Quantum battles in attoscience: tunnelling.

ABSTRACT: What is the nature of tunnelling? This yet unanswered question is as pertinent today as it was at the dawn of quantum mechanics. This article presents a cross section of current perspectives on the interpretation, computational modelling, and numerical investigation of tunnelling processes in attosecond physics as debated in the Quantum Battles in Attoscience virtual workshop 2020.

Communication: Systematic elimination of Stokes divergences emanating from complex phase space caustics.

Stokes phenomenon refers to the fact that an asymptotic expansion of complex functions can differ in different regions of the complex plane, and that beyond the so-called Stokes lines the expansion has an unphysical divergence. An important special case is when the Stokes lines emanate from phase space caustics of a complex trajectory manifold. In this case, symmetry determines that to second order there is a double coverage of the space, one portion of which is unphysical. Building on the seminal but laconic findings of Adachi, we show that the deviation from second order can be used to rigorously determine the Stokes lines and therefore the region of the space that should be removed. The method has applications to wavepacket reconstruction from complex valued classical trajectories. With a rigorous method in hand for removing unphysical divergences, we demonstrate excellent wavepacket reconstruction for the Morse, Quartic, Coulomb, and Eckart systems.

Multivalued classical mechanics arising from singularity loops in complex time.

Complex-valued classical trajectories in complex time encounter singular times at which the momentum diverges. A closed time contour around such a singular time may result in final values for q and p that differ from their initial values. In this work, we develop a calculus for determining the exponent and prefactor of the asymptotic time dependence of p from the singularities of the potential as the singularity time is approached. We identify this exponent with the number of singularity loops giving distinct solutions to Hamilton's equations of motion. The theory is illustrated for the Eckart, Coulomb, Morse, and quartic potentials. Collectively, these potentials illustrate a wide variety of situations: poles and essential singularities at finite and infinite coordinate values. We demonstrate quantitative agreement between analytical and numerical exponents and prefactors, as well as the connection between the exponent and the time circuit count. This work provides the theoretical underpinnings for the choice of time contours described in the studies of Doll et al. [J. Chem. Phys. 58(4), 1343-1351 (1973)] and Petersen and Kay [J. Chem. Phys. 141(5), 054114 (2014)]. It also has implications for wavepacket reconstruction from complex classical trajectories when multiple branches of trajectories are involved.

Obesity-associated hypertension is ameliorated in patients with TLR4 single nucleotide polymorphism (SNP) rs4986790.

BACKGROUND: Obesity is strongly associated with hypertension. Despite numerous mechanistic links the association is not fully understood. Western diet increases uptake of Toll-Like receptor 4 (TLR4) ligands such as free fatty acids or endotoxin. We recently demonstrated that TLR4 ligands are involved in the development of hypertension. We hypothesized that TLR4 ligands are involved in obesity-associated hypertension and investigated the TLR4 single nucleotide polymorphism (SNP rs 498790). This SNP is frequent, associated with cardiovascular disease and characterized by blunted response upon exposure to TLR4 ligands. METHODS: We investigated 3657 patients undergoing coronary angiography. Blood pressure was determined in standardized manner prior angiography. The diagnosis of hypertension was based on record data. Patients were characterized for TLR4 single nucleotide polymorphism (SNP) rs4986790. Patients were stratified according to quartiles of Body mass index (BMI) and according to the polymorphism. The association between the TLR4 polymorphism and blood pressure in obese patients (BMI > 30 kg/m(2)) was investigated by multivariate regression analysis. RESULTS: Out of 3657 patients 3017 patients fulfilled inclusion criteria. In the whole cohort a significant increase of SBP, pulse pressure and diagnosis of hypertension was observed across BMI quartiles. By contrast, no significant increase of SBP, pulse pressure or diagnosis of hypertension was observed in the 319 cases with TLR4 SNP rs4986790 across BMI quartiles. These obese cases had significantly lower SBP, lower pulse pressure (7.0 and 7.6 mmHg) and less diagnosis of hypertension as controls. In obesity the TLR4 SNP rs4986790 was an independent predictor of SBP. CONCLUSION: Systolic blood pressure increase with obesity was blunted in cases with TLR4 SNP rs4986790.

Association of Toll-like receptor 4 polymorphism with age-dependent systolic blood pressure increase in patients with coronary artery disease.

