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1.  Pre- and Postnatal Determinants of Deciduous Molar Hypomineralisation in 6-Year-Old Children. The Generation R Study 
PLoS ONE  2014;9(7):e91057.
Background
Deciduous Molar Hypomineralisation (DMH) and Molar Incisor Hypomineralisation (MIH) are common developmental disturbances in pediatric dentistry. Their occurrence is related. The same determinants as suggested for MIH are expected for DMH, though somewhat earlier in life. Perinatal medical problems may influence the prevalence of DMH but this has not been studied sufficiently.
Objective
This study aimed to identify possible determinants of DMH in a prospective cohort study among 6-year-old children.
Study Design
This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life until young adulthood. The the data were used to identify the determinants of DMH. Clinical photographs of clean, moist teeth were taken with an intra-oral camera in 6690 children (mean age 6.2 years; 49.9% girls). Data on possible determinants that had occurred during pregnancy and/or the child's first year of life were on the basis of manual standardized measurements (like length and weight) and questionnaires. Multivariate analyse with backward and forward selection was performed.
Results
A number of factors in the pre-, peri- and postnatal phase were found to be associated with DMH. After multivariate logistic regression analyses, Dutch ethnic background, low birth weight, maternal alcohol consumption during pregnancy, and fever episodes in the first year of the child's life were found to play a role in the development of DMH in 6-year-old children.
Conclusion
This study shows that Dutch ethnicity, low birth weight, alcohol consumption by the mother during pregnancy and any fever in the first year of the child's life are associated with DMH. Not only childhood factors but also prenatal lifestyle factors need to be taken into account when studying determinants for DMH.
doi:10.1371/journal.pone.0091057
PMCID: PMC4079596  PMID: 24988443
2.  Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error 
Human Molecular Genetics  2013;22(13):2754-2764.
Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study (‘Cooperative Health Research in the Region of Augsburg’); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10−9) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.
doi:10.1093/hmg/ddt116
PMCID: PMC3674806  PMID: 23474815
3.  A genome-wide association study for venous thromboembolism: the extended Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium 
Genetic epidemiology  2013;37(5):512-521.
Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a 2-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended CHARGE VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to ~2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (p≤0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG) (p<5.0×10−13 for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (p<5.0×10-6) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.
doi:10.1002/gepi.21731
PMCID: PMC3990406  PMID: 23650146
venous thrombosis; genetics; genome-wide association; genetic epidemiology
4.  Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function 
Tang, Wenbo | Kowgier, Matthew | Loth, Daan W. | Soler Artigas, María | Joubert, Bonnie R. | Hodge, Emily | Gharib, Sina A. | Smith, Albert V. | Ruczinski, Ingo | Gudnason, Vilmundur | Mathias, Rasika A. | Harris, Tamara B. | Hansel, Nadia N. | Launer, Lenore J. | Barnes, Kathleen C. | Hansen, Joyanna G. | Albrecht, Eva | Aldrich, Melinda C. | Allerhand, Michael | Barr, R. Graham | Brusselle, Guy G. | Couper, David J. | Curjuric, Ivan | Davies, Gail | Deary, Ian J. | Dupuis, Josée | Fall, Tove | Foy, Millennia | Franceschini, Nora | Gao, Wei | Gläser, Sven | Gu, Xiangjun | Hancock, Dana B. | Heinrich, Joachim | Hofman, Albert | Imboden, Medea | Ingelsson, Erik | James, Alan | Karrasch, Stefan | Koch, Beate | Kritchevsky, Stephen B. | Kumar, Ashish | Lahousse, Lies | Li, Guo | Lind, Lars | Lindgren, Cecilia | Liu, Yongmei | Lohman, Kurt | Lumley, Thomas | McArdle, Wendy L. | Meibohm, Bernd | Morris, Andrew P. | Morrison, Alanna C. | Musk, Bill | North, Kari E. | Palmer, Lyle J. | Probst-Hensch, Nicole M. | Psaty, Bruce M. | Rivadeneira, Fernando | Rotter, Jerome I. | Schulz, Holger | Smith, Lewis J. | Sood, Akshay | Starr, John M. | Strachan, David P. | Teumer, Alexander | Uitterlinden, André G. | Völzke, Henry | Voorman, Arend | Wain, Louise V. | Wells, Martin T. | Wilk, Jemma B. | Williams, O. Dale | Heckbert, Susan R. | Stricker, Bruno H. | London, Stephanie J. | Fornage, Myriam | Tobin, Martin D. | O′Connor, George T. | Hall, Ian P. | Cassano, Patricia A. | Chen, Lin
PLoS ONE  2014;9(7):e100776.
Background
Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.
Methods
We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.
Results
The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.
Conclusions
In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.
doi:10.1371/journal.pone.0100776
PMCID: PMC4077649  PMID: 24983941
5.  Associations of NINJ2 Sequence Variants with Incident Ischemic Stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) Consortium 
PLoS ONE  2014;9(6):e99798.
