Population-based Lifelines Cohort Research Articles

Genetic Correlates of Biological Aging and the Influence on Prediction of Mortality.

Longevity and disease-free survival are influenced by a combination of genetics and lifestyle. Biological age (BioAge), a measure of aging based on composite biomarkers, may outperform chronological age in predicting health and longevity. This study investigated the relationship between genetic risks, lifestyle factors, and delta age (Δage), estimated as the difference between biological and chronological age. BioAge and Δage were calculated for 52418 participants from the population-based Lifelines cohort. We computed 2 independent polygenic risk scores (PRS) for health span and DNA methylation-based aging clock to characterize genetic risks. The capacity of BioAge to predict all-cause mortality when adjusted for chronological age and genetic risks for aging, was assessed. Obesity, lifestyle, socioeconomic status, sex, and genetic variations in a population contributed to the differences in the rates of accelerated aging. The overall risk of death for a 1-year increase in BioAge for a given chronological age and sex among the genotyped participants was 11% (HR = 1.11; 95% CI: 1.09, 1.13). After adjusting for genetic factors, BioAge maintained its sensitivity for predicting mortality. Findings from this study ascertain that BioAge can be a useful tool for risk stratification in research and aging interventions.

Hypothyroidism, comorbidity and health-related quality of life: a population-based study.

Hypothyroidism is associated with a decreased health-related quality of life (HRQoL). We hypothesized that individuals with hypothyroidism (defined as use of thyroid hormone (TH)) and especially those having an impaired HRQoL are characterized by a high prevalence of comorbid disorders and that the impact of hypothyroidism and comorbidity on HRQoL is synergistic. Presence of comorbidity was based on data obtained using structured questionnaires, physical examination, biochemical measurements and verified medication use. Single morbidities were clustered into 14 different disease domains. HRQoL was measured using the RAND-36. Logistic regression analyses were used to determine the effect of TH use on the odds of having an affected disease domain and a lower score than an age- and sex-specific reference value for HRQoL. TH was used by 4537/14,7201 participants of the population-based Lifelines cohort with a mean (± s.d.) age of 51.0 ± 12.8 years (88% females). Eighty-five percent of the TH users had ≥1 affected disease domain in contrast to 71% of nonusers. TH use was associated with a higher odds of 13 out of 14 affected disease domains independent of age and sex. In a multivariable model, TH use was associated with a decreased HRQoL across six out of eight dimensions. No significant interactions between TH use and affected disease domains were observed. TH users with an impaired HRQoL had significantly more comorbidity than those not having an impaired HRQoL. In this large, population-based study, we demonstrated that TH users had more comorbidity than individuals not using TH. The coexistence of other chronic medical conditions in subjects with TH use led to further lowering of HRQoL in an additive manner.

Coffee consumption and risk of kidney function decline in a Dutch population-based cohort

Background and aimsWhether coffee consumption is associated with changes in estimated glomerular filtration rate (eGFR) is unknown. We investigated the relationship between coffee consumption and annual eGFR change in a large Dutch population-based study. Methods and resultsThis study was performed in 78,346 participants without chronic kidney disease (CKD) in the population-based Lifelines Cohort Study. Coffee consumption was assessed at baseline using food frequency questionnaires. Outcomes were annual eGFR change and a composite kidney outcome (defined as eGFR <60 mL/min per 1.73 m2 or >20 % eGFR decline). Multivariable linear and logistic regression analyses were used to evaluate the associations of coffee consumption (categories and cups/day) with kidney outcomes. Overall, 90 % of the participants drank coffee daily and 36 % drank >2–4 cups/day. Unadjusted mean ± SD annual eGFR change ranged from −2.86 ± 2.96 (for non-coffee drinkers) to −2.35 ± 2.62 (for participants consuming >6 cups/day) mL/min per 1.73 m2. During 3.6 ± 0.9 years follow-up, 11.1 % of participants reached the composite kidney outcome. As compared to non-coffee drinkers, higher coffee consumption was associated with less annual eGFR decline in multivariable models (β [95 % CIs] ranged from 0.15 [0.07, 0.22] for >0–2 cups/day to 0.29 [0.20, 0.38] for >6 cups/day, P-trend <0.001). Consumption of one more cup of coffee per day was associated with a 3 % lower risk of the composite kidney outcome (OR [95%CI], 0.97 [0.96, 0.99]). The inverse association was more pronounced in a subgroup of individuals with diabetes. ConclusionCoffee consumption was inversely associated with annual eGFR change and CKD risk in a large Dutch population-based cohort.