BACKGROUND: Systolic blood pressure (SBP) increases steadily with age and bears an independent continuous relationship with the incidence of cardiovascular events. Low-grade inflammation is a suspected pathomechanism causing vascular aging and promote coronary artery disease (CAD). Recent animal studies give evidence that Toll-like receptor 4 (TLR4) modulate inflammation and contribute to age-dependent SBP increase. However, there are no data about TLR4 and age-dependent blood pressure increase in human. METHODS AND RESULTS: We therefor investigate a human cohort of 2679 patients with CAD aged between 50-80 years. Genotypes were determined for the TLR4 single nucleotide polymorphism rs4986790 (TLR4 896A/G). Patients were stratified according to tertiles of age and the upper tertile was compared to lower tertiles. In this cohort we show that older patients with the TLR4 896 G allele had significantly lower SBP (TLR4 G allele carriers: 148.2 ± 30.4 mmHg versus A/A allele carrier: 154.9 ± 27.2 mmHg; P < 0.05) and lower pulse pressure (TLR4 G allele carriers: 69.1 ± 29.7 mmHg versus A/A allele carrier: 75.5 ± 26.4 mmHg; P < 0.05) as compared to TLR4 896A/A allele carrier. CONCLUSION: We demonstrate an association between the TLR4 SNP rs4986790 genotype and age-dependant blood pressure increase in patients with coronary artery disease.

Communication: separable potential energy surfaces from multiplicative artificial neural networks.

We present a potential energy surface fitting scheme based on multiplicative artificial neural networks. It has the sum of products form required for efficient computation of the dynamics of multidimensional quantum systems with the multi configuration time dependent Hartree method. Moreover, it results in analytic potential energy matrix elements when combined with quantum dynamics methods using Gaussian basis functions, eliminating the need for a local harmonic approximation. Scaling behavior with respect to the complexity of the potential as well as the requested accuracy is discussed.

Genetic risk of restenosis after percutaneous coronary interventions in the era of drug-eluting stents.

OBJECTIVES: Our previous studies identified three single nucleotide polymorphisms (SNPs), rs419598 in the interleukin-1 receptor antagonist gene (IL1RN), rs235326 in the CD18 gene (ITGB2), and rs5918 in the platelet glycoprotein IIIa gene (ITGB3), as risk factors for restenosis after placement of bare metal stents in coronary arteries. The aim of the present study was to determine whether these SNPs remain risk factors after drug-eluting stent implantation. PATIENTS AND METHODS: The study population included 2028 patients, who underwent drug-eluting stent implantation. The primary study endpoint was angiographic restenosis (diameter stenosis≥50% at the 6-month follow-up angiography) and clinical restenosis (target lesion revascularization at the 3-year follow-up). RESULTS: Angiographic restenosis was observed in 12.8% of the patients with genotype T/T, 14.6% with genotype T/C, and 13.0% with genotype C/C of IL1RN (P=0.60), in 13.1% of the patients with genotype C/C, 13.2% with genotype C/T, and 16.1% with genotype T/T of ITGB2 (P=0.53), and in 13.2% of the patients with genotype T/T, 14.8% with genotype T/C, and 9.6% with genotype C/C of ITGB3 (P=0.50). Clinical restenosis was present in 11.8% of the patients with genotype T/T, 12.5% with genotype T/C, and 9.9% with genotype C/C of IL1RN (P=0.63), in 13.3% of the patients with genotype C/C, 10.0% with genotype C/T, and 13.9% with genotype T/T of ITGB2 (P=0.07), and in 11.9% of the patients with genotype T/T, 12.1% with genotype T/C, and 10.2% with genotype C/C of ITGB3 (P=0.91). CONCLUSION: The SNPs rs419598 in IL1RN, rs235326 in ITGB2, and rs5918 in ITGB3, which have shown an association with restenosis after implantation of bare metal stents, were not related to restenosis after placement of drug-eluting stents.

Loss-of-function mutations in APOC3, triglycerides, and coronary disease.

BACKGROUND: Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. METHODS: We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. RESULTS: An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)). CONCLUSIONS: Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).

Pathway analysis using genome-wide association study data for coronary restenosis--a potential role for the PARVB gene.

BACKGROUND: Coronary restenosis after percutaneous coronary intervention (PCI) still remains a significant limitation of the procedure. The causative mechanisms of restenosis have not yet been fully identified. The goal of the current study was to perform gene-set analysis of biological pathways related to inflammation, proliferation, vascular function and transcriptional regulation on coronary restenosis to identify novel genes and pathways related to this condition. METHODS: The GENetic DEterminants of Restenosis (GENDER) databank contains genotypic data of 556,099SNPs of 295 cases with restenosis and 571 matched controls. Fifty-four pathways, related to known restenosis-related processes, were selected. Gene-set analysis was performed using PLINK, GRASS and ALIGATOR software. Pathways with a p<0.01 were fine-mapped and significantly associated SNPs were analyzed in an independent replication cohort. RESULTS: Six pathways (cell-extracellular matrix (ECM) interactions pathway, IL2 signaling pathway, IL6 signaling pathway, platelet derived growth factor pathway, vitamin D receptor pathway and the mitochondria pathway) were significantly associated in one or two of the software packages. Two SNPs in the cell-ECM interactions pathway were replicated in an independent restenosis cohort. No replication was obtained for the other pathways. CONCLUSION: With these results we demonstrate a potential role of the cell-ECM interactions pathway in the development of coronary restenosis. These findings contribute to the increasing knowledge of the genetic etiology of restenosis formation and could serve as a hypothesis-generating effort for further functional studies.

