Biomedical subjects

Robert Vlietinck

Publications and source records attributed to Robert Vlietinck.

At least 19 recordsLinked to original sources

PubMed2006

Cigarette smoke-induced differential gene expression in blood cells from monozygotic twin pairs.

Chemical carcinogenesis induced by lifestyle factors like cigarette smoking is a major research area in molecular epidemiology. Gene expression analysis of large numbers of genes simultaneously using microarrays holds the opportunity to study the effects of such an exposure at the genome level yielding more mechanism-based information. Therefore, the aim of our study was to investigate multiple gene expressions in blood, indicative for the effects caused by cigarette smoke. Smoking-discordant monozygotic twin pairs (n=9) were studied to diminish influences of genetic background. Using a dedicated microarray containing 600 toxicologically relevant genes, we investigated which genes are differentially expressed in smokers compared to non-smokers. We also looked for genes of which the expression changes correlated with DNA adducts, a biomarker of effective dose for exposure to cigarette smoke carcinogens. The mean DNA adduct level in smokers differed significantly from that in non-smokers (mean +/- standard error 1.96 +/- 0.24 versus 1.17 +/- 0.16 adducts per 10(8) nucleotides, respectively; P=0.04). The genes of which the expression differed most significantly between smokers and non-smokers are ATF4, MAPK14, SOD2, CYP1B1 and SERPINB2. CYP1B1 and SOD2 can directly be linked to cigarette smoke exposure, whereas the other genes are associated with stress or environmentally induced response. Main functions of the genes influenced by cigarette smoking comprise carcinogen metabolism, oxidative stress response and anti-apoptosis.

Actins↗

PubMed2006

Pharmacogenetics in inflammatory bowel disease.

Pharmacogenetics is the study of the association between variability in drug response and (or) drug toxicity and polymorphisms in genes. The goal of this field of science is to adapt drugs to a patient's specific genetic background and therefore make them more efficacious and safe. In this article we describe the variants in genes that influence either the efficacy or toxicity of common drugs used in the treatment of inflammatory bowel diseases (IBD), ulcerative colitis (UC), and Crohn's disease (CD) including sulfasalazine and mesalazine, azathioprine (AZA) and 6-mercaptopurine (6-MP), methotrexate (MTX), glucocorticosteroids (CSs) and infliximab. Furthermore, difficulties with pharmacogenetic studies in general and more specifically in IBD are described. Although pharmacogenetics is a promising field that already contributed to a better understanding of some of the underlying mechanisms of action of drugs used in IBD, the only discovery translated until now into daily practice is the relation between thiopurine S-methyltransferase (TPMT) gene polymorphisms and hematological toxicity of thiopurine treatment. In the future it is necessary to organize studies in well characterized patient cohorts who have been uniformly treated and systematically evaluated in order to quantitate drug response more objectively. An effort should be made to collect genomic DNA from all patients enrolled in clinical drug trials after appropriate informed consent for pharmacogenetic studies.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2006

Does occupational exposure to PAHs, diesel and aromatic amines interact with smoking and metabolic genetic polymorphisms to increase the risk on bladder cancer?; The Belgian case control study on bladder cancer risk.

To investigate the association between occupational exposure to polycyclic aromatic hydrocarbons, aromatic amines and diesel and bladder cancer risk and the modification by smoking and metabolic polymorphisms, have we recruited 200 cases and 385 population controls. The adjusted OR of bladder cancer was 5.75 (95%CI 2.09-15.83) comparing the highest tertile of the cumulative probability of occupational exposure to aromatic amines with no occupational exposure. A possible interaction between occupational exposures to aromatic amines and smoking was found. The increased ORs of GSTM1, GSTT1, NAT2 and SULT1A1 among those ever occupational exposed was explored by estimating the false-positive report probability. We confirm that occupational exposure to aromatic amines is associated with an increase in bladder cancer risk.

Aged↗

PubMed2006

Stress-related negative affectivity and genetically altered serotonin transporter function: evidence of synergism in shaping risk of depression.

