Publications by authors named "Claire Monnereau"

18 Publications

  • Page 1 of 1

DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies.

Genome Med 2020 11 25;12(1):105. Epub 2020 Nov 25.

University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, the Netherlands.

Background: DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits.

Methods: We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment.

Results: DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P = 1; childhood P = 2.00 × 10; adolescence P = 2.10 × 10).

Conclusions: There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.
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http://dx.doi.org/10.1186/s13073-020-00810-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687793PMC
November 2020

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Hum Mol Genet 2019 10;28(19):3327-3338

Unidad de Investigacion Medica en Bioquımica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.
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http://dx.doi.org/10.1093/hmg/ddz161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859434PMC
October 2019

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight.

Nat Commun 2019 04 23;10(1):1893. Epub 2019 Apr 23.

Department of Biological Psychology, Netherlands Twin Register, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (P < 1.06 x 10). In additional analyses in 7,278 participants, <1.3% of birthweight-associated differential methylation is also observed in childhood and adolescence, but not adulthood. Birthweight-related CpGs overlap with some Bonferroni-significant CpGs that were previously reported to be related to maternal smoking (55/914, p = 6.12 x 10) and BMI in pregnancy (3/914, p = 1.13x10), but not with those related to folate levels in pregnancy. Whether the associations that we observe are causal or explained by confounding or fetal growth influencing DNA methylation (i.e. reverse causality) requires further research.
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http://dx.doi.org/10.1038/s41467-019-09671-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478731PMC
April 2019

Maternal body mass index, gestational weight gain, and childhood abdominal, pericardial, and liver fat assessed by magnetic resonance imaging.

Int J Obes (Lond) 2019 03 19;43(3):581-593. Epub 2018 Sep 19.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background/objectives: Maternal obesity and excessive gestational weight gain are associated with an increased risk of obesity in offspring. It remains unclear whether maternal adiposity also affects organ fat, which has important adverse cardiometabolic health consequences and whether the associations reflect intrauterine causal mechanisms. We examined the associations of parental pre-pregnancy body mass index (BMI) and gestational weight gain with general, abdominal, pericardial, and liver fat in 10-year-old children.

Subjects/methods: In a population-based prospective cohort study among 2354 parents and their children, we obtained pre-pregnancy maternal and paternal BMI and gestational weight gain and offspring BMI, fat mass index (total fat/height) by dual-energy X-ray absorptiometry, and subcutaneous fat index (subcutaneous fat/height), visceral fat index (visceral fat/height), pericardial fat index (pericardial fat/height), and liver fat fraction by magnetic resonance imaging (MRI) at 10 years.

Results: A 1-standard deviation score (SDS) higher maternal pre-pregnancy BMI was associated with higher childhood BMI (difference 0.32 (95% confidence interval (CI) 0.28, 0.36) SDS), fat mass index (difference 0.28 (95% CI 0.24, 0.31) SDS), subcutaneous fat index (difference 0.26 (95% CI 0.22, 0.30) SDS), visceral fat index (difference 0.24 (95% CI 0.20, 0.28) SDS), pericardial fat index (difference 0.12 (95% CI 0.08, 0.16) SDS), and liver fat fraction (difference 0.15 (95% CI 0.11, 0.19) SDS). After conditioning each MRI adiposity measure on BMI at 10 years, higher maternal pre-pregnancy BMI remained associated with higher childhood subcutaneous and visceral fat indices. Smaller but not statistically different effect estimates were observed for paternal BMI. Gestational weight gain was not consistently associated with organ fat.

Conclusions: Higher maternal pre-pregnancy BMI, but not gestational weight gain, was associated with higher general and organ fat. Similar associations of pre-pregnancy maternal and paternal BMI with offspring adiposity suggest a role of family shared lifestyle factors and genetics.
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http://dx.doi.org/10.1038/s41366-018-0186-yDOI Listing
March 2019

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium.

Hum Mol Genet 2017 10;26(20):4067-4085

Center for Environmental Research and Children's Health (CERCH), School of Public Health, University of California Berkeley.

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.
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http://dx.doi.org/10.1093/hmg/ddx290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656174PMC
October 2017

Dark Endothelial Spots After Descemet Membrane Endothelial Keratoplasty May Appear as Recurrent Fuchs Dystrophy or Herald Graft Failure or Rejection.

Cornea 2017 Dec;36(12):1480-1485

*Netherlands Institute for Innovative Ocular Surgery, Rotterdam, the Netherlands; †Melles Cornea Clinic, Rotterdam, the Netherlands; and ‡Amnitrans EyeBank, Rotterdam, the Netherlands.