Background
Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.
Methods and Results
We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).
Conclusion
Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings.
doi:10.1371/journal.pone.0099798
PMCID: PMC4069013  PMID: 24959832
6.  Phenotypic Dissection of Bone Mineral Density Reveals Skeletal Site Specificity and Facilitates the Identification of Novel Loci in the Genetic Regulation of Bone Mass Attainment 
PLoS Genetics  2014;10(6):e1004423.
Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (re = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (re = 0.20–0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n∼9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01×10−37), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31×10−14). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4×10−10). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.
Author Summary
The heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To investigate whether the genes underlying bone acquisition act in a site-specific manner, we quantified the shared genetic influences across axial and appendicular skeletal sites by estimating the genetic and residual correlation of BMD at the upper limb, lower limb and the skull. Our results suggest that different skeletal sites as measured by total-body Dual-Energy X-Ray Absorptiometry are to a certain extent under distinct genetic and environmental influences. To further explore the basis for these differences, genome-wide association meta-analyses were performed to identify genetic loci that are preferentially associated with one or more skeletal regions. Variants at 13 loci (including RIN3, a novel BMD associated locus) reached genome-wide significance and several displayed evidence of differential association with BMD across the different skeletal sites in particular CPED1 and WNT16. Our results suggest that it may be advantageous to decompose the total-body BMD measures and perform GWAS at separate skeletal regions. By allowing for site-specific differences, new genetic variants affecting BMD and future risk of osteoporosis may be uncovered.
doi:10.1371/journal.pgen.1004423
PMCID: PMC4063697  PMID: 24945404
7.  Maternal urinary iodine concentration in pregnancy and children's cognition: results from a population-based birth cohort in an iodine-sufficient area 
BMJ Open  2014;4(6):e005520.
Objective
Reports from populations with an insufficient iodine intake suggest that children of mothers with mild iodine deficiency during pregnancy are at risk for cognitive impairments. However, it is unknown whether, even in iodine-sufficient areas, low levels of iodine intake occur that influence cognitive development in the offspring. This study investigated the association between maternal low urinary iodine concentration (UIC) in pregnancy and children's cognition in a population-based sample from a country with an optimal iodine status (the Netherlands).
Setting and participants
In 1525 mother–child pairs in a Dutch multiethnic birth cohort, we investigated the relation between maternal UIC<150 μg/g creatinine, assessed <18 weeks gestation and children's cognition.
Outcomes measures
Non-verbal IQ and language comprehension were assessed during a visit to the research centre using Dutch test batteries when the children were 6 years.
Results
In total, 188 (12.3%) pregnant women had UIC<150 μg/g creatinine, with a median UIC equal to 119.3 μg/g creatinine. The median UIC in the group with UIC>150 μg/g creatinine was 322.9 μg/g and in the whole sample 296.5 μg/g creatinine. There was a univariate association between maternal low UIC and children's suboptimum non-verbal IQ (unadjusted OR=1.44, 95% CI 1.02 to 2.02). However, after adjustment for confounders, maternal low UIC was not associated with children's non-verbal IQ (adjusted OR=1.33, 95% CI 0.92 to 1.93). There was no relation between maternal UIC in early pregnancy and children's language comprehension at 6 years.
Conclusions
The lack of a clear association between maternal low UIC and children's cognition probably reflects that low levels of iodine were not frequent and severe enough to affect neurodevelopment. This may result from the Dutch iodine fortification policy, which allows iodised salt to be added to almost all processed food and emphasises the monitoring of iodine intake in the population.
doi:10.1136/bmjopen-2014-005520
PMCID: PMC4067856  PMID: 24928597
EPIDEMIOLOGY
8.  Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake1234 
Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants.
Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake.
Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 × 10−6 were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n = 7724) provided additional replication data.
Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (β ± SE: 0.25 ± 0.04%; P = 1.68 × 10−8) and lower fat (β ± SE: −0.21 ± 0.04%; P = 1.57 × 10−9) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI)–increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (β ± SE: 0.10 ± 0.02%; P = 9.96 × 10−10), independent of BMI (after adjustment for BMI, β ± SE: 0.08 ± 0.02%; P = 3.15 × 10−7).
Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
doi:10.3945/ajcn.112.052183
PMCID: PMC3652928  PMID: 23636237
9.  High Bone Mineral Density and Fracture Risk in Type 2 Diabetes as Skeletal Complications of Inadequate Glucose Control 
Diabetes Care  2013;36(6):1619-1628.
OBJECTIVE
Individuals with type 2 diabetes have increased fracture risk despite higher bone mineral density (BMD). Our aim was to examine the influence of glucose control on skeletal complications.
