ABSTRACT
Relatively low numbers of kringle 4 type 2 repeats in apolipoprotein(a) and specific haplotypes of the SLC22A3-LPAL2-LPA region on chromosome 6 are associated with an increased risk of coronary disease. We examined the possibility that rs3798220 and rs10455872, short variations located in LPA [the apolipoprotein(a) gene], and related to the number of kringle 4 type 2 repeats, may serve as markers for the association between haplotypes and acute myocardial infarction. Genotypes were determined with TaqMan assays in a sample of 2136 cases and 1211 controls. The minor alleles of rs3798220 and rs10455872 were associated with increased risks (rs3798220-C: adjusted OR 2.14, 95% CI, 1.37-3.33, P = 0.00080; rs10455872-G: adjusted OR 1.74, 95% CI 1.36-2.24, P < 0.00001). After adjustments were made for potential confounders, none of nine polymorphisms included in a haplotype analysis were singly related to disease. Two risk haplotypes were identified; one (CCTTGTGTG; OR 1.25, 95% CI 1.08-1.45, P = 0.0022) was correlated with rs3798220-C and the other (CCCTGGATC; OR 1.65, 95% CI 1.14-2.38, P = 0.0074) with rs10455872-G. Thus, the findings allowed for a more precise definition of risk-associated markers: specific nucleotides in LPA instead of standard haplotypes defined by noneffective variants from the extensive SLC22A3-LPAL2-LPA region.
Subject(s)
Apolipoproteins A/genetics , Myocardial Infarction/genetics , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Female , Genetic Predisposition to Disease , Haplotypes , Humans , Male , Middle AgedABSTRACT
Interleukin 18 is an important mediator of inflammation and has been associated with the development and aggravation of cardiovascular diseases. We report that common variation in the interleukin 18 gene is related to acute myocardial infarction, a frequent clinical manifestation of atherosclerosis and thrombosis in coronary arteries. In a population of European, mainly (90%) German, ancestry (2136 cases with acute myocardial infarction and 1211 controls), the association was based on specific alleles and haplotypes derived from a set of six tagging single nucleotide polymorphisms. The rs1946519-G (located in the 5' upstream region), rs360717-C (exon 1), rs5744241-G (intron 1), rs1834481-C (intron 3), and rs3882891-A (intron 5) alleles (P≤0.039) and a haplotype (GCGCAG haplotype; P=0.0028) containing the GCGCA motif derived from these alleles were associated with an increased risk of AMI. Corresponding with this result, the complementary alleles (rs1946519-T, rs360717-T, rs5744241-A, rs1834481-G, and rs3882891-C) and a haplotype (TTAGCG haplotype; P=0.018) with the TTAGC motif showed protective effects. Haplotypes not including the GCGCA or TTAGC motif were not related to AMI (P≥0.22). These observations suggest that the interleukin 18 gene is a susceptibility locus for acute myocardial infarction, a finding of potential interest in the clinical practice.
Subject(s)
Genetic Predisposition to Disease , Interleukin-18/genetics , Myocardial Infarction/genetics , Polymorphism, Single Nucleotide/genetics , Case-Control Studies , Chromosomes, Human, Pair 11/genetics , Female , Gene Frequency/genetics , Genetic Loci/genetics , Haplotypes/genetics , Humans , Male , Middle Aged , Risk Factors , Smoking/geneticsABSTRACT
In a genome-wide scan, isolated single nucleotide polymorphisms (SNPs), including rs17465637, in the melanoma inhibitory activity 3 gene (MIA3) on chromosome 1 were identified to be associated with coronary artery disease and myocardial infarction (MI). Because the role of common variation at the MIA3 locus has not yet been investigated, the aim of this case-control study was to determine the impact of haplotype-tagging SNPs and haplotypes in the MIA3 region on the risk of MI. In a set of nine haplotype-tagging SNPs, rs17465637, but none of the other SNPs, was associated with MI. After adjustments were made for age, gender, history of arterial hypertension, history of hypercholesterolaemia, current cigarette smoking and diabetes mellitus, multiple logistic regression analyses showed an increased risk in the carriers of one or two C alleles [adjusted odds ratio (OR) 1.17, 95% confidence interval (CI) 1.04-1.32, and 1.37, 95% CI 1.08-1.74, respectively]. Nine common haplotypes (frequency >1%) were established across the MIA3 region. Two of the haplotypes were associated with an increased risk of MI: the frequent (48%) TGACCAAAG haplotype and the rare (2%) CGACCAAAG haplotype (adjusted OR 1.102, 95% CI 1.002-1.212, and 1.574, 95% CI 1.077-2.298, respectively). Showing association between rs17465637 and MI, this work was consistent with results from the original detection study and most prior replication studies addressing this issue. In addition to correspond with such isolated evidence of association with MI, the present study identified specific haplotypes capturing the risk-related variation in the entire MIA3 region.