CONTEXT: Genetic moderation of the depression-inducing effects of stressful life events (SLEs) has been reported, but findings suggest that genes may not moderate the effects of SLEs per se but instead may moderate the risk of depression associated with the stable tendency to develop negative emotions in response to minor environmental experiences. OBJECTIVE: To examine whether a functional polymorphism of the serotonin transporter gene (5-HTTLPR) moderates the association between negative affectivity (neuroticism) and depression and to what degree this can explain previous findings involving SLEs. DESIGN: A prospective cohort study involving 1 baseline and 4 follow-up measurements in 15 months analyzing change in self-reported depressive symptoms across time as a function of negatively attributed SLEs, neuroticism, 5-HTTLPR, and their interactions. SETTING: General community. PARTICIPANTS: A population-based sample of 374 ethnically homogeneous young adult female twins. MAIN OUTCOME MEASURE: A continuous score of self-reported depressive symptoms. RESULTS: The depressogenic effect of SLEs in the 3 months before interview was significantly greater in women with 2 short (S) alleles compared with women with 1 or none. However, this effect disappeared after accounting for the effect of SLEs conditional on neuroticism. Similarly, the depressogenic effect of neuroticism was progressively greater with number of S alleles, and this was unchanged after accounting for the effect of neuroticism conditional on SLEs. CONCLUSIONS: Genotype x environment interactions in depression may be more productively interpreted by involving mechanisms more proximal to psychological experience itself. The probability that stress-related cognitive vulnerabilities for depression result in symptom formation may be moderated by a neurobiologic phenotype characterized by altered processing of negative emotions associated with variation in 5-HTTLPR.

Adolescent↗

PubMed2006

High frequency of iatrogenic monozygotic twins with administration of clomiphene citrate and a change in chorionicity.

The data of the population-based, prospective survey of multiple births in East Flanders, Belgium, show that a greater proportion of monozygotic twins is observed with clomiphene citrate as sole treatment compared with other ovulatory drugs. Among iatrogenic monozygotic twins, the ratio of monochorionic versus dichorionic pairs is higher compared with spontaneous twins.

Chorion↗

PubMed2006

Genome-wide linkage scan for spontaneous DZ twinning.

In humans, spontaneous DZ twinning is known to have a genetic basis. A prior investigation in the Flemish and Dutch population showed that the phenotype of 'having DZ twins' was consistent with an autosomal monogenic dominant model, with a gene frequency of 3.5% and a female-specific lifetime penetrance of 10%. Recessive, X-linked, polygenic and sporadic models were rejected. This study reports on a genome-wide scan of 14 Flemish families containing 57 mothers of spontaneous DZ twins. Two-point linkage analysis using the autosomal dominant model showed nine chromosomal regions with a LOD score around 1. After multipoint linkage analysis, including heterogeneity, three chromosomes continued to give high LOD scores. These regions were further haplotyped with additional markers at 1 cM distance. The multipoint analysis was not in favour of linkage of the DZ twinning trait in most candidate genes and other regions (LOD score < -2) under the genetic model of autosomal dominance. To further evaluate the evidence for linkage given some uncertainty about the correct mode of inheritance of twinning susceptibility other models of inheritance were tested. Results of this analysis showed all models gave highest LOD scores under dominant models. If heterogeneity among the families is taken into account, the peaks that were observed on chromosome 2, 7 and 18 could well contain a potential gene contributing to DZ twinning. These results give suggestive evidence that the mode of inheritance of DZ twinning is probably more complex than was originally expected.

Belgium↗

PubMed2006

Toll-like receptor-1, -2, and -6 polymorphisms influence disease extension in inflammatory bowel diseases.

BACKGROUND: Evidence that a deficient innate immune response toward the bacterial flora of the gut plays a role in the pathogenesis of inflammatory bowel disease (IBD) is growing. This is underscored by the finding of the association between CARD15 variants and Crohn's disease (CD) and D299G in Toll-like receptor (TLR) 4 and IBD. Our aims were to study nonsynonymous polymorphisms in other TLR genes in IBD. METHODS: Thirty-five single nucleotide polymorphisms (SNP) in TLR1-10 were identified from public databases. 284 IBD parent-child trios and a second independent cohort of 285 IBD patients and 191 healthy controls were genotyped with polymerase chain reaction-restriction fragment length polymorphisms. Patients were pooled for genotype-phenotype analyses. RESULTS: Although none of the SNPs was involved in disease susceptibility, a number of variants influenced the disease phenotype. A positive association between TLR1 R80T and pancolitis in UC (P = .045, OR [95% CI] 2.844 [1.026-7.844]) was found. The TLR2 R753G SNP was also associated with pancolitis (P = .027, OR [95% CI] 4.741 [1.197-18.773]). The relative risks for heterozygous patients to develop pancolitis were 5.8 and 3.3 for R80T and R753G, respectively. There was a negative association between TLR6 S249P and ulcerative colitis with proctitis only (P = .026, OR [95% CI] 0.223 [0.096-0.705]). In CD, we found a negative association between ileal disease involvement and TLR1 S602I (P = .03, OR [95% CI] 0.522 [0.286-0.950]). CONCLUSION: TLR2 and its cofactors TLR1 and TLR6 are involved in the initial immune response to bacteria by recognizing peptidoglycan. An association between nonsynonymous variants in the TLR1, -2, and -6 genes and extensive colonic disease in UC and CD was found. Our findings further highlight the role of an abnormal innate immune response in the pathogenesis of IBD.

