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Anika A M Vaarhorst,
Yingchang Lu,
Bastiaan T Heijmans,
Martijn E T Dollé,
Stefan Böhringer,
Hein Putter, Sandra Imholz,
Audrey H H Merry,
Marleen M van Greevenbroek,
J Wouter Jukema,
Anton P M Gorgels,
Piet A van den Brandt,
Michael Müller,
Leo J Schouten,
Edith J M Feskens,
Jolanda M A Boer,
P Eline Slagboom
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ABSTRACT: Genome-wide association studies (GWAS) have identified many single-nucleotide polymorphisms (SNPs) associated with coronary heart disease (CHD) or CHD risk factors (RF). Using a case-cohort study within the prospective Cardiovascular Registry Maastricht (CAREMA) cohort, we tested if genetic risk scores (GRS) based on GWAS-identified SNPs are associated with and predictive for future CHD.
Incident cases (n=742), that is, participants who developed CHD during a median follow-up of 12.1 years (range, 0.0-16.9 years), were compared with a randomly selected subcohort of 2221 participants selected from the total cohort (n=21 148). We genotyped 179 SNPs previously associated with CHD or CHD RF in GWAS as published up to May 2, 2011. The allele-count GRS, composed of all SNPs, the 153 RF SNPs, or the 29 CHD SNPs were not associated with CHD independent of CHD RF. The weighted 29 CHD SNP GRS, with weights obtained from GWAS for every SNP, were associated with CHD independent of CHD RF (hazard ratio, 1.12 per weighted risk allele; 95% confidence interval, 1.04-1.21) and improved risk reclassification with 2.8% (P=0.031). As an exploratory approach to achieve weighting, we performed least absolute shrinkage and selection operator (LASSO) regression analysis on all SNPs and the CHD SNPs. The CHD LASSO GRS performed equal to the weighted CHD GRS, whereas the Overall LASSO GRS performed slightly better than the weighted CHD GRS.
A GRS composed of CHD SNPs improves risk prediction when adjusted for the effect sizes of the SNPs. Alternatively LASSO regression analysis may be used to achieve weighting; however, validation in independent populations is required.
Circulation Cardiovascular Genetics 02/2012; 5(2):202-9. · 6.11 Impact Factor
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Yingchang Lu,
Anika Vaarhorst,
Audrey H H Merry,
Martijn E T Dollé,
Robert Hovenier, Sandra Imholz,
Leo J Schouten,
Bastiaan T Heijmans,
Michael Müller,
P Eline Slagboom,
Piet A van den Brandt,
Anton P M Gorgels,
Jolanda M A Boer,
Edith J M Feskens
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ABSTRACT: Intakes of n-3 polyunsaturated fatty acids (PUFAs), especially EPA (C20:5n-3) and DHA (C22:6n-3), are known to prevent fatal coronary heart disease (CHD). The effects of n-6 PUFAs including arachidonic acid (C20:4n-6), however, remain unclear. δ-5 and δ-6 desaturases are rate-limiting enzymes for synthesizing long-chain n-3 and n-6 PUFAs. C20:4n-6 to C20:3n-6 and C18:3n-6 to C18:2n-6 ratios are markers of endogenous δ-5 and δ-6 desaturase activities, but have never been studied in relation to incident CHD. Therefore, the aim of this study was to investigate the relation between these ratios as well as genotypes of FADS1 rs174547 and CHD incidence.
We applied a case-cohort design within the CAREMA cohort, a large prospective study among the general Dutch population followed up for a median of 12.1 years. Fatty acid profile in plasma cholesteryl esters and FADS1 genotype at baseline were measured in a random subcohort (n = 1323) and incident CHD cases (n = 537). Main outcome measures were hazard ratios (HRs) of incident CHD adjusted for major CHD risk factors.
The AA genotype of rs174547 was associated with increased plasma levels of C204n-6, C20:5n-3 and C22:6n-3 and increased δ-5 and δ-6 desaturase activities, but not with CHD risk. In multivariable adjusted models, high baseline δ-5 desaturase activity was associated with reduced CHD risk (P for trend = 0.02), especially among those carrying the high desaturase activity genotype (AA): HR (95% CI) = 0.35 (0.15-0.81) for comparing the extreme quintiles. High plasma DHA levels were also associated with reduced CHD risk.
