Iris Postmus | Universiteit Leiden (original) (raw)

Papers by Iris Postmus

International journal of epidemiology, Jan 7, 2015

Observational studies in older subjects have shown no or inverse associations between cholesterol... more Observational studies in older subjects have shown no or inverse associations between cholesterol levels and mortality. However, in old age plasma low-density lipoprotein cholesterol (LDL-C) may not reflect the lifetime level due to reverse causality, and hence the risk may be underestimated. In the current study, we used an LDL genetic risk score (GRS) to overcome this problem. A weighted GRS was created using 51 single nucleotide polymorphisms associated with LDL-C levels. The LDL GRS was calculated in three Dutch cohorts: the Leiden Longevity Study (LLS) (n = 3270), the Leiden 85-plus study (n = 316) and the Rotterdam Study (n = 4035). We assessed the association between the LDL GRS and LDL-C levels, chronological age, familial longevity and mortality. Up to 90 years of age, in each age stratum individuals with high LDL GRS had higher LDL-C levels (P = 0.010 to P = 1.1 x 10(-16)). The frequency of LDL-increasing alleles decreased with increasing age [β = -0.021 (SE = 0.01) per ye...

Background: The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide ... more Background: The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDLcholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly. Methods: The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification. Results: Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results. Conclusion: With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/ PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.

Pharmacogenomics, 2012

Statins are the most commonly prescribed class of drug worldwide and therapy is highly effective ... more Statins are the most commonly prescribed class of drug worldwide and therapy is highly effective in reducing low-density lipoprotein cholesterol levels and cardiovascular events. However, there is large variability in clinical response to statin treatment. Recent research provides evidence that genetic variation contributes to this variable response to statin treatment. Until recently, pharmacogenetic studies have used mainly candidate gene approaches to investigate these effects. Since candidate gene studies explain only a small part of the observed variation and results have often been inconsistent, genome-wide association (GWA) studies may be a better approach. In this paper the most important candidate gene studies and the first published GWA studies assessing statin response are discussed. Moreover, we describe the PHASE study, an EU-funded GWA study that will investigate the genetic variation responsible for the variation in response to pravastatin in a large randomized clinic...

Nature communications, 2015

Variants associated with blood lipid levels may be population-specific. To identify low-frequency... more Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

ABSTRACT Abstracts from the 2014 Annual Scientific Meeting of the BHS (doi:10.1038/jhh.2014.60) P... more ABSTRACT Abstracts from the 2014 Annual Scientific Meeting of the BHS (doi:10.1038/jhh.2014.60) Pharmacogenetic GWAS meta-analysis of LDL cholesterol response to statins Purpose: Statins are widely prescribed for the prevention and treatment of cardiovascular disease with great proven effectiveness of 20-30%. However, it is also established that there is inter-individual variability in LDL-C response to statins, which may be partly due to pharmacogenetic variation. The only genetic variants consistently reported from previous studies are located within the APOE and LPA gene regions. To determine whether additional loci may influence LDL-C response to statins, we formed the Genomic Investigation of Statin Therapy (GIST) consortium and conducted a pharmacogenetic meta-analysis of genome-wide association studies of LDL-C response to statins, which is the largest, most comprehensive study of its kind conducted to date. Methods: The meta-analysis comprises GWAS datasets from both randomized controlled trials (RCTs) and observational studies, including approximately 40,000 statin-treated subjects overall, divided into a first discovery stage and a second validation stage. The response variable analysed is the difference between the natural log transformed LDL-C levels on- and off-treatment, and is adjusted for baseline LDL-C, in order to eliminate the confounded effect of association between the genetic variant and baseline LDL-C levels. Further adjustment was made for the type and dose of statins used, in order to combine several different types of statins across the contributing trials and within the observational studies. Results: Overall, at genome-wide significant level, we have identified two new loci: SORT1/CELSR2/PSRC1 (rs646776, β =-0.013, SE=0.002, P=1.05x10-9) and SLCO1B1 (rs2900478, β=0.016, SE=0.003, P=1.22x10-9), which have not been previously identified in GWAS. Furthermore we have successfully confirmed the known associations with APOE (rs445925, β=-0.043, SE=0.005, P=1.58 x 10-18) and LPA (rs10455872, β=-0.059, SE=0.006, P=1.95 x 10-11). Our results were further investigated and validated with additional functional analyses, such as conditional, eQTL and pathway analyses. For example, the genome-wide conditional analysis highlighted 14 independent SNPs explaining 5% of the variance, of which 6 SNPs reached genome-wide significance in our combined meta-analysis. Collectively our functional and pathway analysis confirmed a strong biological and functional role in statin response for several strongly associated gene loci, including APOE, and SORT1/CELSR2/PSRC1. Furthermore, a genetic risk score including our 4 lead SNPs was significantly associated with coronary disease risk in the CARDIoGRAM and C4D consortium. Conclusions: Our findings advance the understanding of the pharmacogenetic architecture of statin response, and illustrate that SNPs with modest effect on LDL response to these widely used drugs can influence coronary artery disease risk.