Adult↗

PubMed2006

The role of vascular endothelial growth factor (VEGF) in inflammatory bowel disease.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a candidate susceptibility gene to inflammatory bowel disease (IBD), both from a functional as well as genetic perspective. Moreover, serum VEGF (sVEGF) levels are increased in IBD and correlate with disease activity. Both VEGF expression and sVEGF levels may be influenced by VEGF gene polymorphisms. AIMS: To study VEGF polymorphisms in IBD susceptibility and their impact on sVEGF levels. METHODS: Four functional VEGF polymorphisms (-C2578A, -G1154A, -G634C, and C936T) were genotyped in two independent cohorts (cohort 1: 372 IBD trios; cohort 2: 452 unrelated IBD patients, 271 healthy controls [HC]; and 93 patients with non-IBD gastrointestinal inflammation [non-IBD GI]), using polymerase chain reaction with restriction fragment length polymorphism and TaqMan minor groove binding. Phenotypical data on all patients as well as sVEGF levels were correlated with the genetic data. RESULTS: Both the VEGF genotype and haplotype frequencies did not differ between IBD patients and controls, and no distortion of transmission was observed. sVEGF levels were increased in IBD but also in non-IBD GI patients, compared with HC, and were only influenced by VEGF polymorphisms in patients with Crohn's disease (-G1154A genotype and -2578/-1154/-634 AAG promoter haplotype). CONCLUSIONS: The VEGF polymorphisms studied are not implicated in susceptibility to IBD and do not predict sVEGF levels. Although increased sVEGF and angiogenesis are important features of IBD, they do not appear genetically determined.

Adolescent↗

PubMed2006

Differences in tumor-associated protein levels among middle-age Flemish women in association with area of residence and exposure to pollutants.

We measured tumor-associated proteins (TAPs) and pollutants in blood, serum, and urine of 200 nonsmoking women 50-65 years of age, residing in the rural municipality of Peer or in Hoboken or Wilrijk, industrial suburbs of Antwerp, Belgium. Persons with occupational exposures or commuting to other towns were excluded. Residents from Hoboken had significantly higher levels of blood lead and serum zinc and polychlorinated biphenyls. Surprisingly, residents of Peer had significantly higher levels of serum cadmium, dioxin-like activity in blood fat, and urinary 1-hydroxypyrene. For 5 of the 12 TAPs assessed in this study, we observed significant differences in serum levels among residents of the three municipalities after adjusting for personal or lifestyle parameters. Although we found levels of internal exposure to pollutants to be quite homogeneous in Flanders, we found significantly higher levels of TAPs only in the industrial suburbs. In multiple regression with all 29 available personal, lifestyle, and internal exposure parameters, blood lead levels showed a positive association with serum levels of anti-p53, carcino-embryonic antigen (CEA), and tissue polypeptide-specific antigen (TPS) and with an index for mean TAP level (I(tap)); dioxin-like activity in serum and serum copper showed a positive association with serum CA 125 (cancer antigen 125); and serum zinc showed a positive association with serum levels of c-erbB-2 ectodomain and TPS. An index of internal exposure showed a positive association with serum levels of both CEA and anti-p53 and with I(tap). This study provides some evidence that levels of internal exposure such as those present in Flanders, in particular concerning lead, are indeed associated with biologic effects.

Aged↗

PubMed2006

Serum dioxin-like activity is associated with reproductive parameters in young men from the general Flemish population.