In this prospective cohort study, we observed a reduced CHD risk with an increased C20:4n-6 to C20:3n-6 ratio, suggesting that δ-5 desaturase activity plays a role in CHD etiology. This should be investigated further in other independent studies.
PLoS ONE 01/2012; 7(7):e41681. · 4.09 Impact Factor
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ABSTRACT: p53 is involved in stress response, metabolism and cardiovascular functioning. The C-allele of rs1042522 in the gene encoding for p53 is associated with longevity and cancer. In this study, we aimed to investigate the association of rs1042522 with changes in blood pressure, BMI and waist circumference using a longitudinal approach. Rs1042522 was analyzed in two longitudinal studies; the Doetinchem Cohort Study (DCS) and the Botnia Prospective Study (BPS). Changes in quantitative traits over time were investigated according to rs1042522 genotypes. An association between rs1042522 and changes in diastolic blood pressure (DBP) in the DCS over time was observed (P=0.004). Furthermore, a borderline significant association was detected with changes in waist circumference over time (P=0.03). These findings were also observed in the BPS (P=0.02 and P=0.05). The C/C-genotype (Pro/Pro) showed the most moderate time-related increase for the studied endpoints. Furthermore, data from the BPS suggested that the C/C-genotype protects against increases in glucose levels over time at 30 and 60 min during oral glucose tolerance test (P=0.01 and P=0.02). In conclusion, we found an association between the C/C-genotype of rs1042522 and changes in DBP and waist circumference over time. This might contribute to the longevity phenotype observed for the same genotype by others.
European journal of human genetics: EJHG 12/2011; 20(6):696-700. · 3.56 Impact Factor
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ABSTRACT: Antibody microarrays (Ab-array) represent a new, innovative proteomics platform for high-throughput protein expression profiling in body fluids. Because they allow for multiplexed measurements in small sample volumes, Ab-arrays are an interesting alternative to conventional indirect sandwich immunoassay (ELISA or DELFIA) tests in clinical or population screening if sets of markers are to be analyzed simultaneously. However, to allow implementation of Ab-arrays in clinical or population screening programs, it is of vital importance to establish that this method is both sensitive and quantitative.
This study developed and optimized a duplex Ab-array for pregnancy-associated plasma protein A (PAPP-A) and human chorion gonadotropin (fβ-hCG), two serum biomarkers currently analyzed by conventional biochemical techniques in prenatal screening. Serum samples from pregnant women, representing the dynamic range of both markers, were analyzed on Ab-arrays, and validated to the, in prenatal screening routinely applied, AutoDelfia system.
Two different array hybridization conditions were tested, i.e., direct and indirect labeling, of which the indirect method displayed a sensitive and quantitative performance and a low intra- and inter-assay variation.
Taken together, these findings indicate that Ab-array technology is a promising alternative for ELISA or DELFIA in population screening programs, allowing future quantitative analysis of multiple biomarkers simultaneously in small volumes of serum.
Clinical Chemistry and Laboratory Medicine 10/2011; 50(2):325-32. · 2.15 Impact Factor
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ABSTRACT: Our objective was to find single nucleotide polymorphisms (SNPs), within transcriptional pathways of glucose and lipid metabolism, which are related to multiple features of the metabolic syndrome (MetS).
373 SNPs were measured in 3575 subjects of the Doetinchem cohort. Prevalence of MetS features, i.e. hyperglycemia, abdominal obesity, decreased HDL-cholesterol levels and hypertension, were measured twice in 6 years. Associations between the SNPs and the individual MetS features were analyzed by log-linear models. For SNPs related to multiple MetS features (P < 0.01), we investigated whether these associations were independent of each other.
Two SNPs, CETP Ile405Val and APOE Cys112Arg, were associated with both the prevalence of low HDL-cholesterol level (Ile405Val P = < .0001; Cys112Arg P = 0.001) and with the prevalence of abdominal obesity (Ile405Val P = 0.007; Cys112Arg P = 0.007). For both SNPs, the association with HDL-cholesterol was partly independent of the association with abdominal obesity and vice versa.
