Association of lipoprotein lipase S447X, apolipoprotein E exon 4, and apoC3 -455T>C polymorphisms on the susceptibility to diabetic nephropathy.

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. In DN patients, triglyceride (TG) level is elevated and lipoprotein lipase (LPL) activity, which hydrolyzes TG, is decreased. The LPL S447X and apolipoprotein E (APOE) exon 4 polymorphisms affect TG levels, and the APOC3 -455T>C polymorphism affects LPL activity. Our aim was to examine the association of these polymorphisms with nephropathy in type 2 diabetes. We examined these polymorphisms in a case-control study of type 2 diabetic patients including 374 with DN and 392 without DN. LPL 447X-containing genotypes (447X+) were significantly decreased in DN patients [18.6 vs 25.6%, odds ratio (OR) = 0.66, p = 0.02], as were APOE epsilon3/epsilon3 genotypes (64.8 vs 73.1%, OR = 0.68, p = 0.01). In addition, combinations of genotypes [APOE epsilon3/epsilon3 and LPL 447X+ (OR = 0.56), APOC3 CC and LPL 447X+ (OR = 0.31), APOE epsilon3/epsilon3 and APOC3 CC (OR = 0.61] were protective for DN compared with the most common combination of the respective polymorphisms. Our findings suggest the importance of interactions among lipid genes in modulating the risk of DN.

Pseudoxanthoma elasticum: evaluation of diagnostic criteria based on molecular data.

BACKGROUND: Pseudoxanthoma elasticum (PXE) is a genetic disorder due to mutations in the gene encoding the transmembrane transporter protein adenosine triphosphate binding cassette (ABC)-C6, resulting in calcification of elastic fibres in the skin, eyes and cardiovascular system. OBJECTIVES: To evaluate the diagnostic criteria for PXE based on molecular data. METHODS: Of 10 families with a positive history of PXE 142 subjects were investigated for clinical symptoms, histological findings and genetic haplotype analysis. RESULTS: Of these, 25 subjects were haplotypic homozygous for PXE and 23 had typical clinical and histopathological manifestations. Two of the 25 patients showed such marked solar elastosis and macular degeneration that PXE could not be confirmed clinically. Sixty-seven subjects were haplotypic heterozygous carriers and 50 were haplotypic homozygous unaffected. Of these 117 subjects, 116 showed no cutaneous or ophthalmological signs of PXE. In one of the 50 haplotypic homozygous unaffected patients important solar elastosis and scarring of the retina mimicked PXE lesions. Only four of the 67 haplotypic heterozygous carriers had biopsies of nonlesional skin; all were histopathologically normal. CONCLUSIONS: In our patients, PXE presents as an autosomal recessive genodermatosis. Correlation of haplotype and phenotype confirmed actual major diagnostic criteria. In patients with marked solar elastosis and/or severe macular degeneration clinical diagnosis can be impossible and molecular testing is needed to confirm the presence of PXE. To the best of our knowledge our large study compares for the first time clinical findings with molecular data.

Multi-locus candidate gene polymorphisms and risk of myocardial infarction: a population-based, prospective genetic analysis.

BACKGROUND: Polymorphisms in candidate genes related to lipid metabolism, thrombosis, hemostasis, cell-matrix adhesion, and inflammation have been suggested clinically useful in risk assessment of cardiovascular disease. METHODS: We evaluated a panel of 92 candidate gene polymorphisms, using a multiplex polymerase chain reaction-immobilized probe assay amongst 523 individuals who subsequently developed myocardial infarction (MI), and amongst 2092 individuals who remained free of reported cardiovascular disease over a mean follow-up period of 13.2 years. RESULTS: Of the 92 polymorphisms tested, three that we previously reported on were associated with risk of MI, [pro12ala in the peroxisome proliferator activated-receptor gamma gene (odds ratio, OR = 0.75, P = 0.02); thr164ile in the beta-2 adrenergic receptor gene (OR = 0.14, P = 0.007); and ala23thr polymorphism in the eotaxin gene (OR = 1.87, P = 0.01)]. However, when adjusted for the other 89 polymorphisms evaluated, these findings were no longer statistically significant. Further, in contrast to reports from other investigators, we found little evidence for association of a C677T polymorphism in the 5,10-methylenetetrahydrofolate reductase gene, the angiotensin-I-converting enzyme 1 insertion/deletion polymorphism, a 4G/5G polymorphism in the serine/cysteine proteinase inhibitor-clade E-member 1 gene, the factor V Leiden mutation, the G20210A factor II mutation, a -455G>A polymorphism in the beta-fibrinogen gene, the cys112arg/arg158cys apolipoprotein E gene polymorphism, a gly460trp polymorphism in the alpha-adducin gene, and a -629C>A polymorphism in the cholesteryl ester transfer protein gene with risk of MI. CONCLUSIONS: After correction for multiple comparisons, the addition of genetic information observed in the present study had little impact on risk prediction models for MI. The present investigation highlights the importance of replication and validation of findings from genetic association studies.

