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Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE statement.
Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modeling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.
Identification of a common variant at the NOS1AP locus strongly associated to QT-interval duration.
QT-interval prolongation is an electrophysiologic phenomenon associated with sudden cardiac death. The QT-interval in the general population is approximately 35% heritable. In genome-wide association studies, a common variant (rs10494366T > G) within the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was identified and consistently associated with QT-interval duration. Yet, the causal variant remains unclear. Therefore, we performed fine mapping of the association of the NOS1AP locus with QT-interval within the Rotterdam Study, a population-based, prospective cohort study of individuals of > or =55 years of age. First, we tested the association of single-nucleotide polymorphisms (SNPs) in or within +/-100 kb of the NOS1AP gene with QT-interval duration, using sex-specific unstandardized residuals after regression on age and RR-interval, in 385 individuals using the combined set of SNPs present in the Affymetrix 500k and Illumina 550k chip arrays. Subsequently, we examined correspondence of the association signals in 4606 individuals using the Illumina 550k array. A C-to-T SNP at chromosome 1 position 160300514 (rs12143842, T-allele frequency = 24%) was associated with a QT-interval duration increase of 4.4 ms per additional T-allele (P = 4.4 x 10(-28)). For comparison, the most strongly associated variant to date, rs10494366T > G, was associated with a 3.5 ms increase (P = 1.6 x 10(-23)) per additional G-allele. None of the inferred haplotypes showed a stronger effect than the individual rs12143842C > T SNP. In conclusion, we found rs12143842 6 kb upstream distance of NOS1AP to be more strongly associated to QT-interval duration than rs10494366T > G. Functional analysis of this marker is warranted.
Aldehyde dehydrogenase 2 and head and neck cancer: a meta-analysis implementing a Mendelian randomization approach.
Alcohol drinking at high doses is a risk factor for head and neck cancer, and exposure to acetaldehyde, the principle metabolite of alcohol, is supposed to account for the increased risk. Individuals homozygous for the 2 variant allele of aldehyde dehydrogenase 2 (ALDH2) are unable to metabolize acetaldehyde, which prevents them from alcohol drinking, whereas 1 2 have 6-fold higher blood acetaldehyde concentration postalcohol consumption with respect to 1 1. According to the concept of Mendelian randomization, because this polymorphism is distributed randomly during gamete formation, its association with head and neck cancer should be not confounded by smoking. We carried out a meta-analysis of ALDH2 and head and neck cancer searching for relevant studies on Medline and Embase up to January 31, 2008, and investigated the consistency between the expected odds ratio (OR) among drinkers from the largest pooled analysis among never smokers and the observed OR from this meta-analysis by an interaction test. Six studies were selected (945 cases, 2,917 controls). The OR of head and neck cancer among 2 2 was 0.53 [95% confidence interval (95% CI), 0.28-1.00] relative to 1 1 and 1.83 (95% CI, 1.21-2.77) among 1 2. The expected OR for head and neck cancer due to alcohol intake among 1 1 was 1.38 (95% CI, 0.88-2.17) and the observed OR among 1 1 compared with 2*2 from this meta-analysis was 1.88 (95% CI, 1.00-3.57; P for interaction = 0.43). Besides showing the effectiveness of the Mendelian randomization approach, these findings support the theory that alcohol increases head and neck cancer risk through the carcinogenic action of acetaldehyde.
Determinants of DNA yield and purity collected with buccal cell samples.
Buccal cells are an important source of DNA in epidemiological studies, but little is known about factors that influence amount and purity of DNA. We assessed these factors in a self-administered buccal cell collection procedure, obtained with three cotton swabs. In 2,451 patients DNA yield and in 1,033 patients DNA purity was assessed. Total DNA yield ranged from 0.08 to 1078.0 microg (median 54.3 microg; mean 82.2 microg +/- SD 92.6). The median UV 260:280 ratio, was 1.95. Samples from men yielded significantly more DNA (median 58.7 microg) than those from women (median 44.2 microg). Diuretic drug users had significantly lower purity (median 1.92) compared to other antihypertensive drug users (1.95). One technician obtained significantly lower DNA yields. Older age was associated with lower DNA purity. In conclusion, DNA yield from buccal swabs was higher in men and DNA purity was associated with age and the use of diuretics.
Genome-based prediction of common diseases: methodological considerations for future research.