BACKGROUND: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and some related environmental contaminants are aryl hydrocarbon receptor (AhR) ligands that exert reproductive and developmental toxicity in laboratory animals. In humans, fertility-related effects are less documented. OBJECTIVE: The aim of this study was to investigate the relationship between dioxin-like biological activity in serum and parameters of reproductive status in men from the general population 5 months after a polychlorinated biphenyl and dioxin food-contamination episode in Belgium. DESIGN: In the framework of the cross-sectional Flemish Environment and Health Study (FLEHS), we recruited 101 men 20-40 years of age and evaluated sperm parameters, measured sex hormones, and gathered information on a number of lifestyle factors. In addition, we determined the AhR-mediated enzymatic response elicited by individual serum samples and expressed it as TCDD equivalent concentrations (CALUX-TEQs) using an established transactivation assay. RESULTS: Age (p = 0.04) and the frequency of fish (p = 0.02) and egg (p = 0.001) consumption were independent positive determinants of serum dioxin-like activity. After correcting for possible confounders, we found that a 2-fold increase in CALUX-TEQ > 16 pg/L was associated with a 7.1% and 6.8% (both p = 0.04) decrease in total and free testosterone, respectively. We also observed a more pronounced drop in semen volume of 16.0% (p = 0.03), whereas sperm concentration rose by 25.2% (p = 0.07). No relationship was found with total sperm count or sperm morphology. CONCLUSIONS: These data suggest an interaction of dioxin-like compounds with the secretory function of the seminal vesicles or prostate, possibly indirectly through an effect on testosterone secretion, at levels not affecting spermatogenesis as such.

Adult↗

PubMed2006

Curves of placental weights of live-born twins.

The purpose of this study is to present curves of estimated placental growth in twins and to evaluate the relative contribution of gestational age, zygosity, chorionicity, fusion of the placentas, sex of the individual and of the twin pair, site of the umbilical cord insertion, birth order, maternal age, and parity. Perinatal data and placental data were obtained from 6315 live-born twin pairs from the East Flanders Prospective Twin Survey. Of 4318 twin pairs, with no missing values, the placental weights of different gestational ages were analyzed using a nonlinear multivariate Gaussian regression. Two groups were distinguished: (1) twins with two separate placentas, and (2) twins with only one placental mass (one placenta in case of monochorionic twins or two fused placentas in case of dichorionic placentas). Overall, placental weight was influenced by gestational age, fusion of the placentas, and parity. In the case of one placental mass, monozygotic dichorionic twins had the lowest weights. If two separate placentas were present, birth order played a role in favor of the first-born twin. For parity and zygosity, the differences were most pronounced between 27 and 29 weeks, whereas the difference for birth order was most pronounced between 33 and 37 weeks. In conclusion, basic physiological characteristics, routinely examined at birth, influence placental weight. Taking these covariates into account allows a better evaluation of the placental weight given a gestational age, as an indicator of growth.

Adult↗

PubMed2005

Birth weight and creatinine clearance in young adult twins: influence of genetic, prenatal, and maternal factors.

Previous studies have shown that low birth weight (LBW) is a risk factor for renal impairment in adult life. The effects of LBW and renal function were studied by using twins, which allows distinguishing among fetoplacental, maternal, and genetic influences. Perinatal data were obtained at birth, and absolute creatinine clearance (not corrected for body surface area) was measured at a mean age of 25.6 yr in 653 individuals. Twins were considered both as individuals and as members of twin pairs. Statistical analyses were performed with and without adjusting for gestational age, zygosity, gender, age, body mass index, glucose level, BP, and smoking status. Creatinine clearance was 4 ml/min lower in twins with LBW (<2500 g) than in twins with a high birth weight (P < 0.04, adjusted). Intrapair birth weight difference correlated positively with the intrapair difference in creatinine clearance equally in monozygotic and dizygotic twins (r = 0.35, P < 0.0001; r = 0.43, P < 0.0001, respectively). This suggests that fetoplacental factors are related to renal function and that genetic factors are less important. There was no significant difference in creatinine clearance between twins who both had LBW as compared with twins who both had a high birth weight. This may suggest that maternal factors, which influence the relation between LBW and renal function, are less important. LBW is related to a lower creatinine clearance at adult age. This relationship is probably due to fetoplacental factors. Surprising, genetic and maternal factors seem less important.

Adult↗

PubMed2005

Genetic and environmental determination of tracking in static strength during adolescence.

The purpose of this study was to determine whether the observed phenotypic stability in static strength during adolescence, as measured by interage correlations in arm pull, is mainly caused by genetic and/or environmental factors. Subjects were from the Leuven Longitudinal Twin Study (n = 105 pairs, equally divided over 5 zygosity groups). Arm-pull data were aligned on age at peak height velocity to attenuate the temporal fluctuations in interage correlations caused by differences in timing of the adolescent growth spurt. Developmental genetic models were fitted using structural equation modeling. After the data were aligned on age at peak height velocity, the annual interage correlations conformed to a quasi-simplex structure over a 4-yr interval. The best-fitting models included additive genetic and unique environmental sources of variation. Additive genetic factors that already explained a significant amount of variation at previous measurement occasions explained 44.3 and 22.5% of the total variation at the last measurement occasion in boys and girls, respectively. Corresponding values for unique environmental sources of variance are 31.2 and 44.5%, respectively. In conclusion, the observed stability of static strength during adolescence is caused by both stable genetic influences and stable unique environmental influences in boys and girls. Additive genetic factors seem to be the most important source of stability in boys, whereas unique environmental factors appear to be more predominant in girls.