Proteomic analysis of the cerebrospinal fluid of patients with schizophrenia.

We applied proteomics technologies to analyze the cerebrospinal fluid of patients with schizophrenia. Such an analysis can result in the identification of proteins, which may play a role in the disease progress and thus lead to the discovery of clues of the etiology of schizophrenia. Cerebrospinal fluid from patients and controls was analyzed by two-dimensional gels and the proteins were identified by matrix-assisted laser desorption ionization mass spectrometry (MS) in the MS and MS/MS mode. 54 different gene products were identified, which were mainly plasma proteins. The level of apolipoprotein A-IV was significantly decreased in the schizophrenic patients compared to that in the controls. Little is known about the function of this apolipoprotein in the central nervous system. The levels of certain other proteins, like haptoglobin, fibrinogen, complement component 3, and Gc-globulin, were altered in the disease group as well, however, the changes did not reach a statistical significance.

Lipid metabolism and occurrence of post-percutaneous transluminal coronary angioplasty restenosis: role of cholesteryl ester transfer protein and paraoxonase/arylesterase.

Plasma lipid metabolic and transfer processes have recently been suggested to play an important role in the development of early restenosis, a major complication of percutaneous transluminal coronary angioplasty (PTCA); in particular, the common variants of genes for cholesteryl ester transfer protein (CETP) and paraoxonase (PONA) have been implicated. We had the opportunity to investigate this question in a large, prospective cohort characterized by quantitative coronary angiography in all subjects. The CETP-TaqIB (intron 1), CETP-MspI (intron 8), and PONA-AlwI (exon 2) polymorphisms were characterized in a cohort of 779 patients of whom 342 ("cases") had developed restenosis (as defined by > 50% loss of lumen compared with immediate postprocedure results) at repeat angiography at 6 months post PTCA. Selected frequencies for CETP B1 and B2 alleles (absence/presence of TaqIB site) were 0.65 and 0.35 (cases) and 0.65 and 0.35 (controls), respectively; frequencies for CETP M1 and M2 alleles (absence/presence of MspI site) were 0.20 and 0.80 (cases), 0.21 and 0.79 (controls), respectively; frequencies for PONA A and B alleles (absence/presence of AlwI site) were 0.73 and 0.27 (cases), 0.72 and 0.28 (controls), respectively. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for gene-gene interaction, or an association between genotype and restenosis or degree of lumen loss (adjusted for covariates). Our data, collected in the largest study of its kind so far, indicate that the common variants for CETP and PONA are not associated with incidence of restenosis after PTCA, and are therefore not useful markers for risk assessment.

Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms.

Osteoporosis is a common disease characterized by a decrease in bone mass, architectural deterioration of the bone tissue, and an increased risk of fracture. The condition is under strong genetic control, involving a large variety of gene products, but to date the genes responsible remain poorly defined. Although population-based studies have identified polymorphisms in several candidate genes that are associated with bone mineral density (BMD), these account for only a small proportion of the population variance in bone mass. In this study, we looked for evidence of an allelic association between polymorphisms in the SOST gene and BMD. This gene was analyzed because loss-of-function mutations in SOST cause sclerosteosis, a sclerosing bone dysplasia associated with increased bone mass due to increased bone formation. We identified 26 different polymorphisms in the SOST gene and selected 5 of these for association analysis in a case-control study of 619 women with either high or low BMD, drawn from a random population-based survey of 5119 perimenopausal white women. The high BMD group comprised 326 women in whom lumbar spine BMD values adjusted for age, height, and weight were in the highest 16% of the population distribution, and the low BMD group comprised 293 women in whom BMD values were in the lowest 16% of the population distribution. The distribution of genotypes and alleles for each Single Nucleotide Polymorphism (SNP) examined did not differ in the low and high BMD groups. We conclude that, in this population, common allelic variations in the SOST gene do not contribute significantly to the regulation of high or low BMD.