Evolutionary landscape of clonal hematopoiesis in 3,359 individuals from the general population.

Knowledge about evolution of clonal hematopoiesis, which may drive malignant progression, is crucial for clinical decision-making. We investigated the landscape of clonal evolution by error-corrected sequencing on 7,045 sequential samples from 3,359 individuals in the prospective population-based Lifelines cohort, with a special focus on cytosis and cytopenia. Spliceosome (SRSF2/U2AF1/SF3B1) and JAK2 mutated clones show highest growth rates over a median 3.6-year period, while clone sizes for DNMT3A and TP53 increase only marginally, independent of cytosis or cytopenia. Nevertheless, large differences are observed between individuals carrying the same mutation, indicative of modulation by non-mutation-related factors. Clonal expansion is not dependent on classical cancer risk factors (e.g., smoking). Risk for incident myeloid malignancy diagnosis is highest for JAK2, spliceosome, or TP53 mutations and absent for DNMT3A, and it is mostly preceded by cytosis or cytopenia. The results provide important insight into high-risk evolutionary patterns to guide monitoring of "CHIP" and "CCUS."

Women of reproductive age living in the North of the Netherlands: Lifelines Reproductive Origins of Adult Health and Disease (Lifelines-ROAHD) cohort

PurposeThe Lifelines Reproductive Origins of Adult Health and Disease (Lifelines-ROAHD) cohort provides a uniquely detailed dataset allowing investigations of determinants of reproductive health as well as the influence of reproductive...

Sex and gender differences in primary care help-seeking for common somatic symptoms: a longitudinal study

Objective Women are reported to consult general practitioners (GPs) more frequently than men. However, previous studies on sex differences in help-seeking behavior for somatic symptoms do not distinguish between sex and gender, do not account for sex differences in presented symptoms, and are frequently conducted in clinical settings, automatically excluding non-help seekers. Therefore, we aim to assess the independent associations of sex and gender with primary care help-seeking for somatic symptoms in the general population. Design and setting Records from the longitudinal population-based Lifelines Cohort Study were linked to routine electronic health records from GPs. Subjects Participants reporting new-onset common somatic symptoms. Main outcome measures Associations between sex and gender, operationalized via a novel gender-index, with primary care help-seeking for somatic symptoms and differences in the strength of the association between gender and help-seeking for somatic symptoms between women and men. Results Of 20,187 individuals with linked data, 8325 participants (67.5% female; mean age = 44.5 years [SD = 12.9]) reported at least one new-onset somatic symptom. Hereof, 255 (3.1%) consulted the GP within 6 weeks of symptom onset. Female sex was positively associated with consulting the GP (OR = 1.78; 95%CI = 1.13–2.80), whereas feminine gender was not (OR = 0.67; 95%CI = 0.39–1.16). The latter association did not differ in strength between men and women. More paid working days are negatively associated with help-seeking (OR = 0.95; 95%CI = 0.91–0.98). Conclusions The results suggest that female sex rather than feminine gender is associated with primary care help-seeking behavior for somatic symptoms. Nevertheless, clinicians should be aware that gender-related variables, such as mean paid working days, may be associated with help-seeking behavior.

Psychiatric disorders and the onset of self-reported fibromyalgia and chronic fatigue syndrome: The lifelines cohort study.