RESEARCH DESIGN AND METHODS
Data of 4,135 participants of the Rotterdam Study, a prospective population-based cohort, were available (mean follow-up 12.2 years). At baseline, 420 participants with type 2 diabetes were classified by glucose control (according to HbA1c calculated from fructosamine), resulting in three comparison groups: adequately controlled diabetes (ACD; n = 203; HbA1c <7.5%), inadequately controlled diabetes (ICD; n = 217; HbA1c ≥7.5%), and no diabetes (n = 3,715). Models adjusted for sex, age, height, and weight (and femoral neck BMD) were used to test for differences in bone parameters and fracture risk (hazard ratio [HR] [95% CI]).
RESULTS
The ICD group had 1.1–5.6% higher BMD, 4.6–5.6% thicker cortices, and −1.2 to −1.8% narrower femoral necks than ACD and ND, respectively. Participants with ICD had 47–62% higher fracture risk than individuals without diabetes (HR 1.47 [1.12–1.92]) and ACD (1.62 [1.09–2.40]), whereas those with ACD had a risk similar to those without diabetes (0.91 [0.67–1.23]).
CONCLUSIONS
Poor glycemic control in type 2 diabetes is associated with fracture risk, high BMD, and thicker femoral cortices in narrower bones. We postulate that fragility in apparently “strong” bones in ICD can result from microcrack accumulation and/or cortical porosity, reflecting impaired bone repair.
doi:10.2337/dc12-1188
PMCID: PMC3661786  PMID: 23315602
10.  Low-density lipoprotein receptor mutations generate synthetic genome-wide associations 
Genome-wide association (GWA) studies have discovered multiple common genetic risk variants related to common diseases. It has been proposed that a number of these signals of common polymorphisms are based on synthetic associations that are generated by rare causative variants. We investigated if mutations in the low-density lipoprotein receptor (LDLR) gene causing familial hypercholesterolemia (FH, OMIM #143890) produce such signals. We genotyped 480 254 polymorphisms in 464 FH patients and in 5945 subjects from the general population. A total of 28 polymorphisms located up to 2.4 Mb from the LDLR gene were genome-wide significantly associated with FH (P<10−8). We replicated the 10 top signals in 2189 patients with a clinical diagnosis of FH and in 2157 subjects of a second sample of the general population (P<0.000087). Our findings confirm that rare variants are able to cause synthetic genome-wide significant associations, and that they exert this effect at relatively large distances from the causal mutation.
doi:10.1038/ejhg.2012.207
PMCID: PMC3641383  PMID: 22968135
familial hypercholesterolemia; synthetic associations; LDLR mutations; genome-wide association studies
11.  Identification of a Rare Coding Variant in Complement 3 Associated with Age-related Macular Degeneration 
Nature genetics  2013;45(11):10.1038/ng.2758.
Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry matched controls revealed two large-effect rare variants; previously described R1210C in the CFH gene (fcase = 0.51%, fcontrol = 0.02%, OR = 23.11), and newly identified K155Q in the C3 gene (fcase = 1.06%, fcontrol = 0.39%, OR = 2.68). The variants suggest decreased inhibition of C3 by Factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.
doi:10.1038/ng.2758
PMCID: PMC3812337  PMID: 24036949
12.  Modifiable Etiological Factors and the Burden of Stroke from the Rotterdam Study: A Population-Based Cohort Study 
PLoS Medicine  2014;11(4):e1001634.
Using data from the Rotterdam study, Michiel Bos and colleagues estimate the proportion of strokes that are attributable to established modifiable etiological factors for stroke.
Please see later in the article for the Editors' Summary
Background
Stroke prevention requires effective treatment of its causes. Many etiological factors for stroke have been identified, but the potential gain of effective intervention on these factors in terms of numbers of actually prevented strokes remains unclear because of the lack of data from cohort studies. We assessed the impact of currently known potentially modifiable etiological factors on the occurrence of stroke.
Methods and Findings
This population-based cohort study was based on 6,844 participants of the Rotterdam Study who were aged ≥55 y and free from stroke at baseline (1990–1993). We computed population attributable risks (PARs) for individual risk factors and for risk factors in combination to estimate the proportion of strokes that could theoretically be prevented by the elimination of etiological factors from the population.
The mean age at baseline was 69.4 y (standard deviation 6.3 y). During follow-up (mean follow-up 12.9 y, standard deviation 6.3 y), 1,020 strokes occurred. The age- and sex-adjusted combined PAR of prehypertension/hypertension, smoking, diabetes mellitus, atrial fibrillation, coronary disease, and overweight/obesity was 0.51 (95% CI 0.41–0.62) for any stroke; hypertension and smoking were the most important etiological factors. C-reactive protein, fruit and vegetable consumption, and carotid intima-media thickness in combination raised the total PAR by 0.06. The PAR was 0.55 (95% CI 0.41–0.68) for ischemic stroke and 0.70 (95% CI 0.45–0.87) for hemorrhagic stroke.
The main limitations of our study are that our study population comprises almost exclusively Caucasians who live in a middle and high income area, and that risk factor awareness is higher in a study cohort than in the general population.