The translation of emerging genomic knowledge into public health and clinical care is one of the major challenges for the coming decades. At the moment, genome-based prediction of common diseases, such as type 2 diabetes, coronary heart disease and cancer, is still not informative. Our understanding of the genetic basis of multifactorial diseases is improving, but the currently identified susceptibility variants contribute only marginally to the development of disease. At the same time, an increasing number of companies are offering personalized lifestyle and health recommendations on the basis of individual genetic profiles. This discrepancy between the limited predictive value and the commercial availability of genetic profiles highlights the need for a critical appraisal of the usefulness of genome-based applications in clinical and public health care. Anticipating the discovery of a large number of genetic variants in the near future, we need to prepare a framework for the design and analysis of studies aiming to evaluate the clinical validity and utility of genetic tests. In this article, we review recent studies on the predictive value of genetic profiling from a methodological perspective and address issues around the choice of the study population, the construction of genetic profiles, the measurement of the predictive value, calibration and validation of prediction models, and assessment of clinical utility. Careful consideration of these issues will contribute to the knowledge base that is needed to identify useful genome-based applications for implementation in clinical and public health practice.
The Rotterdam Study: 2010 objectives and design update.
The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies.
BACKGROUND: An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy. METHODS: This study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort. RESULTS: Minor allele frequency did not differ significantly (p = 0.47) between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort. CONCLUSION: We found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.
A study of the SORL1 gene in Alzheimer's disease and cognitive function.
Several studies have investigated the role of the neuronal sortilin-related receptor (SORL1) gene in Alzheimer's disease (AD), but findings have been inconsistent. We conducted a study of 7 single nucleotide polymorphisms (SNPs), rs668387, rs689021, rs641120, rs1699102, rs3824968, rs2282649, and rs1010159, in the SORL1 gene that were associated to AD in previous studies. We tested for association with AD and cognitive function in 6741 participants of the Rotterdam Study and in 2883 individuals from the Erasmus Rucphen Family study. We performed meta-analyses on AD using our data together with those of previous studies published prior to September 2008 in Caucasians. Further, we studied up to 76 SNPs in a 400 kb region within and flanking the gene to evaluate the evidence that other genetic variants are associated with AD or cognitive function. There was no significant evidence for association between SORL1 SNPs and incident AD patients in the Rotterdam Study. In a meta-analysis of our data with those of others, six out of seven SNPs attained borderline significance. However, removal of the first study reporting association from the meta-analysis resulted in non-significant odds ratios for all SNPs. SNPs rs668387, rs689021, and rs641120 were associated with cognitive function in non-demented individuals at borderline statistical significance in two independent Dutch cohorts, but in the opposite direction. Testing for association using dense SNPs in the SORL1 gene did not reveal significant association with AD, or with cognitive function when adjusting for multiple testing. In conclusion, our data do not support the hypothesis that genetic variants in SORL1 are related to the risk of AD.
Variation in the IGF-1 gene is associated with lymphocyte subset counts in neonates: the Generation R Study.
OBJECTIVE: IGF-1 stimulates growth, development and function of lymphocytes. The aim of this study was to examine whether functional variants of the IGF-1 gene are associated with absolute lymphocyte subset counts in neonates. STUDY DESIGN AND MEASUREMENTS: This study was embedded in the Generation R Study, a prospective cohort study from foetal life onwards. A polymorphism in the IGF-1 promoter region was genotyped in cord blood DNA. Lymphocytes (T, B and NK) and T lymphocyte subsets (helper, cytotoxic, naive and memory) in cord blood were immunophenotyped in 380 neonates by six-colour flow cytometry. RESULTS: In total, 39% of the neonates were homozygous for the 192-bp allele (wild-type), 48% were heterozygous and 13% were noncarrier. No differences in absolute lymphocyte and T lymphocyte subset counts were observed between the 192-bp allele heterozygous and homozygous groups. In noncarriers, we found 15% lower T lymphocyte (P = 0.03), 22% lower B lymphocyte (P = 0.04) and 10% lower NK lymphocyte counts (P = 0.36) than in the 192-bp allele homozygous group. Analyses of T lymphocyte subsets showed 16% lower helper T lymphocyte counts (P = 0.01) in noncarriers. No significant differences were found for cytotoxic, naive and memory T lymphocyte counts. All associations were adjusted for gravidity, mode of delivery, gestational age, birth weight, gender and 1- and 5- min Apgar scores. CONCLUSIONS: Our study showed associations between this IGF-1 promoter region polymorphism and absolute lymphocyte subset counts in neonates. These results should be regarded as hypothesis generating until they have been replicated in other studies.
Genetic factors influence the clustering of depression among individuals with lower socioeconomic status.