Two SNPs, mainly known for their role in lipid metabolism, were associated with two MetS features i.e., low HDL-cholesterol concentration, as well as, independent of this association, abdominal obesity. These SNPs may help to explain why low HDL-cholesterol levels and abdominal obesity frequently co-occur.
Lipids in Health and Disease 01/2011; 10:118. · 2.17 Impact Factor
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ABSTRACT: As a first step to identify novel potential biomarkers for prenatal Down Syndrome screening, we analyzed gene expression in embryos of wild type mice and the Down Syndrome model Ts1Cje. Since current Down Syndrome screening markers are derived from placenta and fetal liver, these tissues were chosen as target.
Placenta and fetal liver at 15.5 days gestation were analyzed by microarray profiling. We confirmed increased expression of genes located at the trisomic chromosomal region. Overall, between the two genotypes more differentially expressed genes were found in fetal liver than in placenta. Furthermore, the fetal liver data are in line with the hematological aberrations found in humans with Down Syndrome as well as Ts1Cje mice. Together, we found 25 targets that are predicted (by Gene Ontology, UniProt, or the Human Plasma Proteome project) to be detectable in human serum.
Fetal liver might harbor more promising targets for Down Syndrome screening studies. We expect these new targets will help focus further experimental studies on identifying and validating human maternal serum biomarkers for Down Syndrome screening.
PLoS ONE 01/2011; 6(4):e18866. · 4.09 Impact Factor
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ABSTRACT: Plasma total cholesterol (TC) levels are highly genetically determined. Although ample evidence of genetic determination of separate lipoprotein cholesterol levels has been reported, using TC level directly as a phenotype in a relatively large broad-gene based association study has not been reported to date.
We genotyped 361 single nucleotide polymorphisms (SNPs) across 243 genes based on pathways potentially relevant to cholesterol metabolism in 3575 subjects that were examined thrice over 11 years. Twenty-three SNPs were associated with TC levels after adjustment for multiple testing. We used 12 of them (rs7412 and rs429358 in APOE, rs646776 in CELSR2, rs1367117 in APOB, rs6756629 in ABCG5, rs662799 in APOA5, rs688 in LDLR, rs10889353 in DOCK7, rs2304130 in NCAN, rs3846662 in HMGCR, rs2275543 in ABCA1, rs7275 in SMARCA4) that were confirmed in previous candidate association or genome-wide-association studies to define a gene risk score (GRS). Average TC levels increased from 5.23 ± 0.82 mmol/L for those with 11 or less cholesterol raising alleles to 6.03 ± 1.11 mmol/L for those with 18 or more (P for trend<0.0001). The association with TC levels was slightly stronger when the weighted GRS that weighted the magnitude of allelic effects was used.
A panel of common genetic variants in the genes pivotal in cholesterol metabolism could possibly help identify those people who are at risk of high cholesterol levels.
Atherosclerosis 11/2010; 213(1):200-5. · 3.79 Impact Factor
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ABSTRACT: The delta-5 and delta-6 desaturases, encoded by the FADS1 and FADS2 genes, are rate-limiting enzymes in polyunsaturated fatty acid (PUFA) biosynthesis. Single nucleotide polymorphisms in the FADS gene cluster region have been associated with both PUFA concentrations in plasma or erythrocyte membrane phospholipids and cholesterol concentrations in recent genome-wide association studies.
We examined whether genetic variations in the FADS gene cluster region interact with dietary intakes of n-3 (omega-3) and n-6 (omega-6) PUFAs to affect plasma total, HDL-, and non-HDL-cholesterol concentrations.
Dietary intakes of n-3 and n-6 PUFAs, plasma concentrations of total and HDL cholesterol, and rs174546, rs482548, and rs174570 in the FADS gene cluster region were measured in 3575 subjects in the second survey of the Doetinchem Cohort Study.
