Specific haplotypes of the P-selectin gene are associated with myocardial infarction

P-selectin is a cellular adhesion molecule that may be involved in the development of atherosclerosis and its complications. We have previously identified thirteen polymorphisms of the P-selectin gene among which five were located in the coding region of the gene (S290N, N562D, V599L, T715P, T741T (A/G)). These polymorphisms were tested individually for association with myocardial infarction (MI) and only the T715P polymorphism was shown to be associated with MI. We here extend this work by performing a haplotype analysis which enables us to assess the consequences on the phenotype of the co-presence of several variants on the same chromosome. For this purpose, a new maximum likelihood method was developed for estimating simultaneously haplotype frequencies and haplotype-phenotype effects. While haplotypes defined by the polymorphisms located in the promoter region of the gene were unrelated to MI, those defined by the polymorphisms in the coding region were globally associated with MI in a sample of 582 cases and 630 controls from the Etude Cas-Témoin sur l'Infarctus du Myocarde. Detailed haplotype analysis confirmed the protective effect of the P715 allele but additionally revealed that the presence of two asparagine codons at sites S290N and N562D was associated with a higher risk of MI, consistenly in France and Northern Ireland, but only when they were carried by the same haplotype. This finding illustrates the complexity of the relationship between gene variability and disease and the necessity to explore in detail the polymorphisms of candidate genes.     

PARKIN-coding polymorphisms are not associated with Parkinson's disease in a population from northeastern Mexico

Early- and late-onset Parkinson's disease (EOPD and LOPD) have been associated with mutations in the PARKIN gene. Several studies have reported association of Parkinson's disease (PD) with different polymorphisms in different ethnic populations. To study the role of PARKIN polymorphisms as risk factors for PD in a genetically homogeneous northeastern Mexican population, four previously described coding polymorphisms (Ser167Asn, Val380Leu, Arg366Trp, and Asp394Asn) were analyzed by using the PCR-RFLP technique. This case–control study comprised 117 unrelated patients (mean age 59 ± 12 years, range 25–83 years) and 122 healthy unrelated control subjects (mean age 50 ± 15 years, range 25–85 years). The homozygous Trp366 and Asn394 genotypes were not present in our study. The Ser167Asn and Val380Leu polymorphisms were not associated with this disease. For the control group, Ser167Asn and Val380Leu were in Hardy–Weinberg disequilibrium. Given that the main causes of Hardy–Weinberg disequilibrium in controls are selection bias or genotyping error, a competing risk of death associated with the mutant gene could be an explanation of this disequilibrium and lack of association.     

Association of single nucleotide polymorphisms in the eosinophil peroxidase gene with Japanese cedar pollinosis

BACKGROUND: Japanese cedar pollinosis is the most common form of hay fever in spring in Japan. We have previously demonstrated that single nucleotide polymorphism Pro358Leu of exon 7 in the eosinophil peroxidase (EPO) gene is associated with cedar pollinosis, although the association has not been confirmed by analysis of the whole gene in a different population. METHODS: We sequenced all exons of the EPO gene in 60 children with pollinosis and their parents using the PCR-restriction fragment length polymorphism method. RESULTS: We found 8 polymorphisms, Ile40Met, Gln122His, Arg202Arg (A660G), Asn303Asn (C909T), Arg326Pro, Arg326His, Pro358Leu, and Asn572Ty, in the EPO gene. As a result of the transmission disequilibrium test, we recognized significant transmissions of 202Arg (660G) in exon 6 in addition to 358Leu of exon 7 in the EPO gene of affected children. CONCLUSIONS: Our results might indicate that polymorphisms of the EPO gene are associated with Japanese cedar pollinosis.     