Purpose: To evaluate the clinical significance of dark spots in the donor endothelial cell layer as observed with specular microscopy, in patients who underwent Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy (FED).

Methods: Specular microscopy images of 83 consecutive eyes up to 7 years after DMEK were retrospectively reviewed in a masked fashion for the presence of dark spots and morphologic changes in the endothelial cell layer and processed for endothelial cell density (ECD) measurements.

Results: A normal endothelial cell layer was found in 52/83 eyes (62.7%) (group 0). In the remaining 31/83 eyes, various dark discolorations with or without altered endothelial cell morphology were categorized into 4 groups. Dark spots were classified as artifacts in 10/83 (12.0%) eyes (group I) and as "superimposed" dots in 10/83 (12.0%) eyes (group II), that is, optical irregularities slightly anterior to a healthy endothelial cell layer. In 11/83 (13.3%) eyes, endothelial stress was characterized by dark grayish discolorations and/or nuclear activation (group III). Most of the latter eyes also had a significant ECD decrease; 3 of these eyes later developed secondary graft failure, of which one was preceded by allograft rejection. None of the eyes showed recurrent guttae typical for FED (group IV).

Conclusions: Dark endothelial spots after DMEK for FED may not represent a recurrent disease, but tissue irregularities just anterior to the graft. However, if associated with changes in endothelial cell morphology, nuclear activation and/or ECD decrease, dark discolorations may reflect "cellular stress" heralding secondary graft failure or (subclinical) allograft rejection.
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http://dx.doi.org/10.1097/ICO.0000000000001375DOI Listing
December 2017

Large-scale genome-wide analysis identifies genetic variants associated with cardiac structure and function.

J Clin Invest 2017 May 10;127(5):1798-1812. Epub 2017 Apr 10.

Background: Understanding the genetic architecture of cardiac structure and function may help to prevent and treat heart disease. This investigation sought to identify common genetic variations associated with inter-individual variability in cardiac structure and function.

Methods: A GWAS meta-analysis of echocardiographic traits was performed, including 46,533 individuals from 30 studies (EchoGen consortium). The analysis included 16 traits of left ventricular (LV) structure, and systolic and diastolic function.

Results: The discovery analysis included 21 cohorts for structural and systolic function traits (n = 32,212) and 17 cohorts for diastolic function traits (n = 21,852). Replication was performed in 5 cohorts (n = 14,321) and 6 cohorts (n = 16,308), respectively. Besides 5 previously reported loci, the combined meta-analysis identified 10 additional genome-wide significant SNPs: rs12541595 near MTSS1 and rs10774625 in ATXN2 for LV end-diastolic internal dimension; rs806322 near KCNRG, rs4765663 in CACNA1C, rs6702619 near PALMD, rs7127129 in TMEM16A, rs11207426 near FGGY, rs17608766 in GOSR2, and rs17696696 in CFDP1 for aortic root diameter; and rs12440869 in IQCH for Doppler transmitral A-wave peak velocity. Findings were in part validated in other cohorts and in GWAS of related disease traits. The genetic loci showed associations with putative signaling pathways, and with gene expression in whole blood, monocytes, and myocardial tissue.

Conclusion: The additional genetic loci identified in this large meta-analysis of cardiac structure and function provide insights into the underlying genetic architecture of cardiac structure and warrant follow-up in future functional studies.

Funding: For detailed information per study, see Acknowledgments.
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http://dx.doi.org/10.1172/JCI84840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409098PMC
May 2017

Influence of genetic variants associated with body mass index on eating behavior in childhood.

Obesity (Silver Spring) 2017 04 28;25(4):765-772. Epub 2017 Feb 28.

The Generation R Study Group, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.

Objective: Childhood eating behaviors are associated with body mass index (BMI). Recent genome-wide association studies have identified many single-nucleotide polymorphisms (SNPs) associated with adult and childhood BMI. This study hypothesized that these SNPs also influence eating behavior.

Methods: In a population-based prospective cohort study among 3,031 children (mean age [standard deviation]: 4.0 [0.1] years), two weighted genetic risk scores, based on 15 childhood and 97 adult BMI SNPs, and ten individual appetite- and/or satiety-related SNPs were tested for association with food fussiness, food responsiveness, enjoyment of food, satiety responsiveness, and slowness in eating.

Results: The 15 SNP-based childhood BMI genetic risk score was not associated with the eating behavior subscales. The 97 SNP-based adult BMI genetic risk score was nominally associated with satiety responsiveness (β: -0.007 standard deviation, 95% confidence interval [CI] -0.013, 0.000). Of the 10 individual SNPs, rs11030104 in BDNF and rs10733682 in LMX1B were nominally associated with satiety responsiveness (β: -0.057 standard deviation, 95% CI -0.112, -0.002).

