Asp substitution in exon 7 of the eNOS gene have been reported to be related to coronary heart disease (CHD). We screened these polymorphisms of the eNOS gene in 308 unrelated nondiabetic subjects with CHD, in 251 unrelated patients with type 2 diabetes with CHD, and in 110 randomly selected healthy subjects without CHD. The 4a and Asp298 allele frequencies of the eNOS gene were 0.19 and 0.36 in nondiabetic patients with CHD, 0.21 and 0.27 in type 2 diabetic patients with CHD, and 0.16 and 0.31 in nondiabetic subjects without CHD (n.s. between the groups). The Asp298 allele in exon 7 of the eNOS gene was not associated with elevated blood pressure in any of the study groups. Among type 2 diabetic patients with CHD the 4a allele in intron 4 of the eNOS gene was associated with elevated levels of systolic (P=0.035) and mean arterial blood pressure (P=0.040). In nondiabetic subjects these associations were not statistically significant. When all study groups were pooled in statistical analysis the 4a allele of the eNOS gene was associated with elevated diastolic (P=0.032) and mean (P=0.030) arterial blood pressure even after adjustment for confounding factors. We conclude that the 4a allele of the eNOS gene is not associated with CHD or type 2 diabetes, but that it is related to elevated blood pressure levels particularly among type 2 diabetic patients with CHD.

The relationship of two apolipoprotein (apo) E gene polymorphisms and coronary heart disease (CHD) was investigated in 118 Finnish families with premature CHD and in 110 healthy control subjects. Affected siblings and probands with premature CHD had higher frequencies of the T allele of the -219G/T promoter polymorphism and the epsilon 4 allele (genotypes epsilon 4/3 or epsilon 4/4) of the apo epsilon 2/epsilon 3/ epsilon 4 polymorphism than those of healthy control subjects. Additionally, when the two apo E gene polymorphisms were combined, affected siblings and probands had a higher frequency of the -219T allele and the epsilon 4 allele combinations than did healthy controls. The -219T and the epsilon 4 alleles both separately and together were associated with higher levels of 2-h glucose in an oral glucose tolerance test. These results indicate that the two polymorphisms of the apo E gene have similar effects on the risk of coronary atherosclerosis in families with premature CHD. This risk was not explained by the effect of apo E gene polymorphisms on cholesterol metabolism, but their effect on cardiovascular risk factor clustering with insulin resistance may be of importance. We conclude that in addition to the epsilon 4 allele, also the -219G/T promoter polymorphism of the apo E gene is associated with early onset CHD.

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