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associ... more We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00610 210 ), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38610 25 ). An interaction test confirmed that these estimates differed from each other (P = 4.95610 213 ). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

PLoS ONE, 2012

Background: Coronary restenosis after percutaneous coronary intervention still remains a signific... more Background: Coronary restenosis after percutaneous coronary intervention still remains a significant problem, despite all medical advances. Unraveling the mechanisms leading to restenosis development remains challenging. Many studies have identified genetic markers associated with restenosis, but consistent replication of the reported markers is scarce. The aim of the current study was to analyze the joined effect of previously in literature reported candidate genes for restenosis in the GENetic DEterminants of Restenosis (GENDER) databank.

International Journal of Epidemiology, 2014

Background: Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previous... more Background: Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans. Methods: We measured LTL in 870 nonagenarian siblings (mean age 93 years), 1580 of their offspring and 725 spouses thereof (mean age 59 years) from the Leiden Longevity Study (LLS). Results: We found that shorter LTL is associated with increased prospective mortality in middle (30-80 years; hazard ratio (HR) ¼ 0.75, P ¼ 0.001) and highly advanced age

Human Molecular Genetics, 2014

The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of ... more The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genomewide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR 5 1.10, P 5 1.74 3 10 28 ). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR 5 0.72, P 5 3.40 3 10 236 ), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n 5 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR 5 0.95, P 5 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Nature communications, 2014

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividua... more Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

International journal of epidemiology, Jan 7, 2015

Observational studies in older subjects have shown no or inverse associations between cholesterol... more Observational studies in older subjects have shown no or inverse associations between cholesterol levels and mortality. However, in old age plasma low-density lipoprotein cholesterol (LDL-C) may not reflect the lifetime level due to reverse causality, and hence the risk may be underestimated. In the current study, we used an LDL genetic risk score (GRS) to overcome this problem. A weighted GRS was created using 51 single nucleotide polymorphisms associated with LDL-C levels. The LDL GRS was calculated in three Dutch cohorts: the Leiden Longevity Study (LLS) (n = 3270), the Leiden 85-plus study (n = 316) and the Rotterdam Study (n = 4035). We assessed the association between the LDL GRS and LDL-C levels, chronological age, familial longevity and mortality. Up to 90 years of age, in each age stratum individuals with high LDL GRS had higher LDL-C levels (P = 0.010 to P = 1.1 x 10(-16)). The frequency of LDL-increasing alleles decreased with increasing age [β = -0.021 (SE = 0.01) per ye...

Background: The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide ... more Background: The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDLcholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly. Methods: The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification. Results: Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results. Conclusion: With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/ PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.

Pharmacogenomics, 2012

Statins are the most commonly prescribed class of drug worldwide and therapy is highly effective ... more Statins are the most commonly prescribed class of drug worldwide and therapy is highly effective in reducing low-density lipoprotein cholesterol levels and cardiovascular events. However, there is large variability in clinical response to statin treatment. Recent research provides evidence that genetic variation contributes to this variable response to statin treatment. Until recently, pharmacogenetic studies have used mainly candidate gene approaches to investigate these effects. Since candidate gene studies explain only a small part of the observed variation and results have often been inconsistent, genome-wide association (GWA) studies may be a better approach. In this paper the most important candidate gene studies and the first published GWA studies assessing statin response are discussed. Moreover, we describe the PHASE study, an EU-funded GWA study that will investigate the genetic variation responsible for the variation in response to pravastatin in a large randomized clinic...

Nature communications, 2015

Variants associated with blood lipid levels may be population-specific. To identify low-frequency... more Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of the Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value <6.61 × 10(-4)), including a rare missense variant in ABCA6 (rs77542162, p.Cys1359Arg, frequency 0.034), which is predicted to be deleterious. The frequency of this ABCA6 variant is 3.65-fold increased in the Dutch and its effect (βLDL-C=0.135, βTC=0.140) is estimated to be very similar to those observed for single variants in well-known lipid genes, such as LDLR.