Basis expansion leaping: a new method to solve the time-dependent Schrödinger equation for molecular quantum dynamics.

A wide variety of molecular systems that have recently come into the reach of experimental and theoretical investigation is dominated by quantum phenomena. However, even state of the art quantum propagation techniques are either unsuitable for general application to molecular systems with strong interference and tunneling characteristics or are computationally prohibitive for systems with more than a few degrees of freedom. In this Letter, we introduce a novel quantum propagation technique with wide applicability, controllable accuracy, and efficient utilization of computational resources. Its performance is validated for tunneling and dissociating systems with 1, 2, and 3 degrees of freedom, and the scaling behavior with respect to system dimensionality and requested accuracy is discussed.

Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis.

OBJECTIVES: This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD. BACKGROUND: Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability. METHODS: We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects. RESULTS: We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele. CONCLUSIONS: The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

Assessment of the 9p21.3 locus in severity of coronary artery disease in the presence and absence of type 2 diabetes.

BACKGROUND: The 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D). We investigated the association of 9p21.3 variants with severity of CAD (defined by the number of vessel diseased [VD]) in the presence and absence of T2D. METHODS: We tested 11 9p21.3-variants for association in a white Italian study (N = 2,908), and carried out replication in 2 independent white populations, a German study (N = 2,028) and a Canadian Study (N=950). SNP association and permutation analyses were conducted. RESULTS: We identified two 9p21.3-variants, rs4977574 (P < 4×10(-4)) and rs2383207 (P < 1.5×10(-3)) that were associated with severity of CAD in subjects without T2D. Association of rs4977574 with severity of CAD was confirmed in the Canadian Study. Results from subgroup analysis among patients with T2D showed an interaction between rs10738610 and T2D with P = 4.82×10(-2). Further investigation showed that rs10738610 (P < 1.99×10(-2)) was found to be significantly associated with severity of CAD in subjects with T2D. CONCLUSIONS: The 9p21.3 locus is significantly associated with severity of CAD. The number of associations of 9p21.3 variants with severity of CAD is variable to the presence and absence of T2D. In a CAD-susceptible region of 115 kb, there is only one variant associated with the severity of coronary vessel disease in the presence of type 2 diabetes.

Two rare variants explain association with acute myocardial infarction in an extended genomic region including the apolipoprotein(A) gene.

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.

No association of ABCB1 C3435T genotype with clopidogrel response or risk of stent thrombosis in patients undergoing coronary stenting.

BACKGROUND: The prodrug clopidogrel requires intestinal absorption by the efflux pump P-glycoprotein MDR1 (multidrug resistant-1), encoded by the ABCB1 gene. Prior studies suggested that a common and functional genetic variant (C3435T, rs1045642) within ABCB1 influences clopidogrel treatment efficacy; however, existing data are highly inconsistent, because other studies failed to replicate this postulated association. Thus, the aim of this study was to assess the association of ABCB1 C3435T genotypes with the antiplatelet efficacy of clopidogrel and the risk of stent thrombosis (ST) in large cohorts of clopidogrel-treated patients undergoing percutaneous coronary intervention. METHODS AND RESULTS: DNA samples from 1524 clopidogrel-treated patients undergoing percutaneous coronary intervention were genotyped for ABCB1 C3435T, and ADP-induced platelet aggregation was assessed in whole blood on a Multiplate analyzer. The clinical impact of the genetic variant was investigated by comparison of genotype frequencies in a registry of 66 cases with definite drug-eluting stent ST versus an ST-free control cohort (n=1408). Platelet aggregation values were similar across ABCB1 C3435T genotypes (P=0.73). No significant influence of ABCB1 C3435T genotypes on the occurrence of ST was found when ST case subjects were compared with control subjects (P=0.89). CONCLUSIONS: ABCB1 C3435T genotypes did not influence the antiplatelet response to clopidogrel or the risk of ST in clopidogrel-treated patients undergoing percutaneous coronary intervention. Routine genotyping of ABCB1 C3435T polymorphisms should not be recommended for risk stratification in clopidogrel-treated patients undergoing percutaneous coronary intervention who are similar to those evaluated in the present study.

Interleukin 18 gene variation and risk of acute myocardial infarction.

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.

A genome-wide association study identifies a region at chromosome 12 as a potential susceptibility locus for restenosis after percutaneous coronary intervention.