This study aimed to assess whether psychiatric disorders predict the onset of fibromyalgia and chronic fatigue syndrome (CFS) which develop in the presence of pre-existing muscle pain or fatigue. The population-based Lifelines cohort study included 148,614 adults with relevant data for the fibromyalgia study and 136,423 for the CFS study. Participants with prior self-reported fibromyalgia (or CFS) at baseline were excluded from the relevant analysis. At follow-up (mean 2.4 years), new onsets of each syndrome were identified by self-report. Logistic regression was used to identify which of the baseline variables predicted new onsets of each syndrome. The total number of psychiatric disorders (depression, anxiety, burnout, panic disorder, social phobia, agoraphobia, obsessive-compulsive, and eating disorders) was used as a predictor. Prior to the analyses the samples were divided into those with and without marked muscle pain (for fibromyalgia analysis) or persistent fatigue (for CFS). During follow-up, there were 685/136,423 (0.5%) new onsets of self-reported FM in participants without marked muscle pain and 281/7481 (3.75%) in those with such pain; for CFS it was 292/124,223 (0.2%) for those without and 192/10,025 (1.9%) for those with baseline fatigue. In both univariate and logistic regression analyses of participants with prior persistent fatigue psychiatric disorder was clearly associated with onset of CFS. This was not so for onset of fibromyalgia in participants with prior muscle pain. Although psychiatric disorders did not predict self-reported fibromyalgia or CFS in participants free of pain or fatigue at baseline, in this study psychiatric disorder did predict self-reported CFS in the presence of pre-existing fatigue. Progress in understanding the etiology of these disorders may require studying separately onsets with and without pre-existing key symptoms.

Diet quality, food intake and incident adult-onset asthma: a Lifelines Cohort Study

PurposeDietary factors have been suggested as drivers of the rising prevalence of adult-onset asthma, but evidence is inconclusive, possibly due to the complex interrelation with obesity. We aim to explore the relation of diet quality and food intake with incident adult-onset asthma in normal weight and overweight adults of the prospective population-based Lifelines Cohort Study.MethodsIncident adult-onset asthma was defined as self-reported asthma at ± 4-year follow-up, in adults free of airway disease at baseline. Diet quality scores and food group intake were assessed at baseline. Log-binomial regression analyses were used to estimate adjusted relative risks (RR) between dietary intake (per portion) and incident adult-onset asthma, in categories of BMI (cutoff: 25 kg/m2).Results477 incident asthma cases (75% female, 62% overweight) and 34,698 controls (60% female, 53% overweight) were identified. Diet quality—assessed by the Lifelines Diet Score and Mediterranean Diet Score—was not associated with incident adult-onset asthma in the two BMI groups. Although the dietary intake of several food groups differed between cases and controls, after adjustment for confounders only few remained associated with adult-onset asthma, including red and processed meat (RR: 0.93 per 15 g intake; 95% CI 0.86–0.99) in the normal weight group and intake of cheese (RR 1.09 per 20 g intake; 95% CI 1.00–1.17) and vegetables (RR 1.10 per 50 g intake; 95% CI 1.00–1.21) in the overweight group.ConclusionThe results of this study question the role of food as a ‘simple’ predictor of adult-onset asthma and call for an integrative approach, including a range of modifiable lifestyle factors and further asthma phenotyping.

Sex Differences in the Spectrum of Clonal Hematopoiesis.

Sex Differences in the Spectrum of Clonal Hematopoiesis.

The work-related burden of dry eye

PurposeTo investigate the relationship between dry eye disease (DED) and work functioning, unemployment, absenteeism, and worry about job loss. MethodsDED and unemployment, absenteeism, and ‘worry about job loss’ were assessed in 71,067 subjects (18–65 years, 60% female) from the Dutch population-based Lifelines cohort using the Women's Health study questionnaire and single-item questions, respectively. Work functioning was assessed in 32,475 participants using the Work role functioning questionnaire 2.0. The relationships between DED and work measures were assessed with logistic regression models, corrected for age, sex, BMI, income, educational level, smoking, and 48 comorbidities. Results8.3% of participants had DED and had more impaired work functioning compared to those without DED (49.2% vs 41.1%, OR 1.21, 95% CI 1.10–1.32, corrected for demographics, smoking and 48 comorbidities). DED carried a similar risk of impaired work functioning as rheumatoid arthritis. For participants with highly symptomatic dry eye impaired work functioning was even higher (59.1%) and similar to that of depression. The impaired work functioning seen with increasing symptoms were greater in undiagnosed subjects versus diagnosed subjects (P = 0.03). After correction for comorbidities, DED remained tied to absenteeism and increased worry about job loss, but not unemployment. ConclusionDED was linked to impaired work functioning and absence, but not unemployment. DEDs impact on work functioning is comparable to that of other severe chronic disorders, and undiagnosed subjects may be more affected. This highlights the importance of recognizing DED as a severe disorder and of screening for dry eye in the workplace to aid with diagnosis and treatment.