OBJECTIVE: To investigate the extent to which shared genetic factors can explain the clustering of depression among individuals with lower socioeconomic status, and to examine if neuroticism or intelligence are involved in these pathways. METHODS: In total 2,383 participants (1,028 men and 1,355 women) of the Erasmus Rucphen Family Study were assessed with the Center for Epidemiologic Studies Depression Scale (CES-D) and the Hospital Anxiety and Depression Scale (HADS-D). Socioeconomic status was assessed as the highest level of education obtained. The role of shared genetic factors was quantified by estimating genetic correlations (rhoG) between symptoms of depression and education level, with and without adjustment for premorbid intelligence and neuroticism scores. RESULTS: Higher level of education was associated with lower depression scores (partial correlation coefficient -0.09 for CES-D and -0.17 for HADS-D). Significant genetic correlations were found between education and both CES-D (rhoG = -0.65) and HADS-D (rhoG = -0.50). The genetic correlations remained statistically significant after adjusting for premorbid intelligence and neuroticism scores. CONCLUSIONS: Our study suggests that shared genetic factors play a role in the co-occurrence of lower socioeconomic status and symptoms of depression, which suggest that genetic factors play a role in health inequalities. Further research is needed to investigate the validity, causality and generalizability of our results.
Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis.
Genes for height have gained interest for decades, but only recently have candidate genes started to be identified. We have performed linkage analysis and genome-wide association for height in approximately 4000 individuals from five European populations. A total of five chromosomal regions showed suggestive linkage and in one of these regions, two SNPs (rs849140 and rs1635852) were associated with height (nominal P = 7.0 x 10(-8) and P = 9.6 x 10(-7), respectively). In total, five SNPs across the genome showed an association with height that reached the threshold of genome-wide significance (nominal P < 1.6 x 10(-7)). The association with height was replicated for two SNPs (rs1635852 and rs849140) using three independent studies (n = 31 077, n=1268 and n = 5746) with overall meta P-values of 9.4 x 10(-10) and 5.3 x 10(-8). These SNPs are located in the JAZF1 gene, which has recently been associated with type II diabetes, prostate and endometrial cancer. JAZF1 is a transcriptional repressor of NR2C2, which results in low IGF1 serum concentrations, perinatal and early postnatal hypoglycemia and growth retardation when knocked out in mice. Both the linkage and association analyses independently identified the JAZF1 region affecting human height. We have demonstrated, through replication in additional independent populations, the consistency of the effect of the JAZF1 SNPs on height. Since this gene also has a key function in the metabolism of growth, JAZF1 represents one of the strongest candidates influencing human height identified so far.
The effect of catechol-O-methyltransferase Met/Val functional polymorphism on smoking cessation: retrospective and prospective analyses in a cohort study.
OBJECTIVE: The Met/Val functional polymorphism of the gene-encoding catechol-O-methyltransferase (COMT) is one of the most widely tested variants for association with different phenotypes of addictive behavior, but replication has been inconsistent for smoking status. We investigated the relationship of this COMT single nucleotide polymorphism with smoking cessation in elderly persons in retrospective and prospective analyses. METHODS: The study is embedded in the population-based Rotterdam Study cohort and included 5,115 persons aged 55 years and more. In the retrospective analyses using logistic regression, current smokers who had smoked 10 or more cigarettes daily for 10 or more years were compared with former smokers. In the prospective analyses, we followed 1,195 current smokers up to 12 years and used Cox proportional hazard model to detect the effect of the COMT single nucleotide polymorphism on self-reported incidence of smoking cessation. RESULTS: The Val/Val genotype of COMT had a consistent association with smoking cessation as compared with the Met/Met+Met/Val genotypes in retrospective [odds ratio=0.79, 95% confidence interval (CI): 0.66-0.96, P=0.02] and prospective analyses (hazard ratio=0.80, 95% CI: 0.63-1.01, P=0.06). In the pooled analyses of prevalent and incident cessation cases that we compared with persisting smokers, the odds ratio was 0.70 (95% CI: 0.55-0.88, P=0.003). No sex difference and no effect of the COMT polymorphism on smoking initiation were observed. CONCLUSION: Our results suggest that COMT Met/Val polymorphism is strongly associated with smoking cessation. The Met allele is the risk allele that decreases the likelihood of smoking cessation in men and women.
Interaction between the Gly460Trp alpha-adducin gene variant and diuretics on the risk of myocardial infarction.