Significant associations between rs174546 genotypes and total and non-HDL-cholesterol concentrations were observed in the group with a high intake of n-3 PUFAs (> or =0.51% of total energy; P = 0.006 and 0.047, respectively) but not in the low-intake group (P for interaction = 0.32 and 0.51, respectively). The C allele was associated with high total and non-HDL-cholesterol concentrations. Furthermore, the C allele was significantly associated with high HDL-cholesterol concentrations in the group with a high intake of n-6 PUFAs (> or =5.26% of total energy, P = 0.004) but not in the group with a low intake (P for interaction = 0.02).
Genetic variation in the FADS1 gene potentially interacts with dietary PUFA intakes to affect plasma cholesterol concentrations, which should be investigated further in other studies.
American Journal of Clinical Nutrition 07/2010; 92(1):258-65. · 6.67 Impact Factor
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ABSTRACT: The known genetic variants determining plasma HDL cholesterol (HDL-C) levels explain only part of its variation. Three hundred eighty-four single nucleotide polymorphisms (SNPs) across 251 genes based on pathways potentially relevant to HDL-C metabolism were selected and genotyped in 3,575 subjects from the Doetinchem cohort, which was examined thrice over 11 years. Three hundred fifty-three SNPs in 239 genes passed the quality-control criteria. Seven SNPs [rs1800777 and rs5882 in cholesteryl ester transfer protein (CETP); rs3208305, rs328, and rs268 in LPL; rs1800588 in LIPC; rs2229741 in NRIP1] were associated with plasma HDL-C levels with false discovery rate (FDR) adjusted q values (FDR_q) < 0.05. Five other SNPs (rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, rs6060717 near SCAND1, and rs3213451 in MBTPS2 in women) were associated with plasma HDL-C levels with FDR_q between 0.05 and 0.2. Two less well replicated associations (rs3135506 in APOA5 and rs1800961 in HNF4A) known from the literature were also observed, but their significance disappeared after adjustment for multiple testing (P = 0.008, FDR_q = 0.221 for rs3135506; P = 0.018, FDR_q = 0.338 for rs1800961, respectively). In addition to replication of previous results for candidate genes (CETP, LPL, LIPC, HNF4A, and APOA5), we found interesting new candidate SNPs (rs2229741 in NRIP1, rs3213451 in MBTPS2, rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, and rs6060717 near SCAND1) for plasma HDL-C levels that should be evaluated further.
The Journal of Lipid Research 12/2008; 49(12):2582-9. · 5.56 Impact Factor
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ABSTRACT: To evaluate the involvement of various collagen genes in the development of fragmented medial coronoid process (FCP) in Labrador Retrievers.
93 dogs originating from 13 litters were used in the study; FCP was diagnosed in 35 dogs, and each affected dog had at least 1 sibling that was also affected. Twelve dams and sires were included in the analysis. All dogs were purebred Labrador Retrievers except for 2 litters (offspring of a female Golden Retriever-Labrador Retriever mixed-breed dog).
For each dog, DNA was isolated from blood samples. Polymorphic microsatellite markers adjacent to 14 candidate genes (ie, COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL6A3, COL9A1, COL9A2, COL9A3, COL10A1, COL11A1, COL11A2, and COL24A1) were analyzed by use of PCR assays; genotypes were determined via automated detection of DNA products. The level of allele sharing between pairs of affected siblings was assessed.
Among the 93 dogs, allele sharing of the 14 collagen genes was determined as follows: COL1A1, 45%; COL1A2, 47%; COL2A1, 37%; COL3A1, 32%; COL5A1, 43%; COL5A2, 32%; COL6A3, 36%; COL9A1, 45%; COL9A2, 49%; COL9A3, 38%; COL10A1, 46%; COL11A1, 52%; COL11A2, 47%; and COL24A1, 47%.
Because siblings share 50% of their genome at random, the fact that the percentages of allele sharing among the analyzed collagen genes were not significantly > 50% indicates that these genes are not determinant candidates for FCP in Labrador Retrievers. The gene for the vitamin D receptor could also be excluded because of its proximity to COL2A1.