A prospective evaluation of the angiotensin-converting enzyme D/I polymorphism and left ventricular remodeling in the 'Healing and Early Afterload Reducing Therapy' study.

The D/I (deletion, D, insertion, I) polymorphism of the angiotensin-converting enzyme (ACE) gene has been extensively studied for its association with a number of cardiovascular and other disease states. However, its potential association with differential clinical efficacy of ACE inhibitors (ACE-I) administered to patients who had suffered a myocardial infarction (MI), i.e. the prevention of left ventricular (LV) remodeling, has so far not been specifically studied. The aim of the study was to investigate whether the D/I polymorphism of the ACE gene is associated with the incidence of post-MI LV remodeling in patients drawn from the 'Healing and Early Afterload Reducing Therapy' (HEART) Study. The ACE D/I polymorphism was characterized by the polymerase chain reaction (PCR) in 265 subjects from the 'Healing and Early Afterload Reducing Therapy' Study, a double-blind, placebo-controlled trial with the objective of determining whether early or delayed administration of the ACE-I, ramipril, in patients with acute anterior wall MI would be optimal in reducing LV enlargement. Selected frequencies for the ACE D and I alleles were 0.59 and 0.41 (placebo-high dose group), 0.56 and 0.44 (low dose-low dose group), and, 0.60 and 0.40 (high dose-high dose group), respectively. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for an association between genotype and outcome regarding LV size or function, nor with the initial blood pressure response after ACE-I administration (adjusted for covariates). Our data provide no evidence for an association of the ACE D/I polymorphism with the risk of LV remodeling post-MI in the presence of ACE-I therapy, and therefore do not suggest that differential clinical efficacy of ACE-inhibitors is related to this genetic marker.

Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease.

Van Buchem disease is an autosomal recessive skeletal dysplasia characterised by generalised bone overgrowth, predominantly in the skull and mandible. Clinical complications including facial nerve palsy, optic atrophy, and impaired hearing occur in most patients. These features are very similar to those of sclerosteosis and the two conditions are only differentiated by the hand malformations and the tall stature appearing in sclerosteosis. Using an extended Dutch inbred van Buchem family and two inbred sclerosteosis families, we mapped both disease genes to the same region on chromosome 17q12-q21, supporting the hypothesis that van Buchem disease and sclerosteosis are caused by mutations in the same gene. In a previous study, we positionally cloned a novel gene, called SOST, from the linkage interval and identified three different, homozygous mutations in the SOST gene in sclerosteosis patients leading to loss of function of the underlying protein. The present study focuses on the identification of a 52 kb deletion in all patients from the van Buchem family. The deletion, which results from a homologous recombination between Alu sequences, starts approximately 35 kb downstream of the SOST gene. Since no evidence was found for the presence of a gene within the deleted region, we hypothesise that the presence of the deletion leads to a down regulation of the transcription of the SOST gene by a cis regulatory action or a position effect.

Mutation in the promoter region of the beta-fibrinogen gene and the risk of future myocardial infarction, stroke and venous thrombosis.

AIM: Polymorphisms in the promoter region of the beta-fibrinogen gene are associated with increased plasma fibrinogen levels. We investigated whether the distribution of the C148T polymorphism is associated with an increase in cardiovascular risk. METHODS AND RESULTS: In a nested case-control design, the distribution of the C148T polymorphism was investigated among 751 participants in the Physicians' Health Study who subsequently developed myocardial infarction, stroke or venous thromboembolism (cases) and among 751 age- and smoking-matched controls over follow-up of 8.6 years. Frequency of the T allele was similar among men who had myocardial infarction (22.7%, P=0.5), stroke (18.4%, P=0.2) or venous thromboembolism (17.0%, P=0.1) compared with those with no cardiovascular events (21.5%). The relative risk for any vascular event among men homozygous or heterozygous for the T allele compared with men homozygous for the C allele was 0.94 (95% CI 0.76-1.16). We found no evidence of an association between the T allele and myocardial infarction (relative risk 1.06; 95% CI 0.82-1.36), stroke (0.87, 0.63-1.21) or venous thromboembolism (0.75; 0.51-1.08). Analysis adjusted for aspirin use and traditional cardiovascular risk factors had no significant effect on these findings. CONCLUSION: In a large prospective cohort, carriage of the T allele for the C148T mutation in the beta-fibrinogen promoter gene was not associated with an increased subsequent risk of cardiovascular events.