中国人WD基因第14和18号外显子的错义突变

目的了解中国人肝豆状核变性（Ｗｉｌｓｏｎ＇ｓｄｉｓｅａｓｅ,ＷＤ）基因第１４和１８号外显子的突变情况,与国外报道的这两个外显子的高突变频率进行比较。方法应用聚合酶链反应－单链构像多态（ＰＣＲ－ＳＳＣＰ）结合ＤＮＡ测序技术,对４４例无亲缘关系的ＷＤ患者及６０例正常对照进行突变检测。结果一例患者在１４号外显子发生了Ａｒｇ１０４１Ｐｒｏ（３１２１Ｇ→Ｃ）纯合错义突变,另一例患者在１８号外显子发生了Ａｓｎ１２７０Ｓｅｒ（３８０９Ａ→Ｇ）杂合错义突变。结论Ａｒｇ１０４１Ｐｒｏ为未报道过的新型错义突变,Ａｓｎ１２７０Ｓｅｒ突变与国外报道一致。但均未呈热区分布。     

Polymorphisms in thrombospondin genes and myocardial infarction: a case-control study and a meta-analysis of available evidence

A role of thrombospondins (TSPs) in atherosclerosis and thrombosis was suggested by associations of single nucleotide polymorphisms in the genes coding for TSP-1 (rs2228262; Asn700Ser), TSP-2 (rs8089; 3' untranslated region), and TSP-4 (rs1866389; Ala387Pro) with myocardial infarction (MI). However, these findings were not consistently confirmed in replication studies. We determined the genotypes related to these polymorphisms in a large case-control sample of MI and performed a meta-analysis of data obtained in the present sample and available from prior studies that included Europeans or Americans of European origin. In the population examined here, the carriers of the minor allele of the polymorphism in the TSP-2 gene (GG and TG genotypes) had a mildly statistically significant higher risk of MI than the homozygous carriers of the major allele (TT genotype) [adjusted odds ratio (OR) 1.19; 95% confidence interval (CI), 1.02 to 1.39]. In similar comparisons, no associations of the polymorphisms in the TSP-1 (adjusted OR 1.12; 95% CI, 0.93 to 1.35) and TSP-4 (adjusted OR 0.99; 95% CI, 0.85 to 1.16) genes with MI were observed. The meta-analysis included 6388 (TSP-1), 4930 (TSP-2), and 6978 (TSP-4) cases. None of the polymorphisms was found to be linked with the risk of MI. Thus, despite associations in certain individual studies, the synthesis of available evidence did not suggest that the TSP polymorphisms included in this study were associated with MI.     

Functional analysis of four naturally occurring variants of human constitutive androstane receptor

The human constitutive androstane receptor (CAR, NR1I3) is a member of the orphan nuclear receptor superfamily that plays an important role in the control of drug metabolism and disposition. In this study, we sequenced all the coding exons of the NR1I3 gene for 334 Japanese subjects. We identified three novel single nucleotide polymorphisms (SNPs) that induce non-synonymous alterations of amino acids (His246Arg, Leu308Pro, and Asn323Ser) residing in the ligand-binding domain of CAR, in addition to the Val133Gly variant, which was another CAR variant identified in our previous study. We performed functional analysis of these four naturally occurring CAR variants in COS-7 cells using a CYP3A4 promoter/enhancer reporter gene that includes the CAR responsive elements. The His246Arg variant caused marked reductions in both transactivation of the reporter gene and in the response to 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO), which is a human CAR-specific agonist. The transactivation ability of the Leu308Pro variant was also significantly decreased, but its responsiveness to CITCO was not abrogated. The transactivation ability and CITCO response of the Val133Gly and Asn323Ser variants did not change as compared to the wild-type CAR. These data suggest that the His246Arg and Leu308Pro variants, especially His246Arg, may influence the expression of drug-metabolizing enzymes and transporters that are transactivated by CAR.     