INTRODUCTION:The Gly460Trp variant of the alpha-adducin gene has been associated with the salt-sensitive and diuretic responsive form of hypertension. OBJECTIVE:The aim of the study was to determine whether the alpha-adducin 460Trp variant allele modifies the risk-lowering effect of diuretics on myocardial infarction (MI). DESIGN, SETTING AND PARTICIPANTS:In a population-based registry of pharmacy records linked to hospital discharge records (PHARMO), we used a nested case-control design. We selected patients hospitalized for MI as cases if they had at least one prescription for antihypertensive drugs in the 3 months prior to their first MI and were registered in PHARMO for at least 1 year. Controls that were matched on age, sex, region and calendar date, met the same eligibility criteria as the patients, but were not hospitalized for MI. Only current users of antihypertensive drugs in whom the Gly460Trp polymorphism was genotyped were included for this study. Logistic regression analysis was used to calculate odds ratio (OR), synergy indices, 95% confidence intervals (CIs) and to adjust for the potential confounding factors high cholesterol, smoking, BMI, diabetes, physical activity, alcohol use, use of loop diuretics, coumarins, antiplatelet drugs, ischemic heart disease and number of antihypertensive drugs. RESULTS:The study included 613 patients and 3627 controls. Compared with users of other antihypertensives, the risk of MI was significantly lower among users of thiazide diuretics (OR 0.71, 95% CI 0.55-0.92). Among patients with the adducin variant the risk of MI was similar among thiazide users as compared with users of other antihypertensives (OR 0.88, 95% CI 0.58-1.33), whereas among wild-type carriers this risk was significantly lower (OR 0.62, 95% CI 0.44-0.87). The interaction between current use of diuretics and the alpha-adducin polymorphism was not statistically significantly increased on the multiplicative scale (synergy index 1.41, 95% CI 0.91-2.17). In sensitivity analyses, we found a nonsignificant trend towards a difference between patients who used potassium-sparing diuretics (synergy index 0.98, 95% CI 0.45-2.12) and patients who did not use potassium-sparing diuretics (synergy index 1.60, 95% CI 0.98-2.60) and a statistically significant difference between patients on monotherapy (synergy index 0.69, 95% CI 0.30-1.59) and those on combination therapy (synergy index 1.90, 95% CI 1.04-3.47). CONCLUSION:This study suggests that the alpha-adducin gene does not play an important role in modifying the risk of nonfatal MI associated with the use of thiazide diuretics.
[Eleven years of autopsy on account of Creutzfeldt-Jakob disease in the Netherlands].
OBJECTIVE: To describe our experience with the diagnostics of Creutzfeldt-Jakob disease (CJD) and other prion diseases in the Netherlands over a period of 11 years (1997-2007). DESIGN: Retrospective. METHODS: In the period 1997-2007 autopsies were carried out on 280 patients with probable or possible CJD at the Dutch Surveillance Center for Prion Diseases in Utrecht. We registered clinical details, results of additional investigations such as EEG, MRI and cerebrospinal fluid tests, and outcomes of neurological investigations. The contribution of the different disorders within this group was estimated retrospectively. RESULTS: A prion disease was diagnosed in 146 patients (52%) with probable or possible CJD. 133 (91%) of these had the sporadic form. 2 patients were diagnosed with the 'variant CJD' (caused by bovine spongiform encephalopathy). 5 patients were diagnosed as having an iatrogenic form of CJD and 6 patients had a genetic form of the disease. A different disease was diagnosed in 134 patients (48%), such as Alzheimer disease (40%), multi-infarct dementia (13%), neoplasm (10%) and Lewy body dementia (8%). In this group, periodic sharp wave complexes were observed on EEG in 17 patients (13%), most frequently in those with Alzheimer disease. The 14-3-3 protein test on cerebrospinal fluid was positive in 28 of these patients (21%), most frequently in patients with vascular dementia and Alzheimer disease. CONCLUSION: In all cases of an unclear clinical picture suggestive of neurodegenerative disease, prion disease must be considered. Periodic sharp wave complexes on EEG and a positive 14-3-3 protein test on cerebrospinal fluid alone are not diagnostic of CJD.
[Human spongiform encephalopathies in the Netherlands].
Cases of Creutzfeldt Jakob disease (CJD) have been centrally registered in the Netherlands since 1997. Each year about 35 cases are reported. All patients with a possible, probable or definite diagnosis are registered in a European database. Recently, patients with a transfusion-transmitted form of CJD have been diagnosed in the United Kingdom. Such cases have not yet occurred in the Netherlands. It is important to continue to detect and centrally register patients with CJD.
Apolipoprotein E gene is related to mortality only in normal weight individuals: the Rotterdam Study.