A novel Q378X mutation exists in the transmembrane transporter protein ABCC6 and its pseudogene: implications for mutation analysis in pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is an inherited disorder of the elastic tissue with characteristic progressive calcification of elastic fibers in skin, eye, and the cardiovascular system. Recently mutations in the ABCC6 gene, encoding a transmembrane transporter protein, were identified as cause of the disease. Surprisingly, sequence and RFLP analysis for exon 9 with primers corresponding to flanking intronic sequence in diseased and haplotype negative members from all of our families and in a control population revealed either a homozygous or heterozygous state for the Q378X (1132C-->T) nonsense mutation in all individuals. With the publication of the genomic structure of the PXE locus we had identified the starting point of a large genomic segmental duplication within the locus in the cytogenetic interval defined by the Cy19 and Cy185 somatic cell hybrid breakpoints on chromosome 16p13.1. By means of somatic cell hybrid mapping we located this starting point telomeric to exon 10 of ABCC6. The duplication, however, does not include exon 10, but exons 1-9. These findings suggest that one or several copies of an ABCC6 pseudogene (psiABCC6) lie within this large segmental duplication. At least one copy contains exons 1-9 and maps to the chromosomal interval defined by the Cy163 and Cy11 breakpoints. Either this copy and/or an additional copy of psiABCC6 within Cy19-Cy183 carries the Q378X mutation that masks the correct identification of this nonsense mutation as being causative in pseudoxanthoma elasticum. Long-range PCR of exon 9 starting from sequence outside the genomic replication circumvents interference from the psiABCC6 DNA sequences and demonstrates that the Q378X mutation in the ABCC6 gene is associated with PXE in some families. These findings lead us to propose that gene conversion mechanisms from psiABCC6 to ABCC6 play a functional role in mutations causing PXE.

Statistical considerations for genome-wide scans: design and application of a novel software package POLYMORPHISM.

OBJECTIVE: Given the cost and complexity of genome-wide scans, optimization of study design is of critical importance. Available algorithms only partially satisfy this need. We designed a software package called 'POLYMORPHISM' to meet these needs. METHODS: The program is designed to calculate linkage parameters for both 'single-point' and 'two-point' settings that are applicable also to incompletely informative microsatellite markers. In single-point analysis, the heterozygosity, polymorphism information content (PIC) and linkage information content (LIC) statistics based on marker allele frequencies are provided. In two-point analysis, joint PIC values for two markers, the conditional probability of detecting linkage phase, the frequency of double heterozygotes and the expected number of informative meioses are calculated. RESULTS: Results were obtained using S.A.G.E./DESPAIR (Design of Linkage Studies Based on Pairs of Relatives) in addition to applying this program to a Centre d'Etude du Polymorphisme pedigree-derived genotyping data set, which estimated critical parameters used in a two-stage genome scan. A single nucleotide polymorphism (SNP)-based one-stage genomic screen strategy is also considered. CONCLUSIONS: LIC values are crucial for getting accurate estimates on those parameters that are important for a two-stage genome screening study. Optimization of the cost-effectiveness of an SNP-based genomic screen strategy is possible by modeling a balance between marker information content and marker density.

Platelet glycoprotein IIIa Pl(a) polymorphism, fibrinogen, and platelet aggregability: The Framingham Heart Study.