Genomic structure and eight novel exonic polymorphisms of the human N-cadherin gene

 Analysis of the detailed genomic structure of human N-cadherin revealed that the 16-exon gene is more than 72 kb in length and that it consists of a mosaic of exons. Five repeated cadherin domains, a transmembrane domain, and a cytoplasmic domain are encoded by exons 4 to 13, 13 and 14, and 14 to 16, respectively. A search for molecular variants in the entire coding region in 96 Japanese individuals resulted in the identification of eight sequence polymorphisms including three CCT- or GCC-type trinucleotide repeat polymorphisms adjacent to the initiation codon and five other novel single-nucleoticle polymorphisms (SNPs) in the coding region. Three of the five SNPs accompanied an amino acid substitution: Ala118Thr, Ala826Thr, and Asn845Ser. Knowlege of the fine gene structure and eight novel polymorphisms will be useful for the genetic study of the role of N-cadherin in diseases involving cell adhesion in the brain and in cardiomyocytes. Received: January 23, 2002 / Accepted: March 12, 2002     

Structure and analysis of the human dimethylglycine dehydrogenase gene

Dimethylglycine dehydrogenase (DMGDH; E.C. 1.5.99.2) is an enzyme involved in the catabolism of choline, catalyzing the oxidative demethylation of dimethylglycine (DMG) to form sarcosine. Subsequently, sarcosine dehydrogenase (SDH; E.C. 1.5.99.1) converts sarcosine to glycine via a similar reaction. Both enzymes are found as monomers in the mitochondrial matrix, and both contain 1 mol of covalently bound flavin adenine dinucleotide. DMGDH and SDH also utilize a noncovalently bound folate coenzyme that receives the "1-carbon" groups that are removed by DMGDH and SDH, forming "active formaldehyde." We have recently described a new inborn error of metabolism of DMGDH characterized by an unusual fish-like body odor. To augment our study of this new disorder, we have isolated two human genomic clones that together contain 16 exons of coding sequence for the hDMGDH gene. Fluorescent in situ hybridization analysis of the hDMGDH gene indicates that it is found on chromosome 5q12.2-q12.3. In addition, several polymorphisms have been identified in the hDMGDH cDNA sequence. Population analysis of two Ser/Pro polymorphisms found 367 amino acids apart reveals a skew of alleles, with the haplotypes Ser/Pro or Pro/Ser (79%) overrepresented compared to the number of Ser/Ser or Pro/Pro alleles observed. Possible functional consequences of these findings are discussed. Characterization of the gene structure for hDMGDH will aid in the study of patients with inherited defects of this enzyme.     

Mismatch repair analysis of inherited MSH2 and/or MSH6 variation pairs found in cancer patients

Mismatch repair (MMR) malfunction causes the accumulation of mismatches in the genome leading to genomic instability and cancer. The inactivation of an MMR gene (MSH2, MSH6, MLH1, or PMS2) with an inherited mutation causes Lynch syndrome (LS), a dominant susceptibility to cancer. MMR gene variants of uncertain significance (VUS) may be pathogenic mutations, which cause LS, may result in moderately increased cancer risks, or may be harmless polymorphisms. Our study suggests that an inherited MMR VUS individually assessed as proficient may, however, in a pair with another MMR VUS found in the same colorectal cancer (CRC) patient have a concomitant contribution to the MMR deficiency. Here, eight pairs of MMR gene variants found in cancer patients were functionally analyzed in an in vitro MMR assay. Although the other pairs do not suggest a compound deficiency, the MSH2 VUS pair c.380A>G/c.982G>C (p.Asn127Ser/p.Ala328Pro), which nearly halves the repair capability of the wild-type MSH2 protein, is presumed to increase the cancer risk considerably. Moreover, two MSH6 variants, c.1304T>C (p.Leu435Pro) and c.1754T>C (p.Leu585Pro), were shown to be MMR deficient. The role of one of the most frequently reported MMR gene VUS, MSH2 c.380A>G (p.Asn127Ser), is especially interesting because its concomitant defect with another variant could finally explain its recurrent occurrence in CRC patients.     

GIGYF2 Asn56Ser and Asn457Thr mutations in Parkinson disease patients

Parkinson disease (PD) is one of the most common neurodegenerative disorders with major clinical features of bradykinesia, rigidity, resting tremor, and postural instability. At least thirteen gene loci responsible for PD or parkinsonism have been found and nine causative genes have been identified. Recently, Asn56Ser or Asn457Thr mutations in the Grb10-Interacting GYF Protein-2 gene (GIGYF2) were found to occur in about 2.4% familial PD Italian and French patients. We conducted genetic examination of Asn56Ser or Asn457Thr mutations, but none was found in 310 PD patients from North America. We did identify a non-disease-associated polymorphism Pro460Thr. Our results suggest that the GIGYF2 Asn56Ser and Asn457Thr mutations are a rare cause of PD in North American Caucasian population.     

