Johannes H. Smit

Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts

Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797–22,562 persons, aged 18–104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 × 10−8), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 × 10−11; LDL, P = 2.6 × 10−10), TMEM57 (TC, P = 5.4 × 10−10), CTCF-PRMT8 region (HDL, P = 8.3 × 10−16), DNAH11 (LDL, P = 6.1 × 10−9), FADS3-FADS2 (TC, P = 1.5 × 10−10; LDL, P = 4.4 × 10−13) and MADD-FOLH1 region (HDL, P = 6 × 10−11). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.

Major Depressive Disorder and Hypothalamic-Pituitary-Adrenal Axis Activity: Results From a Large Cohort Study

CONTEXT There is a central belief that depression is associated with hyperactivity of the hypothalamic-pituitary-adrenal axis, resulting in higher cortisol levels. However, results are inconsistent. OBJECTIVE To examine whether there is an association between depression and various cortisol indicators in a large cohort study. DESIGN, SETTING, AND PARTICIPANTS Data are from 1588 participants of the Netherlands Study of Depression and Anxiety who were recruited from the community, general practice care, and specialized mental health care. Three groups were compared: 308 control subjects without psychiatric disorders, 579 persons with remitted (no current) major depressive disorder (MDD), and 701 persons with a current MDD diagnosis, as assessed using the DSM-IV Composite International Diagnostic Interview. MAIN OUTCOME MEASURES Cortisol levels were measured in 7 saliva samples to determine the 1-hour cortisol awakening response, evening cortisol levels, and cortisol suppression after a 0.5-mg dexamethasone suppression test. RESULTS Both the remitted and current MDD groups showed a significantly higher cortisol awakening response compared with control subjects (effect size [Cohen d] range, 0.15-0.25). Evening cortisol levels were higher among the current MDD group at 10 pm but not at 11 pm. The postdexamethasone cortisol level did not differ between the MDD groups. Most depression characteristics (severity, chronicity, symptom profile, prior childhood trauma) were not associated with hypothalamic-pituitary-adrenal axis activity except for comorbid anxiety, which tended to be associated with a higher cortisol awakening response. The use of psychoactive medication was generally associated with lower cortisol levels and less cortisol suppression after dexamethasone ingestion. CONCLUSIONS This large cohort study shows significant, although modest, associations between MDD and specific hypothalamic-pituitary-adrenal axis indicators. Because a higher cortisol awakening response was observed among both subjects with current MDD and subjects with remitted MDD, this may be indicative of an increased biological vulnerability for depression.

Confirmatory factor analysis of the General Self-Efficacy Scale

A confirmatory factor analysis of the factor structure of the adapted General Self-Efficacy Scale, created by Sherer et al. (1982) [Psychological Reports, 51, 663-671], was conducted to assess whether the scales purported 3 factors emerged. The results generally supported the 3-factor model, but a model with 3 correlated factors and one higher-order factor (general self-efficacy) proved to fit the data even better.

Comorbidity Patterns of Anxiety and Depressive Disorders in a Large Cohort Study: the Netherlands Study of Depression and Anxiety (NESDA)

BACKGROUND Comorbidity of depressive and anxiety disorders is common and has been shown to be a consistent predictor of chronicity. Comorbidity patterns among specific depressive and anxiety disorders have not been extensively reported. This study examines comorbidity patterns and temporal sequencing of separate depressive and anxiety disorders using data from a large psychiatric cohort. METHOD Baseline data (N = 1,783) of the Netherlands Study of Depression and Anxiety, collected between September 2004 and February 2007, were used. Current and lifetime comorbidity rates for depressive and anxiety disorders (DSM-IV-TR criteria) were calculated. Associations of comorbidity with sociodemographic, vulnerability, and clinical characteristics, and temporal sequencing of disorders were examined. RESULTS Of those with a depressive disorder, 67% had a current and 75% had a lifetime comorbid anxiety disorder. Of persons with a current anxiety disorder, 63% had a current and 81% had a lifetime depressive disorder. Comorbidity of depressive and anxiety disorders was associated with more childhood trauma (OR = 1.19; 95% CI, 1.06-1.33), higher neuroticism (OR = 1.05; 95% CI, 1.02-1.08), earlier age at onset of first disorder (OR = 1.59; 95% CI, 1.22-2.07), longer duration of depressive and/or anxiety symptoms (OR = 1.01; 95% CI, 1.01-1.01), and higher symptom severity (ORs ranging from 1.01 to 1.03; all P values < .05). In 57% of comorbid cases, anxiety preceded depression, and in 18%, depression preceded anxiety. Comorbidity with preceding depression compared to preceding anxiety was associated with a shorter duration of symptoms of depressive and/or anxiety symptoms (OR = 0.99; 95% CI, 0.98-0.99), earlier age at first onset (OR = 0.46; 95% CI, 0.31-0.68), and fewer fear symptoms (OR = 0.98; 95% CI, 0.97-0.99). CONCLUSIONS Comorbidity rates in anxiety and depressive disorders were very high, indicating that it is advisable to assess both disorders routinely regardless of the primary reason for consultation. This is especially important since comorbid patients showed a specific vulnerability pattern, with more childhood trauma, neuroticism, and higher severity and duration of symptoms.