Adolescent↗

PubMed2005

Genetic and environmental causes of tracking in explosive strength during adolescence.

PURPOSE: To determine whether the observed phenotypic stability in explosive strength during adolescence, as measured by inter-age correlations in vertical jump (VTJ), is mainly caused by genetic and/or environmental factors. METHODS: Subjects are from the Leuven Longitudinal Twin Study (LLTS) (n = 105 pairs, equally divided over five zygosity groups). VTJ data were aligned on age at peak height velocity (APHV) to attenuate the temporal fluctuations in inter-age correlations caused by differences in timing of the adolescent growth spurt. Simplex models were fitted using structural equation modelling. RESULTS: After aligning the data on APHV, the annual inter-age correlations show a clear simplex structure over a 4 year interval. The best fitting models included additive genetic and unique environmental sources of variation. Heritability estimates ranged between 60.8% (CI 37.7%-77.2%) and 87.3% (CI 74.2%-94.0%) for boys and between 76.5% (CI 56.7%-89.0%) and 88.6% (CI 77.8%-94.1%) for girls. Up to 56.4% and 62.8% of the total variation at the last measurement occasion is explained by additive genetic factors that already explained a significant amount of variation at previous measurement occasions in boys and girls respectively. It thus can be concluded that the observed stability of explosive strength during adolescence is mainly caused by a stable genetic influence in boys and girls. CONCLUSIONS: Additive genetic factors seem to be the main cause of the observed phenotypic stability in VTJ performance in boys and girls during adolescence.

Adolescent↗

PubMed2005

Association of organic cation transporter risk haplotype with perianal penetrating Crohn's disease but not with susceptibility to IBD.

BACKGROUND & AIMS: Three years after the identification of NOD2/CARD15, 2 more genes for inflammatory bowel diseases (IBDs) were reported. The carnitine/organic cation transporter (OCTN) on 5q31 (IBD5) is associated with Crohn's disease (CD) and DLG5 (10q23), a member of membrane-associated guanylate kinase (MAGUK) family, with IBD. We studied mutation prevalence, assessed phenotypic expression, and performed conditional analysis to examine evidence for gene-gene interactions. METHODS: A cohort of 2032 individuals was genotyped for disease-associated OCTN and DLG5 variants, including 981 patients with IBD (CD, n = 769; ulcerative colitis, n = 186; indeterminate colitis, n = 26) followed up at a tertiary IBD center. For 373 patients, DNA from both parents was available (cohort 1) for transmission disequilibrium testing analysis; case-control analysis was performed in 608 patients and 305 controls (cohort 2). RESULTS: There was no distortion of transmission toward affected offspring for any of the variant alleles. Case-control analysis also failed to shown an association. A higher frequency of DLG5 113A was observed in CARD15-positive patients (12.2%) compared with CARD15-negative patients (8.7%; P = .033). The OCTN-TC risk haplotype was associated with penetrating disease (odds ratio, 1.474; 95% confidence interval, 1.028-2.114; P = .035). For DLG5, there were no associations with a particular phenotype. CONCLUSIONS: DLG5 and OCTN do not play a role in the susceptibility to IBD, CD, or ulcerative colitis in the Flemish population but play a role in the phenotypic expression of the disease. OCTN variants were associated with perianal and penetrating CD. More studies in independent populations are urgently needed to assess the validity of DLG5 and OCTN in the pathogenesis of IBD.

Adolescent↗

PubMed2005

Genetic analysis of physical activity in twins.