OBJECTIVE: To investigate the relationship between the apolipoprotein E (APOE) gene and the risk of mortality in normal weight, overweight and obese individuals. METHODS AND RESULTS: In a population-based study of 7,983 individuals aged 55 years and older, we compared the risks of all-cause and coronary heart disease (CHD) mortality by APOE genotype, both overall and in subgroups defined by body mass index (BMI). We found significant evidence for interaction between APOE and BMI in relation to total cholesterol (p=0.04) and HDL cholesterol (p<0.001). Overall, APOE*2 carriers showed a decreased risk of all-cause mortality. Analyses within BMI strata showed a beneficial effect of APOE*2 only in normal weight persons (adjusted hazard ratio (HR) 0.7[95% CI 0.5-0.9]). APOE*2 was not associated with a lower risk of all-cause mortality in overweight or obese persons. The effect of APOE*2 in normal weight individuals tended to be due to the risk of CHD mortality (adjusted HR 0.5 [95% CI 0.2-1.2]). CONCLUSION: The APOE*2 allele confers a lower risk of all-cause mortality only to normal weight individuals.
CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms, smoking, consumption of alcohol and fruit and vegetables and risk of head and neck cancer.
As risk-modifiers of alcohol and tobacco effects, metabolic genes polymorphisms were investigated as susceptibility candidates for squamous cell carcinoma of the head and neck (SCCHN).A total of 210 cases and 245 hospital controls, age and gender matched, were genotyped for CYP1A1, CYP2E1, GSTM1, GSTT1, EPHX1 exons 3 and 4, and NAT2 polymorphisms. A measurement of the biological interaction among two risk factors was estimated by the attributable proportion (AP) due to interaction and its 95% confidence interval (CI).SCCHN risk was associated with high-levels of alcohol intake [OR = 3.50 (95%CI: 1.93-6.35) and OR = 6.47 (95%CI: 2.92-14.35) for 19-30 g/day and >30 g/day, respectively], cigarette smoking [OR = 3.47 (95%CI: 1.88-6.41) and OR = 7.65 (95%CI: 4.20-13.90) for 1-25 and >25 pack-years of smoking, respectively] and low-fruit and vegetables consumption (OR = 2.45; 95%CI: 1.53-3.92). No differences were observed for the genotypes or haplotypes distributions among cases and controls, and no biological interaction emerged from gene-gene and gene-environment interaction analyses. An attributable proportion (AP) due to biological interaction of 0.65 (95%CI: 0.40-0.90) was detected for heavy drinkers with a low intake of fruit and vegetables, and an AP of 0.40 (95%CI: 0.10-0.72) resulted forever smokers with low fruit and vegetables consumption.Even in presence of high alcohol consumption or cigarette smoking, a high intake of fruit and vegetables might prevent the development of around one quarter of SCCHN cases. The lack of interaction between the studied polymorphisms and the environmental exposures suggests that chronic consumption of tobacco and alcohol overwhelm enzyme defences, irrespective of genotype.
The Generation R Study: design and cohort update until the age of 4 years.
The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health from fetal life until young adulthood. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and healthcare for pregnant women and children. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. Of all eligible children at birth, 61% participate in the study. In addition, more detailed assessments are conducted in a subgroup of 1,232 pregnant women and their children. Data collection in the prenatal phase and postnatal phase until the age of 4 years includes questionnaires, detailed physical and ultrasound examinations, behavioural observations and biological samples. This paper gives an update of the study design and cohort profile until the children's age of 4 years. Eventually, results forthcoming from the Generation R Study have to contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.
Lack of association of two common polymorphisms on 9p21 with risk of coronary heart disease and myocardial infarction; results from a prospective cohort study.
BACKGROUND: Recent genome wide association (GWA) studies identified two Single Nucleotide Polymorphisms (SNP) (rs10757278 and rs10757274) in the region of the CDK2NA and CDK2NB genes to be consistently associated with the risks of coronary heart disease (CHD) and myocardial infarction (MI). We examined the SNPs in relation to the risk of CHD and MI in a large population based study of elderly population. METHODS: The Rotterdam Study is a population-based, prospective cohort study among 7983 participants aged 55 years and older. Associations of the polymorphisms with CHD and MI were assessed by use of Cox proportional hazards analyses. RESULTS: In an additive model, the age and sex adjusted hazard ratios (HRs) (95% confidence interval) for CHD and MI were 1.03 (0.90, 1.18) and 0.94 (0.82, 1.08) per copy of the G allele of rs10757274. The corresponding HRs were 1.03 (0.90, 1.18) and 0.93 (0.81, 1.06) for the G allele of rs10757278. The association of the SNPs with CHD and MI was not significant in any of the subgroups of CHD risk factors. CONCLUSION: we were not able to show an association of the studied SNPs with risks of CHD and MI. This may be due to differences in genes involved in the occurrence of CHD in young and older people.