DNA base excision repair gene polymorphisms modulate human cognitive performance and decline during normal life span

To test the hypothesis that single nucleotide polymorphisms (SNPs) in DNA repair genes are associated with cognitive performance during normal aging, the relationship between SNPs in selected exons in DNA base excision repair (BER) genes and cognitive performance was examined in 712 healthy Norwegian individuals aged 20-75 years. SNPs examined included PolB(Pro242Arg), hOGG1(Ser326Cys), MutYH (Met22Val), MutYH(His324Gln), APE1(Gln51His), APE1(Glu148Asp), XRCC1(Lys298Asn), XRCC1(Arg7Leu), NEIL1(Asp252Asn), and NEIL2(Arg257Leu). XRCC1(Arg7Leu) and PolB(Pro242Arg) were characterized by single nucleotide variations (≤0.1% homozygote SNPs). hOGG1(Ser326Cys) (Ser/Cys 40.8%/Cys/Cys 5.7%), MutYH(His324Gln) (His/Gln37%/Gln/Gln 6.0%) and APE1(Glu148Asp) (Glu/Asp 51.3%/Asp/Asp 23.0%) were characterized by higher SNP frequencies. MutYH(Met22Val), APE1(Gln51His) and NEIL2(Arg257Leu) occurred at intermediate SNP frequencies of 11.5, 7.6 and 5.3%, respectively. Interestingly, hOGG1(Ser326Cys) and APE1(Gln51His) had genotype by age interactions with general cognitive function, reasoning, control and speed of processing in cross-sectional analysis and a significant effect on longitudinal decline. Dispersed association effects involving MutYH(His324Gln), MutYH(Met22Val), PolB(Pro242Arg) and NEIL2(Arg257Leu) were also detected when APOE or CHRNA4, were included in the statistical model, a result consistent with proposed involvement of the latter markers in human cognitive decline and/or function. In summary, the results support the notion that polymorphisms in BER genes modulate cognitive performance in healthy elderly individuals.     

Lack of association between complement factor H polymorphisms and coronary artery disease or myocardial infarction

Complement factor H (CFH) plays a critical role in the protection of host cells and tissues from damage by complement activation and has been suggested to protect against the progression of atherosclerosis. A polymorphism in the CFH gene, Y402H, known to be strongly associated with age-related macular degeneration, has been analyzed in relation to coronary artery disease (CAD) in several studies with conflicting results. We investigated the association of polymorphisms of the CFH gene in two large-scale studies on CAD and myocardial infarction (MI). The AtheroGene Study included a cohort of cases with CAD (n = 1,303) prospectively followed for a median period of 6.2 years, among whom198 experienced a cardiovascular event, and a group of 483 control subjects. The AtheroGene Study population was genotyped for the Y402H, I62V, and E936D polymorphisms. There was no significant difference in genotypic or allelic frequencies between CAD cases and controls. Among cases, no significant association was found with prospective cardiovascular outcome. Many inflammatory proteins, including the C-reactive protein, were measured, and none of the polymorphisms showed an association with these markers. The Etude Cas-Témoin de l'Infarctus du Myocarde (ECTIM) Study compared 1,034 patients with MI and 1,039 controls from France and United Kingdom. The ECTIM Study population was genotyped for the Y402H polymorphism. Genotype and allele frequencies were similar in cases and controls. These results do not support an involvement of common nonsynonymous polymorphisms of the CFH gene in predisposition to CAD and its complications.     