Conclusions
About half of all strokes are attributable to established causal and modifiable factors. This finding encourages not only intervention on established etiological factors, but also further study of less well established factors.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, 15 million people worldwide have a stroke. About 6 million of these people die within hours, and another 5 million are left disabled. Stroke occurs when the brain's blood supply is suddenly interrupted by a blood vessel in the brain being blocked by a blood clot (ischemic stroke) or bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. In the longer term, post-stroke rehabilitation can help overcome the disabilities caused by stroke, and various drugs alongside behavioral counselling can reduce the risk of a second stroke.
Why Was This Study Done?
Fifty years ago, it was discovered that treatment of high blood pressure (hypertension) reduces the risk of stroke among people with severe hypertension. This discovery led researchers to search for other potentially modifiable etiological factors for stroke (risk factors that cause stroke). The list of established etiological factors now includes smoking, diabetes, atrial fibrillation (an irregular heartbeat), heart disease, and overweight/obesity, in addition to hypertension. But how many strokes would modification of these causal risk factors prevent? In this population-based cohort study, the researchers calculate the individual and combined population attributable risks (PARs) for these established etiological factors to provide an estimate of what proportion of strokes could theoretically be prevented by optimal treatment of known etiological factors. A population-based cohort study enrolls a group of people, determines their characteristics at baseline, and follows them to see whether specific characteristics are associated with specific outcomes. A PAR of an etiological factor for a disease indicates the proportion of that disease in the population that would not occur in the absence of the risk factor.
What Did the Researchers Do and Find?
The researchers used data from 6,844 participants in the Rotterdam Study, which was designed to investigate the causes and consequences of long-term and disabling diseases in the elderly. At baseline, all of the participants were over 55 years old and free from stroke. During follow-up, 1,020 strokes occurred among the participants. Using data on exposure at baseline to various etiological factors for stroke, the researchers calculated PARs for individual factors and used a special statistical technique to calculate PARs for the factors in combination. The combined PAR of prehypertension/hypertension, smoking, diabetes, atrial fibrillation, heart disease, and overweight/obesity was 0.51 for any stroke. That is, about half of the strokes in the study population were attributable to this combination of etiological factors. Hypertension and smoking were the most important individual factors (PARs of 0.36 and 0.16, respectively). Notably, the inclusion of several less well established etiological factors (increased blood levels of C-reactive protein, low fruit and vegetable consumption, and thickening of the lining of arteries) only raised the total PAR for any stroke by 0.06.
What Do These Findings Mean?
These findings indicate that about half of the strokes in the study cohort were attributable to established modifiable etiological factors and could theoretically be prevented by eliminating these risk factors from the population. Previous studies have estimated that a larger proportion of strokes could be prevented by eliminating known etiological factors. The researchers acknowledge that some aspects of their study may have led to an underestimation of the proportion of stroke attributable to established etiological factors and note that their findings may not be generalizable to underprivileged or racially diverse populations. Nevertheless, they argue that previous studies are likely to have overestimated the PARs for stroke because they were based on case–control studies (in which exposure to etiological factors was assessed after a stroke had occurred in cases and control individuals, rather than before a stroke as in a population-based cohort study) and often did not use optimal statistical techniques to calculate the total PAR. Importantly, these new findings underscore the importance of interventions targeted at reducing smoking and hypertension and support the search for additional etiological factors for stroke.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001634.
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); its Know Stroke site provides educational materials about stroke prevention, treatment, and rehabilitation including personal stories (in English and Spanish); the US National Institutes of Health SeniorHealth website has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices website also provides information about stroke for patients and their families, including personal stories
MedlinePlus has links to additional resources about stroke (in English and Spanish)
Information about the Rotterdam Study is available
The UK not-for-profit website Healthtalkonline provides personal stories about stroke
doi:10.1371/journal.pmed.1001634
PMCID: PMC4004543  PMID: 24781247
13.  Systematic identification of trans-eQTLs as putative drivers of known disease associations 
Nature genetics  2013;45(10):1238-1243.
Identifying the downstream effects of disease-associated single nucleotide polymorphisms (SNPs) is challenging: the causal gene is often unknown or it is unclear how the SNP affects the causal gene, making it difficult to design experiments that reveal functional consequences. To help overcome this problem, we performed the largest expression quantitative trait locus (eQTL) meta-analysis so far reported in non-transformed peripheral blood samples of 5,311 individuals, with replication in 2,775 individuals. We identified and replicated trans-eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Although we did not study specific patient cohorts, we identified trait-associated SNPs that affect multiple trans-genes that are known to be markedly altered in patients: for example, systemic lupus erythematosus (SLE) SNP rs49170141 altered C1QB and five type 1 interferon response genes, both hallmarks of SLE2-4. Subsequent ChIP-seq data analysis on these trans-genes implicated transcription factor IKZF1 as the causal gene at this locus, with DeepSAGE RNA-sequencing revealing that rs4917014 strongly alters 3’ UTR levels of IKZF1. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
doi:10.1038/ng.2756
PMCID: PMC3991562  PMID: 24013639
14.  Analysis of Rare Variants in the C3 Gene in Patients with Age-Related Macular Degeneration 
PLoS ONE  2014;9(4):e94165.