The relationship between sedentary behavior and dry eye disease

PurposeSedentary behavior (SB) has been linked with low-grade systemic inflammation, which could play a role in the development of dry eye disease (DED). This cross-sectional study aims to investigate the association between SB and DED. MethodsWe assessed 48,418 participants from the population-based Lifelines cohort (58% female, 18–96 years). Women's Health Study (WHS)-defined DED was the primary outcome. SB was assessed using the Marshall Sitting Questionnaire. The relationship between DED and SB was analyzed using logistic regressions, corrected for age, sex, BMI, smoking status, demographics, and 48 comorbidities. Any potential modifying effect of physical activity (PA) was also assessed, and the analyses were repeated excluding the most computer-intensive domains, investigating SB independent from screen exposure. ResultsWHS-defined DED was present in 9.1% of participants. Greater SB was associated with an increased risk of DED (odds ratio (OR) 1.015 per hour/day, 95%CI 1.005–1.024, P = 0.004). The association between SB and DED was only significant for those with less than WHO-recommended PA (OR 1.022, 95%CI 1.002–1.042, P = 0.027), and not in participants meeting WHO's recommendation (OR 1.011, 95%CI 0.999–1.023, P = 0.076). Lastly, when excluding computer-related sitting, the relationship between SB and DED was attenuated, and no longer significant (OR 1.009, 95%CI 0.996–1.023, P = 0.19). ConclusionsGreater sedentary time was tied to an increased risk of DED, especially for those with lower PA levels than WHO recommendations. However, as there was no significant association when computer-intensive sitting time was excluded, screen use could explain the observed relationship and should be noted as a possible key confounder.

Metabolic features and glucocorticoid-induced comorbidities in patients with giant cell arteritis and polymyalgia rheumatica in a Dutch and Danish cohort

ObjectivesGiant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are age-associated inflammatory diseases that frequently overlap. Both diseases require long-term treatment with glucocorticoids (GCs), often associated with comorbidities. Previous population-based cohort...

Abnormal Platelet Counts and Clonal Hematopoiesis in the General Population

Clonal hematopoiesis (CH) is defined by the presence of somatic mutations that may cause clonal expansion of hematopoietic cells. Here, we investigated the association between platelet count abnormalities, CH and consequences on overall survival and the development of hematological malignancies. Individuals with thrombocytopenia (n = 631) or thrombocytosis (n = 178) ≥60 years, and their age- and sex-matched controls, were selected within the population-based Lifelines cohort (n = 167,729). Although the prevalence of CH was not increased in thrombocytopenia cases compared with their controls (37.9% vs 39.3%; P = 0.639), mutations in spliceosome genes (SF3B1, SRSF2, U2AF1) were significantly enriched in thrombocytopenia cases (P = 0.007). Overall, CH in combination with thrombocytopenia did not impact on survival, but thrombocytopenia in combination with multiple mutated genes (hazard ratio [HR] = 2.08, 95% confidence interval [CI], 1.24-3.50; P = 0.006), mutations in TP53 (HR = 5.83, 95% CI, 2.49-13.64; P < 0.001) or spliceosome genes (HR = 2.69, 95% CI, 1.29-5.63; P = 0.009) increased the risk of death. The prevalence of CH in thrombocytosis cases was higher compared with controls (55.8% vs 37.7%; P < 0.001). Especially mutations in JAK2 (P < 0.001) and CALR (P = 0.003) were enriched in individuals with thrombocytosis. The presence of CH in individuals with thrombocytosis did not impact on overall survival. However, during follow-up of 11 years 23% of the individuals with thrombocytosis and CH were diagnosed with hematological malignancies. From these, 81% were diagnosed with myeloproliferative disease and 76% carried driver mutations JAK2, CALR, or MPL.

Musical and Multilingual Experience Are Related to Healthy Aging: Better Some Than None But Even Better Together.