ABSTRACT Abstracts from the 2014 Annual Scientific Meeting of the BHS (doi:10.1038/jhh.2014.60) P... more ABSTRACT Abstracts from the 2014 Annual Scientific Meeting of the BHS (doi:10.1038/jhh.2014.60) Pharmacogenetic GWAS meta-analysis of LDL cholesterol response to statins Purpose: Statins are widely prescribed for the prevention and treatment of cardiovascular disease with great proven effectiveness of 20-30%. However, it is also established that there is inter-individual variability in LDL-C response to statins, which may be partly due to pharmacogenetic variation. The only genetic variants consistently reported from previous studies are located within the APOE and LPA gene regions. To determine whether additional loci may influence LDL-C response to statins, we formed the Genomic Investigation of Statin Therapy (GIST) consortium and conducted a pharmacogenetic meta-analysis of genome-wide association studies of LDL-C response to statins, which is the largest, most comprehensive study of its kind conducted to date. Methods: The meta-analysis comprises GWAS datasets from both randomized controlled trials (RCTs) and observational studies, including approximately 40,000 statin-treated subjects overall, divided into a first discovery stage and a second validation stage. The response variable analysed is the difference between the natural log transformed LDL-C levels on- and off-treatment, and is adjusted for baseline LDL-C, in order to eliminate the confounded effect of association between the genetic variant and baseline LDL-C levels. Further adjustment was made for the type and dose of statins used, in order to combine several different types of statins across the contributing trials and within the observational studies. Results: Overall, at genome-wide significant level, we have identified two new loci: SORT1/CELSR2/PSRC1 (rs646776, β =-0.013, SE=0.002, P=1.05x10-9) and SLCO1B1 (rs2900478, β=0.016, SE=0.003, P=1.22x10-9), which have not been previously identified in GWAS. Furthermore we have successfully confirmed the known associations with APOE (rs445925, β=-0.043, SE=0.005, P=1.58 x 10-18) and LPA (rs10455872, β=-0.059, SE=0.006, P=1.95 x 10-11). Our results were further investigated and validated with additional functional analyses, such as conditional, eQTL and pathway analyses. For example, the genome-wide conditional analysis highlighted 14 independent SNPs explaining 5% of the variance, of which 6 SNPs reached genome-wide significance in our combined meta-analysis. Collectively our functional and pathway analysis confirmed a strong biological and functional role in statin response for several strongly associated gene loci, including APOE, and SORT1/CELSR2/PSRC1. Furthermore, a genetic risk score including our 4 lead SNPs was significantly associated with coronary disease risk in the CARDIoGRAM and C4D consortium. Conclusions: Our findings advance the understanding of the pharmacogenetic architecture of statin response, and illustrate that SNPs with modest effect on LDL response to these widely used drugs can influence coronary artery disease risk.

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associ... more We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00610 210 ), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38610 25 ). An interaction test confirmed that these estimates differed from each other (P = 4.95610 213 ). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

PLoS ONE, 2012

Background: Coronary restenosis after percutaneous coronary intervention still remains a signific... more Background: Coronary restenosis after percutaneous coronary intervention still remains a significant problem, despite all medical advances. Unraveling the mechanisms leading to restenosis development remains challenging. Many studies have identified genetic markers associated with restenosis, but consistent replication of the reported markers is scarce. The aim of the current study was to analyze the joined effect of previously in literature reported candidate genes for restenosis in the GENetic DEterminants of Restenosis (GENDER) databank.

International Journal of Epidemiology, 2014

Background: Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previous... more Background: Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans. Methods: We measured LTL in 870 nonagenarian siblings (mean age 93 years), 1580 of their offspring and 725 spouses thereof (mean age 59 years) from the Leiden Longevity Study (LLS). Results: We found that shorter LTL is associated with increased prospective mortality in middle (30-80 years; hazard ratio (HR) ¼ 0.75, P ¼ 0.001) and highly advanced age

Human Molecular Genetics, 2014

The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of ... more The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genomewide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR 5 1.10, P 5 1.74 3 10 28 ). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR 5 0.72, P 5 3.40 3 10 236 ), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n 5 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR 5 0.95, P 5 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Nature communications, 2014

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividua... more Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.