American Journal of Veterinary Research 10/2006; 67(10):1713-8. · 1.27 Impact Factor
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ABSTRACT: Canine-dilated cardiomyopathy (DCM) in dogs is a disease of the myocardium associated with dilatation and impaired contraction of the ventricles and is suspected to have a genetic cause. A missense mutation in the desmin gene (DES) causes DCM in a human family. Human DCM closely resembles the canine disease. In the present study, we evaluated whether DES gene mutations are responsible for DCM in Dobermann dogs. We have isolated bacterial artificial chromosome clones (BACs) containing the canine DES gene and determined the chromosomal location by fluorescence in situ hybridization (FISH). Using data deposited in the NCBI trace archive and GenBank, the canine DES gene DNA sequence was assembled and seven single nucleotide polymorphisms (SNPs) were identified. From the canine DES gene BAC clones, a polymorphic microsatellite marker was isolated. The microsatellite marker and four informative desmin SNPs were typed in a Dobermann family with frequent DCM occurrence, but the disease phenotype did not associate with a desmin haplotype. We concluded that mutations in the DES gene do not play a role in Dobermann DCM. Availability of the microsatellite marker, SNPs and DNA sequence reported in this study enable fast evaluation of the DES gene as a DCM candidate gene in other dog breeds with DCM occurrence.
Gene 11/2004; 340(2):241-9. · 2.34 Impact Factor
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ABSTRACT: The serotonin receptor 1B gene (htr1B) has been suggested to be implicated in mental disorders in both humans and other species. We have isolated a canine bacterial artificial chromosome (BAC) clone containing htr1B, revealed the coding and surrounding DNA sequence of canine htr1B and designed primer sets for genomic sequencing of the gene. A mutation scan in 10 dogs revealed five single nucleotide polymorphisms in the htr1B coding sequence. By random sequencing of subclones of the BAC a polymorphic microsatellite repeat was found. We found evidence for at least four extended haplotypes in six dogs of the same breed. The chromosomal localization of the gene was confirmed by fluorescence in situ hybridisation and radiation hybrid mapping. This work provides a starting point for mutation scans and association studies on dogs with behavioural problems.
Gene 03/2004; 326:131-9. · 2.34 Impact Factor
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[show abstract]
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ABSTRACT: Canine-dilated cardiomyopathy (DCM) in dogs is a disease of the myocardium associated with dilatation and impaired contraction of the ventricles and is suspected to have a genetic cause. A missense mutation in the desmin gene (DES) causes DCM in a human family. Human DCM closely resembles the canine disease. In the present study, we evaluated whether DES gene mutations are responsible for DCM in Dobermann dogs. We have isolated bacterial artificial chromosome clones (BACs) containing the canine DES gene and determined the chromosomal location by fluorescence in situ hybrizidation (FISH). Using data deposited in the NCBI trace archive and GenBank, the canine DES gene DNA sequence was assembled and seven single nucleotide polymorphisms (SNPs) were identified. From the canine DES gene BAC clones, a polymorphic microsatellite marker was isolated. The microsatellite marker and four informative desmin SNPs were typed in a Dobermann family with frequent DCM occurrence, but the disease phenotype did not associate with a desmin haplotype.We concluded that mutations in the DES gene do not play a role in Dobermann DCM. Availability of the microsatellite marker, SNPs and DNA sequence reported in this study enable fast evaluation of the DES gene as a DCM candidate gene in other dog breeds with DCM occurrence.
Gene.
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[show abstract]
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ABSTRACT: The serotonin receptor 1B gene (htr1B) has been suggested to be implicated in mental disorders in both humans and other species. We have isolated a canine bacterial artificial chromosome (BAC) clone containing htr1B, revealed the coding and surrounding DNA sequence of canine htr1B and designed primer sets for genomic sequencing of the gene. A mutation scan in 10 dogs revealed five single nucleotide polymorphisms in the htr1B coding sequence. By random sequencing of subclones of the BAC a polymorphic microsatellite repeat was found. We found evidence for at least four extended haplotypes in six dogs of the same breed. The chromosomal localization of the gene was confirmed by fluorescence in situ hybridisation and radiation hybrid mapping. This work provides a starting point for mutation scans and association studies on dogs with behavioural problems.
Gene.