Conclusions: These findings do not strongly support the hypothesis that BMI-associated SNPs also influence eating behavior at this age. A potential role for BMI SNPs in satiety responsiveness during childhood was observed; however, no associations with the other eating behavior subscales were found.
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http://dx.doi.org/10.1002/oby.21778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496668PMC
April 2017

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

Nat Genet 2016 12 31;48(12):1462-1472. Epub 2016 Oct 31.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
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http://dx.doi.org/10.1038/ng.3698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695684PMC
December 2016

Associations of genetic risk scores based on adult adiposity pathways with childhood growth and adiposity measures.

BMC Genet 2016 08 18;17(1):120. Epub 2016 Aug 18.

The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, P.O. Box 2040, 3000, CA, Rotterdam, The Netherlands.

Background: Results from genome-wide association studies (GWAS) identified many loci and biological pathways that influence adult body mass index (BMI). We aimed to identify if biological pathways related to adult BMI also affect infant growth and childhood adiposity measures.

Methods: We used data from a population-based prospective cohort study among 3,975 children with a mean age of 6 years. Genetic risk scores were constructed based on the 97 SNPs associated with adult BMI previously identified with GWAS and on 28 BMI related biological pathways based on subsets of these 97 SNPs. Outcomes were infant peak weight velocity, BMI at adiposity peak and age at adiposity peak, and childhood BMI, total fat mass percentage, android/gynoid fat ratio, and preperitoneal fat area. Analyses were performed using linear regression models.

Results: A higher overall adult BMI risk score was associated with infant BMI at adiposity peak and childhood BMI, total fat mass, android/gynoid fat ratio, and preperitoneal fat area (all p-values < 0.05). Analyses focused on specific biological pathways showed that the membrane proteins genetic risk score was associated with infant peak weight velocity, and the genetic risk scores related to neuronal developmental processes, hypothalamic processes, cyclicAMP, WNT-signaling, membrane proteins, monogenic obesity and/or energy homeostasis, glucose homeostasis, cell cycle, and muscle biology pathways were associated with childhood adiposity measures (all p-values <0.05). None of the pathways were associated with childhood preperitoneal fat area.

Conclusions: A genetic risk score based on 97 SNPs related to adult BMI was associated with peak weight velocity during infancy and general and abdominal fat measurements at the age of 6 years. Risk scores based on genetic variants linked to specific biological pathways, including central nervous system and hypothalamic processes, influence body fat development from early life onwards.
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http://dx.doi.org/10.1186/s12863-016-0425-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991119PMC
August 2016

Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index.

Hum Mol Genet 2016 Jan 24;25(2):389-403. Epub 2015 Nov 24.

School of Women's and Infants' Health, The University of Western Australia, Perth, Australia.

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
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http://dx.doi.org/10.1093/hmg/ddv472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854022PMC
January 2016

The Influence of Known Genetic Variants on Subclinical Cardiovascular Outcomes in Childhood: Generation R Study.

Circ Cardiovasc Genet 2015 Aug 24;8(4):596-602. Epub 2015 Apr 24.

From the The Generation R Study Group (R.V.G.P., C.M., A.H., V.W.V.J., J.F.F.), Department of Epidemiology (R.V.G.P., C.M., A.H., V.W.V.J., J.F.F.), and Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands (R.V.G.P., C.M., V.W.V.J., J.F.F.).

Background: Genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) for subclinical cardiovascular outcomes in adults. We examined the influence of these variants on the same outcomes in childhood.

Methods And Results: In a population-based prospective cohort study among 4137 children, we examined the associations of SNPs, individually and incorporated in genetic risk scores, which were identified in adults for cardiac (2 SNPs for left ventricular end-diastolic diameter and 5 SNPs for aortic root diameter) and blood pressure outcomes (29 SNPs for systolic and diastolic blood pressure, 22 SNPs for mean arterial pressure, and 10 SNPs for pulse pressure) with the same outcomes in children (median age of 6.0 years [95% range, 4.5-8.7]). Weighted and unweighted risk scores for aortic root diameter were associated with childhood aortic root diameter (difference per additional average risk allele 0.09 mm [95% CI: 0.05, 0.13]). Weighted and unweighted risk scores for pulse pressure were associated with childhood pulse pressure (difference per additional average risk allele 0.22 mm Hg [95% CI: 0.08, 0.35] and 0.18 mm Hg [95% CI: 0.05, 0.31], respectively), but not with childhood systolic or diastolic blood pressure or mean arterial pressure. The risk scores for blood pressure and mean arterial pressure were not associated with any of the childhood blood pressure outcomes.