Age-related macular degeneration (AMD) is a progressive retinal disorder affecting over 33 million people worldwide. Genome-wide association studies (GWASs) for AMD identified common variants at 19 loci accounting for 15–65% of the heritability and it has been hypothesized that the missing heritability may be attributed to rare variants with large effect sizes. Common variants in the complement component 3 (C3) gene have been associated with AMD and recently a rare C3 variant (Lys155Gln) was identified which exerts a large effect on AMD susceptibility independent of the common variants. To explore whether additional rare variants in the C3 gene are associated with AMD, we sequenced all coding exons in 84 unrelated AMD cases. Subsequently, we genotyped all identified variants in 1474 AMD cases and 2258 controls. Additionally, because of the known genetic overlap between AMD and atypical hemolytic uremic syndrome (aHUS), we genotyped two recurrent aHUS-associated C3 mutations in the entire cohort. Overall, we identified three rare variants (Lys65Gln (P = 0.04), Arg735Trp (OR = 17.4, 95% CI = 2.2–136; P = 0.0003), and Ser1619Arg (OR = 5.2, 95% CI = 1.0–25; P = 0.05) at the C3 locus that are associated with AMD in our EUGENDA cohort. However, the Arg735Trp and Ser1619Arg variants were not found to be associated with AMD in the Rotterdam Study. The Lys65Gln variant was only identified in patients from Nijmegen, the Netherlands, and thus may represent a region-specific AMD risk variant.
doi:10.1371/journal.pone.0094165
PMCID: PMC3988049  PMID: 24736606
15.  Disk degeneration of the upper lumbar disks is associated with hip pain 
European Spine Journal  2012;22(4):721-726.
Purpose
A possible cause of hip pain is the presence of radiating pain from the higher lumbar spine. Identification of factors associated with hip pain arising from the lumbar spine would aid the physician. The first step in identifying possible factors is to look at the association between hip pain and osteoarthritis of the lumbar spine.
Methods
In an open population based study of people 55 years and older (Rotterdam study), 2,819 lumbar radiographs were scored for the presence and severity of individual radiographic features of disk degeneration. Hip osteoarthritis was scored on anteroposterior pelvic radiographs, and questionnaires including self-reported hip pain were taken. Logistic regression adjusted for possible confounders was used to determine the association between self-reported hip pain and the individual radiographic features of lumbar disk degeneration.
Results
The presence of dis space narrowing grade ≥1 at level L1/L2 was significantly associated with hip pain in the last month (men OR = 2.0; 95 % CI 1.1–3.8 and women OR = 1.7; 95 % CI 1.1–2.5). The presence of disk space narrowing grade ≥1 at level L2/L3 was only significantly associated with hip pain in women. The strength of the associations increased for self-reported chronic hip pain, especially in men (L1/L2 OR = 2.5; 95 % CI 1.3–5.0). The presence of disk space narrowing at the lower levels (L3/L4/L5/S1) was not significantly associated with hip pain.
Conclusion
Our data provide evidence for an association between hip pain and disk space narrowing at disk level L1/L2 and L2/L3. In case of uncertainty of the cause of hip pain, evaluation of lumbar radiographs may help to identify those hip pain patients who might have pain arising from the lumbar spine.
doi:10.1007/s00586-012-2559-6
PMCID: PMC3631034  PMID: 23135791
Hip pain; Back pain; Lumbar disk degeneration
16.  Non-steroidal anti-inflammatory drugs and the risk of atrial fibrillation: a population-based follow-up study 
BMJ Open  2014;4(4):e004059.
Objective
To investigate the association of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of atrial fibrillation in a prospective community-based follow-up study of elderly individuals with uniform case assessment and data on potential confounders.
Design
Data came from the population-based follow-up study, the Rotterdam Study.
Participants
The study comprised 8423 participants without atrial fibrillation at baseline.
Main outcome measures
Atrial fibrillation was ascertained from ECG assessments as well as medical records. Use of NSAIDs was obtained from automated prescription records by linkage with participating pharmacies. We used Cox proportional hazards models to study the association between NSAID drug use and atrial fibrillation. Use of NSAIDs was included in the model as a time-varying variable.
Results
At baseline, the mean age of the study population was 68.5 years (SD: 8.7) and 58% were women. During a mean follow-up of 12.9 years, 857 participants developed atrial fibrillation. Current use of NSAIDs was associated with increased risk compared with never-use (HR 1.76, 95% CI 1.07 to 2.88). Also, recent use (within 30 days after discontinuation of NSAIDs) was associated with an increased risk of atrial fibrillation compared with never-use (HR 1.84, 95% CI 1.34 to 2.51) adjusted for age, sex and several potential confounders.