Polymorphism R92Q of the tumour necrosis factor receptor 1 gene is associated with myocardial infarction and carotid intima-media thickness--the ECTIM, AXA, EVA and GENIC Studies

The TNFRSF1A gene was screened for polymorphisms in 95 subjects with premature myocardial infarction (MI), who also had one parent who had an MI. A total of 10 polymorphisms were found: three in the promoter region, two in exons and five in introns. All polymorphisms were genotyped in ECTIM, a case-control study of MI (1815 subjects). The nonsynonymous 92Q allele was found in 1.8, 1.0 and 1.7% of controls from Strasbourg, Belfast and Glasgow - respectively; in cases: 4.2, 2.2 and 3.2%. The population-adjusted odds ratio (OR) for MI associated with allele Q carrying was 2.15 (95% CI: 1.09-4.23). To check its possible implication in atherosclerosis, this polymorphism was then genotyped in the AXA Study (ultrasound examinations of carotid and femoral arteries in the context of an employment medical examination, 733 subjects), the EVA Study (ultrasound examinations of carotid arteries in a study of cognitive and vascular ageing, 1092 subjects) and the GENIC Study (on brain infarction (BI), 912 subjects). In the AXA Study, among smokers, carrying the 92Q allele was positively associated with the presence of a carotid plaque (OR 5.07; 95% CI: 1.64-15.63) and with a thickening of the carotid intima-media thickness (IMT) (0.59 (0.11) vs 0.54 (0.11), P=0.045). In the EVA Study, carriers of allele 92Q had an increased mean carotid IMT (0.70 (0.09) vs 0.67 (0.13), P=0.02). No significant association of the 92Q allele was found with BI in the GENIC Study. Overall, these results may suggest that carriers of the 92Q allele may be at increased risk of atherosclerosis.     

Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population

Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.3%. The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function.      

Assessment of French patients with LPL deficiency for French Canadian mutations.

Mutations in the LPL gene show high levels of allelic heterogeneity between and within different populations. Complete LPL deficiency has a very high prevalence in French Canadians, where only three missense mutations account for > 97% of cases, most consistent with founder mutations introduced early in Quebec by French immigrants. In order to determine whether these mutations were present in France, 12 unrelated French families with defined LPL deficiency were investigated for the presence of the mutations found in French Canadians. Of the 24 expected alleles, six (25%) represented mutations in French Canadians (Gly188Glu four alleles, Asp250Asn and Pro207Leu one allele each). Comparison of French Canadian and French alleles identified the same haplotype in all carriers of the Gly188Glu and of the Asp250Asn, suggesting a common origin. In contrast, the Pro207Leu occurred on different haplotypes in France and Quebec, compatible with a different ancestral origin.     

Polymorphisms in the coding exons of the human luteinizing hormone receptor gene. Mutations in brief no. 124. Online

Four polymorphisms were identified in the coding exons of the human luteinizing hormone/chorionic gonadotropin receptor (hLHR) gene. A CTGCAG insertion occurred after nucleotide 54 in 8 of 34 independent chromosomes examined. The heterozygosity frequency was 0.353. This Leu-Gln dipeptide insertion in the first Leucine repeat of the hLHR extracellular domain did not affect the ligand binding affinity of the receptor. Among the 54 chromosomes analyzed, 64.8% was A and 35.2% was G at nucleotide 872 in exon 10. The heterozygosity frequency was 0.115. The A/G substitution led to the replacement of Asn by Ser in the G allele and the abolition of a potential N-glycosylation site. Another polymorphism occurred at nucleotide 935. Fifty nine percent of chromosomes examined were A and 41% were G at this site with the encoded amino acid being Ser in the former and Asn in the latter. The heterozygosity frequency was 0.192. This polymorphism did not have biological consequence. Both of the exon 10 polymorphisms showed ethnic prevalence with the 872 G allele and 935 A allele predominantly in non-Caucasians. The fourth polymorphism was neutral and occurred at nucleotide 1065 in exon 11, with C in 60% and T in 40% of the 50 chromosomes examined. These polymorphisms are useful for tracking the inheritance of specific hLHR allele.     