Life experiences that are complex, sustained, and intense, such as active participation in music and speaking multiple languages, have been suggested to contribute to maintaining or improving cognitive performance and mental health. The current study focuses on whether lifetime musical and multilingual experiences differentially relate to cognition and well-being in older adults, and tests whether there is a cumulative effect of both experiences. A total of 11,335 older adults from the population-based Lifelines Cohort Study completed a musical and multilingual background and experience questionnaire. Latent class analysis was used to categorize individuals into subgroups according to their various musical and multilingual experiences resulting in a (1) nonmusical, low-multilingual group; (2) nonmusical, high-multilingual group; (3) musical, low-multilingual group; and (4) musical high-multilingual group. To determine whether the groups differed in terms of cognition or emotional affect, differences in Ruff Figural Fluency Test (RFFT) and Positive and Negative Affect Schedule scores were investigated by means of multinomial logistic regression analysis. Having high-multilingual, and not musical, experience was related to better RFFT performance compared to no experience, but not to more positive affect. Having both musical and high-multilingual experiences is related to better RFFT performance and more positive affect in advanced age compared to having only one experience or none. Importantly, these results were found independently of age, level of education, and socioeconomic status. Musical and multilingual experiences are related to healthy aging, especially when combined, which supports the suggestion that a broader spectrum of lifetime experiences relates to cognitive reserve.

Do influence at work and possibilities for development mitigate the impact of job demands for workers with and without depression.

Jobs characterized by low job demands and high job resources are associated with better work outcomes, yet it remains unclear whether this is the case for workers with depression. This study examined whether depression moderates the relationship between job demands, job resources, and maintaining employment. Data from the longitudinal population-based Lifelines cohort study were matched with register data on employment from Statistics Netherlands (N=55 950). Job demands included quantitative demands and work pace; job resources included influence at work and possibilities for development. The two-way interaction between job demands and depression and the three-way interaction between job demands, job resources and depression were examined in a zero-inflated Poisson regression model with path 1, including a binary employment outcome, and path 2, a count variable including months out of employment. The interaction effect of job demands and depression on being employed was significant [b=-0.22, 95% confidence interval (CI) -0.44‒0.01]. Workers without depression were more likely to be employed whereas workers with depression were less likely to be employed if they had high job demands. The three-way interaction between job demands, job resources, and depression was significant for months out of employment (b=0.15, 95% CI 0.01‒0.29), indicating that workers with depression had more months out of employment when reporting high job demands and high job resources compared to workers without depression. Discussion Although increasing influence at work and possibilities for development to prevent negative work outcomes may be beneficial for workers without depression, this approach might be limited for workers with depression.

Job resources do not mitigate the impact of job demands for workers with depression

Abstract Introduction Jobs characterized by low to moderate job demands and high job resources are associated with better work outcomes among healthy workers, yet it remains unclear whether this is the case for workers with depression. This study examined whether depression moderates the relationship between job demands, job resources, and maintaining employment. Methods Data from the longitudinal population-based Lifelines cohort study were matched with register data on employment status from Statistics Netherlands (n = 55,950). The two-way interaction between job demands and depression and the three-way interaction between job demands, job resources and depression were examined in a zero-inflated Poisson regression model with path 1 including a binary employment outcome and path 2 a count variable including months out of employment. Results The interaction effect of job demands and depression on being employed was significant (b=-0.22, 95% CI: -0.44; 0.01), showing that workers without depression were more likely to be employed whereas workers with depression were less likely to be employed if they had high job demands. The three-way interaction between job demands, job resources, and depression was significant for months out of employment (b = 0.15, 95% CI: 0.01; 0.29), indicating that workers with depression had more months out of employment when reporting high job demands and high job resources compared to workers without depression. Discussion Although increasing resources to prevent negative work outcomes may be beneficial for workers without depression, this approach might be limited for the vulnerable subgroup of workers with depression. Key messages

Genome-wide SNP-by air pollution interaction and airflow obstruction development in the Dutch population-based Lifelines cohort

Genome-wide SNP-by air pollution interaction and airflow obstruction development in the Dutch population-based Lifelines cohort

The relationship between habitual water intake and dry eye disease.