BACKGROUND: The reduced contribution of physical activity (PA) to daily energy expenditure contributes to the increased prevalence of obesity. A genetic control of activity-induced energy expenditure (AEE) may contribute to a genetic susceptibility to obesity. OBJECTIVE: Our aim was to investigate the relative contribution of genetic and environmental factors to the variation and covariation in AEE and PA. DESIGN: Twelve monozygotic and 8 same-sex dizygotic (including 2 same-sex sibling pairs; age differences: 2 and 2.5 y) twin pairs aged between 18 and 39 y participated. AEE was measured in a respiration chamber for 24 h and with doubly labeled water in daily life for 2 wk. PA was recorded simultaneously with a triaxial accelerometer. Structural equation modeling was used to separate and quantify the observed variance into sex-adjusted additive genetic and common and unique environmental contributions. RESULTS: In the respiration chamber, common and unique environmental factors explained the variance in AEE and PA, and no genetic contribution was found. In daily life, genetic factors explained 72% of the variance in AEE and 78% of the variance in PA. Unique environmental factors explained the remaining variance. The same additive genetic factors explained 67% of the covariance in AEE and PA in daily life. CONCLUSIONS: In the present exploratory study that used gold standard measurements for AEE and PA but a limited sample size, genetic influence explained a large part of the variation in AEE and PA in daily life, whereas both AEE and PA were influenced by environment only within the confined area of the respiration chamber.

Acceleration↗

PubMed2005

The IBD international genetics consortium provides further evidence for linkage to IBD4 and shows gene-environment interaction.

BACKGROUND AND AIMS: The inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis are complex disorders with an important genetic determinant. One gene associated with CD has been identified: NOD2/CARD15. Two independent genome-wide scans found significant evidence (logarithm of odds [LOD] 3.6) and suggestive evidence (LOD 2.8) for linkage on locus 14q11-12, also known as the IBD4 locus. To further characterize this locus, we assessed gene-environment interaction (IBD4 x smoking) and phenotypic heterogeneity in a large cohort of IBD-affected sibling pairs as part of an ongoing international collaborative effort. PATIENTS AND METHODS: A total of 733 IBD families, comprising 892 affected sibling pairs, were genotyped for microsatellites D14S261, D14S283, D14S972, and D14S275, spanning the IBD4 locus. Information on gender, ethnicity, age at onset, smoking at diagnosis, extraintestinal manifestations, and disease location was available. RESULTS: A significant distortion in the mean allele sharing (MAS) between affected siblings was observed for CD patients only at each of the four markers (54.6%, 52.8%, 50.4%, and 53.3%, respectively). Maximum linkage for CD was observed at marker D14S261 (multipoint nonparametric linkage score 2.36; P </= 0.01; MAS 54.6%). MAS was higher in CD families in which all siblings or at least one sibling smoked compared with nonsmoking CD families (MAS, 58.90%, 57.50%, and 52.80%, respectively). CONCLUSIONS: The IBD International Genetics Consortium replicated the IBD4 locus on chromosome 14q for CD and also showed evidence for a gene-environment interaction at this locus. Further studies are needed to explore the mechanism by which smoking influences IBD4.

Adolescent↗

PubMed2005

Influence of the endothelial nitric oxide synthase gene on conventional and ambulatory blood pressure: sib-pair analysis and haplotype study.

BACKGROUND: Nitric oxide is involved in the regulation of vascular basal tone and blood pressure. Polymorphisms of NOS3, the gene that codes for endothelial nitric oxide synthase, have been associated with essential hypertension. OBJECTIVE: To look for linkage and association of three di-allelic polymorphisms (Glu298Asp, intron 4 VNTR and T-786C) and the intron 13 CA-repeat of NOS3 with blood pressure as a continuous trait. METHODS: Genotyping was performed in 110 dizygotic white twin pairs from Flanders, Belgium. The influence of NOS3 polymorphisms on conventional and ambulatory blood pressure was assessed by sib-pair analysis and haplotype association analysis. RESULTS: Genotype frequencies were similar to those previously reported in white populations. Sib-pair analysis did not show a significant influence of either polymorphism on blood pressure. Haplotype analysis disclosed a significant association between NOS3 haplotypes and daytime ambulatory diastolic (P = 0.02) and systolic (P < 0.0001) blood pressure, the latter remaining significant after multiple testing was taken into account (P = 0.032). The association between daytime ambulatory systolic blood pressure and NOS3 haplotypes was mainly attributable to four haplotypes accounting for 11.9% of all represented haplotypes. CONCLUSION: We show for the first time a highly significant association of ambulatory blood pressure with NOS3 haplotypes in well-characterized white individuals from Flanders. These results pave the way for studies looking for the influence of NOS3 on blood pressure in high-risk subsets such as diabetic or hypertensive patients. They indicate the importance of ambulatory blood pressure and haplotype analysis in revealing the moderate effect of polymorphisms on blood pressure.

Adult↗