Significant impact of the highly informative (CA)n repeat polymorphism of the APOA‐II gene on the plasma APOA‐II concentrations and HDL subfractions: The ECTIM study

High density lipoproteins (HDL) are heterogeneous in their apolipoprotein composition and the role of apolipoprotein A‐II (APOA‐II) in HDL structure and metabolism is poorly understood. Yet, studies of naturally occurring variations of APOA‐II in mice and experiments in transgenic mice overexpressing the APOA‐II gene (APOA‐II) have shown that APOA‐II expression influences APOA‐II plasma levels and HDL size and composition. In humans, two RFLPs (BstNI and MspI) have been described in the APOA‐II gene. These RFLPs, however, have been inconstantly associated with variations in APOA‐II plasma levels. In particular, the large multicentric ECTIM Study did not show any significant effect of the two RFLPs. Other polymorphisms consisting of repetitive sequences have been proposed as more informative markers than RFLPs. Thus, data from the ECTIM Study were reconsidered by integrating the additional information obtained from a highly informative multiallelic (CA)_n‐repeat polymorphism located in the second intron of the gene. The population study was composed of 763 non‐treated male controls and 594 cases of myocardial infarction. In controls, the (CA)₁₉ allele was associated with significantly decreased APOA‐II (P < 0.0009) and LpA‐II:A‐I (P < 0.02) plasma levels. Although the APOA‐I plasma levels were not affected by the polymorphism, the (CA)₁₉ allele was associated with an increased LpA‐I/LpA‐II:A‐I ratio (P < 0.004). No effect, however, could be detected on myocardial infarction. Study of the linkage disequilibrium and the estimation of haplotype frequencies indicated that the impact of the APOA‐II locus could hardly be detected by using the BstNI and MspI RFLPs. These data revive interest in evaluating the role of the APOA‐II locus in the control of APOA‐II plasma levels and HDL composition. © 2002 Wiley‐Liss, Inc.     

Allelic variation in the NPY gene in 14 Indian populations

NPY is a 36-aminoacid peptide expressed in several areas of the nervous system. Neuropeptide Y (NPY) receptors represent a widely diffused system that is involved in the regulation of multiple biological functions. The human NPY gene is located in chromosome 7. The functional significance of coding Leu7Pro polymorphism in the signal peptide of preproNPY is known. Six hundred and fifty four individuals of 14 ethnic Indian populations were screened for three mutations in the NPY gene, including Leu7Pro. We found that the Pro7 frequencies among the studied populations were much higher than in previous studies from other parts of the world. The highest allele frequency of Pro7 was detected in the Kota population in the Nilgiri Hill region of south India, and this may reflect a founder event in the past or genetic drift. All populations followed the Hardy–Weinberg equilibrium for the assayed markers. A total of five haplotypes were observed, only two of which were found to occur with a high frequency in all populations. No linkage disequilibrium (LD) was observed across the tested alleles in any population with the exception of Leu7Pro and Ser50Ser in the Badaga population (χ ² = 13.969; p = 0.0001).     

Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study

Apolipoprotein E (APOE) is a major protein in lipid metabolism existing in three common isoforms: APOE2, -3 and -4. The varepsilon4 allele of the APOE gene ( APOE ) coding for the APOE4 isoform is associated with an increased risk of myocardial infarction (MI) and of Alzheimer's disease (AD). Recently, several polymorphisms in the APOE regulatory region have been reported. Some of these have been associated with AD and modified APOE allelic mRNA expression in AD brains. Here, we have investigated whether three of these promoter polymorphisms (-491AT, -427CT and -219GT) can also modify cardiovascular risk. The hypothesis was tested in a large multicentre case-control study of MI, the ECTIM Study, on 567 cases and 678 controls. Among the three APOE promoter polymorphisms tested, only the-219T allele was associated with a significantly increased risk of MI (OR = 1.29, 95% CI: 1.09-1.52, P < 0.003) and the effect was shown to be independent of the presence of the other mutations, including the APOE epsilon2/epsilon3/epsilon4 polymorphism. Moreover, the-219T allele greatly decreased the APOE plasma concentrations in a dose-dependent manner ( P < 0.008). These data indicate that the-219GT polymorphism of the APOE regulatory region emerges as a new genetic susceptibility risk factor for MI and constitutes another common risk factor for both neurodegenerative and cardiovascular diseases.