Conclusions
In this study, use of NSAIDs was associated with an increased risk of atrial fibrillation. Further studies are needed to investigate the underlying mechanisms behind this association.
doi:10.1136/bmjopen-2013-004059
PMCID: PMC3987714  PMID: 24713211
Pharmacology
17.  Evaluation of Systematic Assessment of Asthma-Like Symptoms and Tobacco Smoke Exposure in Early Childhood by Well-Child Professionals: A Randomised Trial 
PLoS ONE  2014;9(3):e90982.
Objectives
This study aimed to evaluate the effectiveness of systematic assessment of asthma-like symptoms and environmental tobacco smoke (ETS) exposure during regular preventive well-child visits between age 1 and 4 years by well-child professionals.
Methods
Sixteen well-child centres in Rotterdam, the Netherlands, were randomised into 8 centres where the brief assessment form regarding asthma-like symptoms and ETS exposure was used and 8 centres that applied usual care. 3596 and 4179 children (born between April 2002 and January 2006) and their parents visited the intervention and control centres, respectively. At child’s age 6 years, physician-diagnosed asthma ever, wheezing, fractional exhaled nitric oxide (FeNO), airway resistance (Rint), health-related quality of life (HRQOL) and ETS exposure at home ever were measured. Linear mixed models were applied.
Results
No differences in asthma, wheezing, FeNO, Rint or HRQOL measurements between intervention and control group were found using multilevel regression in an intention-to-treat analysis (p>0.05). Children of whom the parents were interviewed by using the brief assessment form at the intervention well-child centres had a decreased risk on ETS exposure at home ever, compared to children who visited the control well-child centres, in an explorative per-protocol analysis (aOR = 0.71, 95% CI:0.59–0.87).
Conclusions
Systematic assessment and counselling of asthma-like symptoms and ETS exposure in early childhood by well-child care professionals using a brief assessment form was not effective in reducing the prevalence of physician-diagnosed asthma ever and wheezing, and did not improve FeNO, Rint or HRQOL at age 6 years. Our results hold some promise for interviewing parents and using information leaflets at well-child centres to reduce ETS exposure at home in preschool children.
Trial Registration
Controlled-Trials.com ISRCTN15790308.
doi:10.1371/journal.pone.0090982
PMCID: PMC3953324  PMID: 24626147
18.  Total antioxidant capacity of the diet and major neurologic outcomes in older adults 
Neurology  2013;80(10):904-910.
Objective:
To evaluate total antioxidant capacity of the diet, measured by the ferric-reducing antioxidant power (FRAP) assay, in relation to risks of dementia and stroke, as well as key structural brain volumes, in the elderly.
Methods:
We prospectively studied 5,395 participants in the Rotterdam Study, aged 55 years and older, who were dementia free and provided dietary information at study baseline; 5,285 individuals were also stroke free at baseline, and 462 were dementia and stroke free at the time of an MRI brain scan 5 years after baseline. Dietary data were ascertained using a semiquantitative food-frequency questionnaire, and combined with food-specific FRAP measurements from published tables; this information was aggregated across the diet to obtain “dietary FRAP scores.” Multivariable-adjusted Cox proportional hazard models were used to estimate relative risks of dementia and stroke, and multivariable-adjusted linear regression was used to estimate mean differences in structural brain volumes, across tertiles of dietary FRAP scores.
Results:
During a median 13.8 years of follow-up, we identified approximately 600 cases each of dementia and stroke. In multivariable-adjusted models, we observed no associations between dietary FRAP scores and risk of dementia (p trend = 0.3; relative risk = 1.12, 95% confidence interval = 0.91–1.38, comparing the highest vs lowest FRAP tertiles) or risk of stroke (p trend = 0.3; relative risk = 0.91, 95% confidence interval = 0.75–1.11, comparing extreme FRAP tertiles); results were similar across subtypes of these outcomes. Dietary FRAP scores were unrelated to brain tissue volumes as well.
Conclusions:
Total antioxidant capacity of the diet, measured by dietary FRAP scores, does not seem to predict risks of major neurologic diseases.
doi:10.1212/WNL.0b013e3182840c84
PMCID: PMC3653208  PMID: 23427318
19.  Genetics of cortisol secretion and depressive symptoms: A candidate gene and genome wide association approach 
Psychoneuroendocrinology  2011;36(7):1053-1061.
Summary
Background
Depressive patients often have altered cortisol secretion, but few studies have investigated genetic variants in relation to both cortisol secretion and depression. To identify genes related to both these conditions, we (1) tested the association of single nucleotide polymorphisms (SNPs) in hypothalamic-pituitary-adrenal-axis (HPA-axis) candidate genes with a summary measure of total cortisol secretion during the day (cortisolAUC) (2) performed a genome wide association study (GWAS) of cortisolAUC; and (3) tested the association of identified cortisol-related SNPs with depressive symptoms.
Methods
We analyzed data on candidate SNPs for the HPA-axis, genome-wide scans, cortisol secretion (n=1711) and depressive symptoms (the Centre for Epidemiology Studies Depression Scale, CES-D) (n=2928) in elderly persons of the Rotterdam Study. We used data from the Whitehall II study (n=2836) to replicate the GWAS findings.