BACKGROUND: Recent data suggest that the Pl(A2) allele of the platelet glycoprotein IIIa receptor may be a genetic risk factor for cardiovascular disease. We previously reported that the Pl(A2) allele was associated with increased platelet aggregability, as indicated by lower epinephrine threshold concentrations. Paradoxically, however, it has been reported that Pl(A2)-positive platelets have reduced fibrinogen binding. Because fibrinogen mediates platelet aggregability, we hypothesized that plasma fibrinogen levels may interact with Pl(A) genotype in modulating platelet aggregability. Methods and Results-- Glycoprotein IIIa Pl(A) genotype, fibrinogen level, and platelet aggregability were ascertained in 1340 subjects enrolled into the Framingham Offspring Study. Platelet aggregability was evaluated by the Born method. Higher fibrinogen levels were associated with increased epinephrine-induced aggregation (P=0.002) and a trend for ADP-induced aggregation (P=0.07). The fibrinogen effect was genotype specific, however, in that the increase in platelet aggregability with higher fibrinogen was present for the Pl(A1/A1) genotype (P=0.0005 and P=0.03 for epinephrine- and ADP-induced aggregation, respectively) but not for the Pl(A2)-positive genotype (P>0.90). CONCLUSION: Higher fibrinogen levels were associated with increased platelet aggregability. However, the association between fibrinogen and platelet aggregability was genotype specific. This interaction may be responsible for the conflicting findings regarding Pl(A) genotype and platelet aggregability. Further study of this gene-environment interaction may provide insight into cardiovascular disease risk.

Genetic and environmental contributions to platelet aggregation: the Framingham heart study.

BACKGROUND: Platelet aggregation plays an important role in arterial thrombosis in coronary heart disease, stroke, and peripheral arterial disease. However, the contribution of genetic versus environmental influences on interindividual variation in platelet aggregability is poorly characterized. METHODS AND RESULTS: We studied the heritability of platelet aggregation responses in 2413 participants in the Framingham Heart Study. The threshold concentrations of epinephrine and ADP required to produce biphasic platelet aggregation and collagen lag time were determined. Mixed-model linear regression was used to calculate correlation coefficients within sibships and within spouse pairs. Variance and covariance component methods were used to estimate the proportion of platelet aggregation attributable to measured covariates versus additive genetic effects. After accounting for environmental covariates, the adjusted sibling correlations for epinephrine, ADP, and collagen lag time were 0.24, 0.22, and 0.31, respectively (P=0.0001 for each). In contrast, adjusted correlations for spouse-pairs were -0.01, 0.05, and -0.02, respectively (all P>0.30). The estimated heritabilities were 0.48, 0.44, and 0.62, respectively. Measured covariates accounted for only 4% to 7% of the overall variance in platelet aggregation, and heritable factors accounted for 20% to 30%. The platelet glycoprotein IIIa Pl(A2) polymorphism and the fibrinogen Hind III beta-148 polymorphism contributed <1% to the overall variance. CONCLUSIONS: In our large, population-based sample, heritable factors play a major role in determining platelet aggregation, and measured covariates play a lesser role. Future studies are warranted to identify the key genetic variants that regulate platelet function and to lay the groundwork for rational pharmacogenetic approaches.

Ace D/I polymorphism and incidence of post-PTCA restenosis: a prospective, angiography-based evaluation.

Early restenosis is the major complication of percutaneous transluminal coronary angioplasty (PTCA), occurring in approximately 30% of all initially successful procedures. The D/I polymorphism of the ACE gene, which has variably been reported to represent a risk factor for manifestations of ischemic heart disease, has recently been implicated in the pathophysiology of restenosis after PTCA by some investigators but not by others. All studies conducted thus far involved relatively small sample sizes. We investigated the possible association of ACE D/I genotype and post-PTCA restenosis in a large, prospective sample of patients followed by quantitative coronary angiography. The ACE D/I gene polymorphism was characterized in a cohort of 779 patients, of whom 342 (cases) had developed restenosis (as defined by >50% loss of lumen compared with immediate postprocedure results) at repeat quantitative coronary angiography at 6 months after PTCA. Allele frequencies for the ACE D and I: alleles were 0.58 and 0.42 in cases and 0.58 and 0.42 in control subjects. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for an association between genotype and restenosis or degree of lumen loss. The data from this largest study of its kind conducted so far provide no evidence for an association of the ACE D/I allelic polymorphism with incidence of restenosis after PTCA. On the basis of the power of this study, we conclude that in a general population, the ACE D/I polymorphism is not a useful marker to assess risk of post-PTCA restenosis.

A prospective evaluation of the CD14 C(-260)T gene polymorphism and the risk of myocardial infarction.