Conclusions: Genetic risk scores based on SNPs for aortic root diameter and pulse pressure in adults are associated with the same outcomes in children. SNPs related to cardiovascular outcomes in adulthood at least partly influence cardiovascular development from early life onwards.
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http://dx.doi.org/10.1161/CIRCGENETICS.114.000915DOI Listing
August 2015

Descemet Membrane Endothelial Keratoplasty--Reply.

JAMA Ophthalmol 2015 Jun;133(6):725

Netherlands Institute for Innovative Ocular Surgery (NIIOS), Rotterdam, the Netherlands2Melles CorneaClinic Rotterdam, Rotterdam, the Netherlands3Amnitrans Eyebank Rotterdam, Rotterdam, the Netherlands.

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http://dx.doi.org/10.1001/jamaophthalmol.2015.0486DOI Listing
June 2015

Dehydration of corneal anterior donor tissue with polyethylene glycol (PEG)-enriched media.

Cell Tissue Bank 2015 Sep 29;16(3):399-409. Epub 2014 Nov 29.

Amnitrans EyeBank Rotterdam, Rotterdam, The Netherlands.

Anterior donor grafts (including scleral rim, without Descemet membrane) increase in thickness and become hazy upon storage in organ culture (OC) medium. Transfer of these grafts to standard dehydration media just before transplantation does not reduce their thickness to normal. Therefore, we assessed the efficacy of different media enriched with polyethylene glycol (PEG) as dehydrating agents for organ-cultured anterior donor grafts. Grafts were harvested and stored in the commercial OC medium 'Max' (without dextran) for 1 week, and subsequently dehydrated in the standard commercial dehydration medium 'Jet' (with dextran) supplemented with 4-20% PEG3350, or 'Max' supplemented with 20% PEG6000 and PEG20.000, or 5-20% PEG35.000. Central corneal thickness (CCT), as assessed by anterior segment-optical coherence tomography, and transparency were evaluated before, and at 1, 4 and 7 days of dehydration. Transfer of grafts after 1 week of OC (average 1,200 µm) to 'Jet' supplemented with PEG3350 revealed a concentration-dependent effect of dehydration; CCT was restored to normal (500-600 µm) when 10% PEG3350 was added. However, transparency was only temporarily restored; after 1 day, the grafts turned hazy. In contrast, grafts transferred to 'Max' supplemented with 20% PEG35.000 were transparent throughout the evaluation period, but were dehydrated to beyond normal levels (average 300 µm). 'Max' supplemented with 5% PEG35.000 dehydrated grafts to normal values and restored transparency throughout. Thus, dehydration of anterior donor grafts prior to surgery in dextran-free OC medium supplemented with 5% PEG35.000 reduces graft thickness to normal and may facilitate anterior keratoplasty procedures.
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http://dx.doi.org/10.1007/s10561-014-9484-3DOI Listing
September 2015

Multicenter study of descemet membrane endothelial keratoplasty: first case series of 18 surgeons.

JAMA Ophthalmol 2014 Oct;132(10):1192-8

Netherlands Institute for Innovative Ocular Surgery (NIIOS), Rotterdam, the Netherlands2Melles CorneaClinic Rotterdam, Rotterdam, the Netherlands3Amnitrans Eyebank Rotterdam, Rotterdam, the Netherlands.

Importance: Surgeons starting to perform Descemet membrane endothelial keratoplasty (DMEK) should be informed about the learning curve and experience of others.

Objective: To document the clinical outcome of standardized "no-touch" DMEK and its complications during the learning curves of experienced surgeons.

Design, Setting, And Participants: Retrospective multicenter study. A total of 431 eyes from 401 patients with Fuchs endothelial dystrophy (68.2%) and bullous keratopathy (31.8%) underwent DMEK performed by 18 surgeons in 11 countries.

Exposures: Descemet membrane endothelial keratoplasty.

Main Outcomes And Measures: Best-corrected visual acuity (BCVA), endothelial cell density, and intraoperative and postoperative complications.