Results
Of the 1456 SNPs in 33 candidate genes, minor alleles of 4 SNPs (rs9470080, rs9394309, rs7748266 and rs1360780) in the FKBP5 gene were associated with a decreased cortisolAUC (p<1 × 10(−4) after correction for multiple testing using permutations). These SNPs were also associated with an increased risk of depressive symptoms (rs9470080: OR 1.19 (95%CI 1.0; 1.4). The GWAS for cortisol yielded 2 SNPs with p-values of 1×10(−06) (rs8062512, rs2252459), but these associations could not be replicated.
Conclusions
These results suggest that variation in the FKBP5 gene is associated with both cortisolAUC and the likelihood of depressive symptoms.
doi:10.1016/j.psyneuen.2011.01.003
PMCID: PMC3940151  PMID: 21316860
salivary cortisol; candidate gene; GWAS; FKBP5; depressive symptoms
20.  Television viewing through ages 2-5 years and bullying involvement in early elementary school 
BMC Public Health  2014;14:157.
Background
High television exposure time at young age has been described as a potential risk factor for developing behavioral problems. However, less is known about the effects of preschool television on subsequent bullying involvement. We examined the association between television viewing time through ages 2-5 and bullying involvement in the first grades of elementary school. We hypothesized that high television exposure increases the risk of bullying involvement.
Method
TV viewing time was assessed repeatedly in early childhood using parental report. To combine these repeated assessments we used latent class analysis. Four exposure classes were identified and labeled “low”, “mid-low”, “mid-high” and “high”. Bullying involvement was assessed by teacher questionnaire (n = 3423, mean age 6.8 years). Additionally, peer/self-report of bullying involvement was obtained using a peer nomination procedure (n = 1176, mean age 7.6 years). We examined child risk of being a bully, victim or a bully-victim (compared to being uninvolved in bullying).
Results
High television exposure class was associated with elevated risks of bullying and victimization. Also, in both teacher- and child-reported data, children in the high television exposure class were more likely to be a bully-victim (OR = 2.11, 95% CI: 1.42-3.13 and OR = 3.68, 95% CI: 1.75-7.74 respectively). However, all univariate effect estimates attenuated and were no longer statistically significant once adjusted for maternal and child covariates.
Conclusions
The association between television viewing time through ages 2-5 and bullying involvement in early elementary school is confounded by maternal and child socio-demographic characteristics.
doi:10.1186/1471-2458-14-157
PMCID: PMC3944918  PMID: 24520886
Television; Bullying; Aggression; Children
21.  A genome-wide association study of intra-ocular pressure suggests a novel association in the gene FAM125B in the TwinsUK cohort 
Human Molecular Genetics  2014;23(12):3343-3348.
Glaucoma is a major cause of blindness in the world. To date, common genetic variants associated with glaucoma only explain a small proportion of its heritability. We performed a genome-wide association study of intra-ocular pressure (IOP), an underlying endophenotype for glaucoma. The discovery phase of the study was carried out in the TwinsUK cohort (N = 2774) analyzing association between IOP and single nucleotide polymorphisms (SNPs) imputed to HapMap2. The results were validated in 12 independent replication cohorts of European ancestry (combined N = 22 789) that were a part of the International Glaucoma Genetics Consortium. Expression quantitative trait locus (eQTL) analyses of the significantly associated SNPs were performed using data from the Multiple Tissue Human Expression Resource (MuTHER) Study. In the TwinsUK cohort, IOP was significantly associated with a number of SNPs at 9q33.3 (P = 3.48 × 10−8 for rs2286885, the most significantly associated SNP at this locus), within the genomic sequence of the FAM125B gene. Independent replication in a composite panel of 12 cohorts revealed consistent direction of effect and significant association (P = 0.003, for fixed-effect meta-analysis). Suggestive evidence for an eQTL effect of rs2286885 was observed for one of the probes targeting the coding region of the FAM125B gene. This gene codes for a component of a membrane complex involved in vesicular trafficking process, a function similar to that of the Caveolin genes (CAV1 and CAV2) which have previously been associated with primary open-angle glaucoma. This study suggests a novel association between SNPs in FAM125B and IOP in the TwinsUK cohort, though further studies to elucidate the functional role of this gene in glaucoma are necessary.
doi:10.1093/hmg/ddu050
PMCID: PMC4030784  PMID: 24518671
22.  Toward an operative diagnosis of fussy/picky eating: a latent profile approach in a population-based cohort 
Background
Definitions and assessment methods of fussy/picky eating are heterogeneous and remain unclear.
We aimed to identify an eating behavior profile reflecting fussy/picky eating in children and to describe characteristics of fussy eaters.
Methods
Eating behavior was assessed with the Child Eating Behavior Questionnaire (CEBQ) in 4914 4-year olds in a population-based birth cohort study. Latent Profile Analysis (LPA) was used to identify eating behavior profiles based on CEBQ subscales.