The T allele at position -260 of the CD14 lipopolysaccharide receptor gene (CD14) has recently been hypothesized to be a risk factor for myocardial infarction (MI). However, no prospective data relating this polymorphism to risk of future MI are available. In the physicians' health study (PHS), 14916 apparently healthy men were followed over a 12-year period for incident MI. Employing a nested case-control study design, the CD14 C(-260)T polymorphism was evaluated among 387 study participants who developed MI (cases) and among an equal number of age- and smoking-matched study participants who remained free of vascular diseases during follow-up (controls). All observed genotype frequencies were in Hardy-Weinberg equilibrium. However, the allele and genotype distributions of the CD14 polymorphism were similar among cases and controls, both in the total cohort and in all subgroups evaluated. Furthermore, no evidence of association was observed assuming additive, dominant, or recessive mode of inheritance. For example, the relative risk of future MI in a comparison of homozygous mutants to homozygous wild types was 1.00 (95% CI=0.7-1.5; P=0.9). In this large prospective study, the CD14 C(-260)T gene polymorphism was not associated with risks of future MI. Thus, in contrast to prior studies, these data indicate that screening for CD14 C(-260)T genotypes is unlikely to be a useful tool for risk assessment.

Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST).

Sclerosteosis is a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterized by a generalized hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients. By linkage analysis in one extended van Buchem family and two consanguineous sclerosteosis families we previously mapped both disease genes to the same chromosomal 17q12-q21 region, supporting the hypothesis that both conditions are caused by mutations in the same gene. After reducing the disease critical region to approximately 1 Mb, we used the positional cloning strategy to identify the SOST gene, which is mutated in sclerosteosis patients. This new gene encodes a protein with a signal peptide for secretion and a cysteine-knot motif. Two nonsense mutations and one splice site mutation were identified in sclerosteosis patients, but no mutations were found in a fourth sclerosteosis patient nor in the patients from the van Buchem family. As the three disease-causing mutations lead to loss of function of the SOST protein resulting in the formation of massive amounts of normal bone throughout life, the physiological role of SOST is most likely the suppression of bone formation. Therefore, this gene might become an important tool in the development of therapeutic strategies for osteoporosis.

[Relationship between alpha-ENaC gene Thr663Ala polymorphism and ischemic stroke].

OBJECTIVE: To determine the relationship between Thr663Ala polymorphism in amiloride-sensitive epithelial sodium channel alpha-subunit (alpha-ENaC) gene and ischemic stroke in Chinese population. METHODS: Two hundred and ninety-four patients with cerebral infarction and 280 controls without stroke were screened by polymerase chain reaction (PCR) and corresponding Thr663Ala polymorphism probe hybridization. RESULTS: Thr663Ala polymorphism was in agreement with Hardy-Weinberg equilibrium. Both the carriers proportion (70.75%) and the frequency (48.64%) of 663Ala allele in patients were more prevalent than that in controls (62.86% and 40.89%) (P < 0.05). The presence of at least one 663Ala allele conferred an odds ratio for stroke of 1.429 (95%CI: 1.009-2.025), and the proportion of attributable risk of population (PAR%) was 11.63%. CONCLUSION: Thr 663Ala polymorphism of alpha-ENaC gene may be a genetic risk of ischemic stroke in Chinese population.

A prospective evaluation of the interleukin-1 receptor antagonist intron 2 gene polymorphism and the risk of myocardial infarction.

While an interleukin-1 receptor antagonist gene polymorphism (IL1RN-VNTR) has recently been hypothesized to be a risk factor for coronary artery disease, no prospective data relating this polymorphism to subsequent risk of coronary events are available. We therefore investigated the association between IL1RN-VNTR genotype and the incidence of myocardial infarction (MI) in a large, prospective cohort of initially healthy men. The IL1RN-VNTR was evaluated among 385 MI case subjects and an equal number of age- and smoking-matched control subjects during a 12-year follow-up. Overall, the allele and genotype distributions were similar among cases and controls, both in the total cohort and in all subgroups evaluated. All observed genotype frequencies were in Hardy-Weinberg equilibrium. Furthermore, the relative risk in a comparison of homozygous mutant to homozygous wild-type was 0.89 (95%CI = 0.5-1.6; P = 0.9). In this large, prospective study, the IL1RN-VNTR gene polymorphism is not associated with risks of future MI. These data also highlight the importance of hypothesis testing studies in genetic epidemiology, particularly for hypotheses generated from small samples or post hoc subgroup analyses.