The purpose of this study is to test the hypothesis that greater habitual water intake is associated with lower risk of dry eye disease (DED). We included 51 551 participants from the population-based Lifelines cohort (mean age=51.2 years) in this cross-sectional association study. DED was assessed using the Women's Health Study (WHS) dry eye questionnaire. Water intake was calculated from food frequency questionnaires. Logistic regressions were used to analyse the relationship between DED and water intake or 24-h urine volume, corrected for age, sex, body mass index, physical activity, smoking status, education, income, 48 comorbidities, and 15 medication groups. The main outcome measure was WHS-defined DED. Highly symptomatic dry eye and clinical diagnosis of DED were secondary outcomes. In total, 9.1% of the population had WHS-defined DED. Higher water intake was associated with increased prevalence of WHS-defined DED (OR: 1.011 per 100 ml/day, 95% CI: 1.004-1.017, p=0.003). After excluding those with a clinical diagnosis, greater water intake was still tied to increased risk of having DED symptoms (OR: 1.010 per 100 ml/day, 95% CI: 1.006-1.015, p < 0.001). Higher 24-h urine volumes were also associated with higher risk of WHS-defined DED (OR: 1.010 per 100 ml/day, 95% CI: 1.005-1.015, p < 0.001). In this large, population-based study, higher water intake was not tied to reduced risk of DED. Rather, it was associated with a modest increased risk of DED. Interventional studies are needed to fully understand the effect of water intake on DED, but this study found no evidence that greater water intake is beneficial for DED.

Risk Factors for Self-reported Irritable Bowel Syndrome With Prior Psychiatric Disorder: The Lifelines Cohort Study

Background/AimsThe role of psychiatric disorder in irritable bowel syndrome (IBS) is not clear. This study aims to assess whether individuals who have psychiatric disorder prior to IBS onset differ in their risk factors from the remainder.MethodsThe prospective, population-based Lifelines cohort study includes 132 922 adults without prior IBS or taking IBS medication at baseline. Baseline data included socio-demographic status, physical and psychiatric disorders, psycho-social and behavioral variables. At follow-up (mean 2.4 years later) new onsets of IBS were recorded by self-report. The predictors of new onsets of IBS were assessed using logistic regression; participants with and without prior psychiatric disorders were analyzed separately.ResultsAt follow-up 1507 (1.1%) participants reported new onset IBS. Of these, 27% reported prior psychiatric disorder. Predictors of IBS in this group were 2 or more psychiatric disorders (OR, 2.74; 95% CI, 1.3-5.6), female sex, proton pump inhibitors, numerous bodily symptoms, impaired sleep, low BMI and negative health perception. These variables, except psychiatric disorders and BMI, also predicted IBS in those without prior psychiatric disorder but, in this group, gallstones, asthma, fibromyalgia, reported allergies, impairment through bodily pain, and frequent healthcare were also predictors.ConclusionsDespite its limitations this study suggests that prior psychiatric disorder is an important risk factor in a quarter of IBS onsets. Negative health perception and multiple bodily symptoms are associated with all IBS onsets in line with the cognitive-behavior model of IBS. Prior psychiatric disorder may predict an optimal response to psychiatric treatment. Further studies could usefully study mechanisms linking IBS to prior psychiatric disorder.

The Predictors of Somatic Symptoms in a Population Sample: The Lifelines Cohort Study.

Multiple bodily symptoms predict poor health status, high healthcare use, and onset of functional somatic syndromes. This study aimed to identify the predictors of somatic symptoms with special reference to mental disorders. The prospective, population-based Lifelines cohort study included 80,888 adults who were followed up for a mean of 2.4 years. At baseline sociodemographic status, self-reported medical disorders, functional somatic syndromes, stress, neuroticism, mental disorders (assessed with Mini-International Neuropsychiatric Interview), health perception, and analgesic use were assessed. These variables were tested as predictors of number of somatic symptoms at follow-up using linear regression analysis, which adjusted for baseline somatic symptoms ( n = 65,904). Logistic regression was used to identify the predictors of a persistently high number of somatic symptoms. The strongest predictors of somatic symptoms at follow-up were life events and difficulties score, and number of general medical illnesses/functional somatic syndromes. Neuroticism and mental disorders were also independent predictors in all analyses. Generalized anxiety, major depressive, and panic disorders were all independent predictors when entered individually into the regression analysis. A persistently high number of somatic symptoms were predicted most strongly by functional somatic syndromes, negative health perception, and paracetamol use. Number of somatic symptoms should be regarded as a multifactorial measure with many predictors. Mental disorders form one predictor, but there are other stronger ones, including stress and general medical disorders. The bidirectional relationship between functional somatic syndromes and multiple somatic symptoms is compatible with the notion that perception of bodily symptoms is a key component of both.