Results and discussion
We found a “fussy” eating behavior profile (5.6% of children) characterized by high food fussiness, slowness in eating, and satiety responsiveness in combination with low enjoyment of food and food responsiveness. Fussy eaters were more often from families with low household income than non-fussy eaters (42% vs. 31.8% respectively; Χ 2 (1) = 9.97, p < .01). When they were 14 months old, fussy eaters had a lower intake of vegetables (t [3008] = 2.42, p < .05) and fish (t [169.77] = 2.40, p < .05) but higher intake of savory snacks (t [153.69] = -2.03, p < .05) and sweets (t [3008] = -2.30, p < .05) compared to non-fussy eaters. Also, fussy eaters were more likely to be underweight at 4 years of age (19.3%) than non-fussy eaters (12.3%; Χ 2 (1) = 7.71, p < .01).
Conclusions
A distinct fussy eating behavior profile was identified by LPA, which was related to family and child characteristics, food intake, and BMI. This behavior profile might be used in future research and the development of interventions.
doi:10.1186/1479-5868-11-14
PMCID: PMC3922255  PMID: 24512388
Fussy eating; Children; Latent profile analysis; Population-based cohort study; Dietary intake; BMI; Child and family characteristics
23.  The Genome of the Netherlands: design, and project goals 
Within the Netherlands a national network of biobanks has been established (Biobanking and Biomolecular Research Infrastructure-Netherlands (BBMRI-NL)) as a national node of the European BBMRI. One of the aims of BBMRI-NL is to enrich biobanks with different types of molecular and phenotype data. Here, we describe the Genome of the Netherlands (GoNL), one of the projects within BBMRI-NL. GoNL is a whole-genome-sequencing project in a representative sample consisting of 250 trio-families from all provinces in the Netherlands, which aims to characterize DNA sequence variation in the Dutch population. The parent–offspring trios include adult individuals ranging in age from 19 to 87 years (mean=53 years; SD=16 years) from birth cohorts 1910–1994. Sequencing was done on blood-derived DNA from uncultured cells and accomplished coverage was 14–15x. The family-based design represents a unique resource to assess the frequency of regional variants, accurately reconstruct haplotypes by family-based phasing, characterize short indels and complex structural variants, and establish the rate of de novo mutational events. GoNL will also serve as a reference panel for imputation in the available genome-wide association studies in Dutch and other cohorts to refine association signals and uncover population-specific variants. GoNL will create a catalog of human genetic variation in this sample that is uniquely characterized with respect to micro-geographic location and a wide range of phenotypes. The resource will be made available to the research and medical community to guide the interpretation of sequencing projects. The present paper summarizes the global characteristics of the project.
doi:10.1038/ejhg.2013.118
PMCID: PMC3895638  PMID: 23714750
whole-genome sequence; trio-design; population genetics
24.  Genetic variants influencing circulating lipid levels and risk of coronary artery disease 
Objectives
Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of LDL-c, HDL-c and triglycerides.
Methods and results
We combined genome-wide association data from eight studies, comprising up to 17,723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37,774 participants from eight populations and also in a population of Indian Asian descent. We also assessed the association between SNPs at lipid loci and risk of CAD in up to 9,633 cases and 38,684 controls.
We identified four novel genetic loci that showed reproducible associations with lipids (P values 1.6 × 10−8 to 3.1 × 10−10). These include a potentially functional SNP in the SLC39A8 gene for HDL-c, a SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-c and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with one or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (P values 1.1 × 10−3 to 1.2 × 10−9).
Conclusions
We have identified four novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-c, genetic loci mainly associated with circulating triglycerides and HDL-c are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
doi:10.1161/ATVBAHA.109.201020
PMCID: PMC3891568  PMID: 20864672
lipids; lipoproteins; genetics; epidemiology
25.  Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers 
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) = 0.75, P = 0.001) and highly advanced age (≥90 years; HR = 0.92, P = 0.028), and show that this association cannot be explained by the association of LTL with the immune-related markers insulin-like growth factor 1 to insulin-like growth factor binding protein 3 molar ratio, C-reactive protein, interleukin 6, cytomegalovirus serostatus or white blood cell counts. We found no difference in LTL between the middle-aged LLS offspring and their spouses (β = 0.006, P = 0.932). Neither did we observe an association of LTL-associated genetic variants with mortality in a prospective meta-analysis of multiple cohorts (n = 8165).
Conclusions: We confirm LTL to be a marker of prospective mortality in middle and highly advanced age and additionally show that this association could not be explained by the association of LTL with various immune-related markers. Furthermore, the approaches performed here do not further support the hypothesis that LTL variation contributes to the genetic propensity for longevity.
doi:10.1093/ije/dyt267
PMCID: PMC4052133  PMID: 24425829
Leukocyte telomere length; prospective mortality; immune-related markers; familial longevity; genetics; human

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