Percutaneous coronary intervention (PCI) has become an effective therapy to treat obstructive coronary artery diseases (CAD). However, one of the major drawbacks of PCI is the occurrence of restenosis in 5-25% of all initially treated patients. Restenosis is defined as the re-narrowing of the lumen of the blood vessel, resulting in renewed symptoms and the need for repeated intervention. To identify genetic variants that are associated with restenosis, a genome-wide association study (GWAS) was conducted in 295 patients who developed restenosis (cases) and 571 who did not (controls) from the GENetic Determinants of Restenosis (GENDER) study. Analysis of ~550 000 single nucleotide polymorphisms (SNPs) in GENDER was followed by a replication phase in three independent case-control populations (533 cases and 3067 controls). A potential susceptibility locus for restenosis at chromosome 12, including rs10861032 (P(combined) = 1.11 × 10(-7)) and rs9804922 (P(combined) = 1.45 × 10(-6)), was identified in the GWAS and replication phase. In addition, both SNPs were also associated with coronary events (rs10861032, P(additive) = 0.005; rs9804922, P(additive) = 0.023) in a trial based cohort set of elderly patients with (enhanced risk of) CAD (PROSPER) and all-cause mortality in PROSPER (rs10861032, P(additive) = 0.007; rs9804922, P(additive) = 0.013) and GENDER (rs10861032, P(additive) = 0.005; rs9804922, P(additive) = 0.023). Further analysis suggests that this locus could be involved in regulatory functions.

No association of paraoxonase-1 Q192R genotypes with platelet response to clopidogrel and risk of stent thrombosis after coronary stenting.

AIMS: In clopidogrel-treated patients undergoing coronary stenting, high on-treatment platelet reactivity was linked to a higher risk of stent thrombosis (ST). Platelet response to clopidogrel is significantly influenced by genetic factors. Recently published findings showed a highly significant impact of a common polymorphism (Q192R) within the paraoxonase-1 (PON1) gene on clopidogrel treatment efficacy but no influence of the CYP2C19*2 genetic variant as previously demonstrated. The aim of this study was to assess the impact of the PON1 Q192R genotype in parallel to that of CYP2C19*2 on the antiplatelet effect of clopidogrel and the risk of ST in clopidogrel-treated patients. METHODS AND RESULTS: In 1524 patients undergoing percutaneous coronary intervention, ADP-induced platelet aggregation was assessed in relation to PON1 Q192R and CYP2C19*2 genotypes. The clinical impact of genetic variants was investigated by comparing genotype frequencies of both genetic variants in a registry of 127 cases with early ST vs. an early ST-free control cohort (n = 1439). For PON1 Q192R genotypes, platelet aggregation values were similar across all genotype groups (P = 0.65). For CYP2C19*2 genotypes, significantly higher aggregation values were found in CYP2C19 wt/*2 and *2/*2 patients when compared with wt/wt allele carriers (P < 0.0001). Comparing genotype frequencies between ST cases and controls, no differences were observed for PON1 Q192R genotype distributions (P = 0.23), whereas the genotype distribution differed for CYP2C19*2 genotypes (P = 0.019). CONCLUSION: The PON1 Q192R genotype did not influence platelet response to clopidogrel or the risk of ST in clopidogrel-treated patients, whereas the CYP2C19*2 genotype impacted on both antiplatelet effect of clopidogrel and risk of coronary ST.

The chromosome 9p21 region and myocardial infarction in a European population.

OBJECTIVE: Sequence variation at Ch9p21 is a predisposing genetic factor for a number of diseases, including myocardial infarction (MI) and diabetes. We determined the risk of MI associated with various alleles and haplotypes, established and compared the predictive values of risk alleles, tested for the independence of associations between different risk alleles and MI, and sought to provide evidence for dual association of alleles with MI and diabetes. METHODS: With the use of 35 single nucleotide polymorphisms, together capturing common variation seen in the associated interval, we genotyped 3657 MI cases and 1211 controls prospectively sampled in a European population. RESULTS: Polymorphisms rs10757278 and rs1333049 both exhibited the strongest individual risk signal (OR, 1.45; 95% CI, 1.32-1.59). Two haplotype blocks were established, each of which was mainly represented by a pair of a risk-conferring and a protective haplotype, but none of the risk-associated haplotypes exhibited stronger effects than rs10757278 or rs1333049 alone. Specific polymorphisms (rs7865618, rs1537378, rs7857345, rs1333049) were identified as independent predictors of MI in multivariable models adjusted for conventional cardiovascular risk factors. In specific instances, the presence of two or three polymorphisms in a model, instead of only one, improved the discriminating power. Finally, evidence was provided to suggest dual association of rs7865618 with MI and diabetes. CONCLUSION: In keeping with published results, this work was consistent with the association of alleles and haplotypes at Ch9p21 with MI and extended prior knowledge by also showing independence of associations among different risk alleles and an association of a specific polymorphism with both MI and diabetes.

Extended evidence for association between the melanoma inhibitory activity 3 gene and myocardial infarction.

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.