Results: Of 275 eyes available for BCVA pooled analysis, BCVA improved in 258 eyes (93.8%), remained unchanged in 12 (4.4%), and deteriorated in 5 (1.8%). Two hundred seventeen eyes (78.9%) reached a BCVA of at least 20/40 (≥0.5), 117 (42.5%) at least 20/25 (≥0.8), and 61 (22.2%) at least 20/20 (≥1.0). Eyes with at least 6 months of follow-up (n = 176) reached similar BCVA outcomes. Mean (SD) decrease in endothelial cell density at 6 months was 47% (20%) (n = 133 [P = .02]). Intraoperative complications were rare, including difficulties in inserting, unfolding, or positioning of the graft (1.2%) and intraoperative hemorrhage (0.5%). The main postoperative complication was graft detachment (34.6%); 20.4% underwent a single rebubbling procedure, occasionally requiring a second (2.6%) and a third rebubbling (0.7%), and 17.6% underwent a second keratoplasty.

Conclusions And Relevance: Our multicenter study showed that the standardized no-touch DMEK technique was feasible in most hands. The main challenges for surgeons starting to perform the procedure may be (1) to decide whether graft preparation is outsourced or performed during surgery, (2) to limit the number of graft detachments and secondary procedures, and (3) to obtain organ cultured donor corneal tissue.
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http://dx.doi.org/10.1001/jamaophthalmol.2014.1710DOI Listing
October 2014

Endothelial cell changes as an indicator for upcoming allograft rejection following descemet membrane endothelial keratoplasty.

Am J Ophthalmol 2014 Sep 28;158(3):485-95. Epub 2014 May 28.

Netherlands Institute for Innovative Ocular Surgery, Rotterdam, Netherlands; Melles Cornea Clinic Rotterdam, Rotterdam, Netherlands; Amnitrans EyeBank Rotterdam, Rotterdam, Netherlands. Electronic address:

Purpose: To report early, specific changes in donor endothelial cell morphology as a predictor of an upcoming allograft rejection after Descemet membrane endothelial keratoplasty (DMEK).

Design: Retrospective, observational case series.

Methods: Out of a cohort of 500 eyes that underwent DMEK at a tertiary referral center, 7 eyes developed typical clinical signs of an allograft rejection. Specular microscopy images before, during, and after the rejection episode were analyzed and compared with a case-control group of 49 asymptomatic DMEK eyes that matched baseline characteristics of the rejection group. Endothelial cell morphology was evaluated by subjective scoring (range 1-5) in a masked fashion as well as by an objective comparison of endothelial cell density, cell size, coefficient of variation, and hexagonality in rejection vs control eyes.

Results: Subjective scores (median) were higher before and after rejection (2.5 and 5, respectively) than in the DMEK control group (2.0 and 2.5, respectively) at comparable time points (P = .0230 and P = .0005, respectively). Endothelial cell density also differed before (P = .0106) and after rejection (P = .0240), while hexagonality differed before (P = .0499) but not after rejection (P = .1767).

Conclusion: Our study suggests that allograft rejection may not be an acute event, but rather a slow-onset immune response. Early, specific changes in endothelial cell morphology were found to "announce" an upcoming allograft rejection. If so, monitoring donor endothelium after DMEK or other forms of keratoplasty may be used to anticipate a rejection episode and/or to prevent an allograft rejection from clinically manifesting itself.
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http://dx.doi.org/10.1016/j.ajo.2014.05.030DOI Listing
September 2014

Predicting the "First dose in children" of CYP3A-metabolized drugs: Evaluation of scaling approaches and insights into the CYP3A7-CYP3A4 switch at young ages.

J Clin Pharmacol 2014 Sep 28;54(9):1006-15. Epub 2014 Mar 28.

Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands; Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Europe, Leiderdorp, The Netherlands.

First-dose-in-children relies on the prediction of clearance from adults for which little information is available on the accuracy of the scaling-approaches applied. For CYP3A-metabolized compounds, scaling of clearance is further challenged by different isoforms and by the CYP3A7 to CYP3A4 switch at young ages. This investigation aimed to evaluate the accuracy of two frequently used scaling approaches and to gain insights into the ontogeny of CYP3A. Hence, a literature database was compiled containing 203 clearance values from term-neonates to adults for 18 CYP3A-metabolized compounds. The clearances in adults were scaled to children using (i) allometric scaling plus maturation function and (ii) a mechanistic approach based on the well-stirred model. Three maturation functions were separately evaluated. In children >3 months, all approaches were interchangeable heeding the maturation function applied and biases were mostly observed in children <3 months. The results from a sensitivity analysis indicate that these biases are possibly caused by disregarding the CYP3A7 activity which could account for up to 86% of the metabolism in term-neonates. Only the mechanistic approach using an overall-CYP3A maturation function led to unbiased predictions of clearances across all ages. The current investigation adds to the predictions of the first-dose-in-children of compounds (partially) metabolized by CYP3A.
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http://dx.doi.org/10.1002/jcph.294DOI Listing
September 2014
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