Relationships of Serum 25-Hydroxyvitamin D to Bone Mineral Density and Serum Parathyroid Hormone and Markers of Bone Turnover in Older Persons

CONTEXT Serum 25-hydroxyvitamin D [25(OH)D] may influence serum PTH and other parameters of bone health up to a threshold concentration, which may be between 25 and 80 nmol/liter. OBJECTIVE The aim of the study was to assess the threshold serum 25(OH)D with regard to PTH, bone turnover markers, and bone mineral density (BMD). DESIGN AND SETTING This was part of the Longitudinal Aging Study Amsterdam, an ongoing cohort study. PARTICIPANTS A total of 1319 subjects (643 men and 676 women) between the ages of 65 and 88 yr participated in the study. MAIN OUTCOME MEASURES Serum 25(OH)D, PTH, osteocalcin, urinary deoxypyridinoline/creatinine, quantitative ultrasound of the heel, BMD of lumbar spine and hip, total body bone mineral content, and physical performance. The relationship between the variables was explored by analysis of covariance and the locally weighted regression (LOESS) plots. RESULTS Serum 25(OH)D was below 25 nmol/liter in 11.5%, below 50 nmol/liter in 48.4%, below 75 nmol/liter in 82.4%, and above 75 nmol/liter in 17.6% of the respondents. Mean serum PTH decreased gradually from 5.1 pmol/liter when serum 25(OH)D was below 25 nmol/liter to 3.1 pmol/liter when serum 25(OH)D was above 75 nmol/liter (P < 0.001) without reaching a plateau. All BMD values were higher in the higher serum 25(OH)D groups, although only significantly for total hip (P = 0.01), trochanter (P = 0.001), and total body bone mineral content (P = 0.005). A threshold of about 40 nmol/liter existed for osteocalcin and deoxypyridinoline/creatinine, 50 nmol/liter for BMD, and 60 nmol/liter for physical performance. CONCLUSIONS Low serum 25(OH)D concentrations are common in the elderly. Bone health and physical performance in older persons are likely to improve when serum 25(OH)D is raised above 50-60 nmol/liter.

Elder abuse in the community: prevalence and consequences.

OBJECTIVES: (1) To assess the prevalence and the consequences of chronic verbal aggression, physical aggression, financial mistreatment, and neglect in a community‐based sample; (2) to investigate the circumstances that led to the abuse and the ways in which the victims handled the problem.

Genetic loci influencing kidney function and chronic kidney disease.

Using genome-wide association, we identify common variants at 2p12–p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10−10 to 10−15). Of these, rs10206899 (near NAT8, 2p12–p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 × 10−5 and P = 3.6 × 10−4, respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.

Homocysteine and Vitamin B12 Status Relate to Bone Turnover Markers, Broadband Ultrasound Attenuation, and Fractures in Healthy Elderly People

Hyperhomocysteinemia may contribute to the development of osteoporosis. The relationship of Hcy and vitamin B12 with bone turnover markers, BUA, and fracture incidence was studied in 1267 subjects of the Longitudinal Aging Study Amsterdam. High Hcy and low vitamin B12 concentrations were significantly associated with low BUA, high markers of bone turnover, and increased fracture risk.

Salivary Cortisol Levels in Persons With and Without Different Anxiety Disorders

Objective: To examine the association between several subtypes of anxiety disorders and various cortisol indicators in a large cohort study. Anxiety disorders have been suggested to be linked to hypothalamic-pituitary-adrenal (HPA) axis activity, although results are scarce and inconsistent. No earlier studies have examined consistency of HPA axis findings across several anxiety subtypes and whether associations are state or trait dependent. Methods: Data are derived from 1427 participants of the Netherlands Study of Depression and Anxiety. Three groups were compared: 342 control participants without psychiatric disorders; 311 persons with a remitted (no current) anxiety disorder (social phobia, generalized anxiety disorder, panic disorder); and 774 persons with a current anxiety disorder, as diagnosed using the Composite International Diagnostic Interview psychiatric interview. Cortisol levels were measured in seven saliva samples, determining the 1-hour cortisol awakening response, evening cortisol, and cortisol response after 0.5 mg of dexamethasone ingestion. Results: Current anxiety disorder was associated with higher awakening cortisol levels (p = .002). These findings were mainly present for patients with panic disorder with agoraphobia and anxious patients with comorbid depressive disorder. Remitted anxiety only showed a trend toward higher morning cortisol (p = .08). No associations were observed for anxiety status and evening cortisol level or cortisol suppression after dexamethasone. Conclusions: This study showed a modest but significantly higher 1-hour cortisol awakening response among anxiety patients, which was driven by those with panic disorder with agoraphobia and those with comorbid depression. HPA = hypothalamic-pituitary-adrenal; AUCg = area under the curve to the ground; AUCi = area under the curve to the increase; PD = panic disorder; PDA = panic disorder with agoraphobia; GAD = generalized anxiety disorder; MDD = major depressive disorder; BAI = Beck Anxiety Inventory.

Association of depressive disorders, depression characteristics and antidepressant medication with inflammation.

Growing evidence suggests that immune dysregulation may be involved in depressive disorders, but the exact nature of this association is still unknown and may be restricted to specific subgroups. This study examines the association between depressive disorders, depression characteristics and antidepressant medication with inflammation in a large cohort of controls and depressed persons, taking possible sex differences and important confounding factors into account. Persons (18–65 years) with a current (N=1132) or remitted (N=789) depressive disorder according to DSM-IV criteria and healthy controls (N=494) were selected from the Netherlands Study of Depression and Anxiety. Assessments included clinical characteristics (severity, duration and age of onset), use of antidepressant medication and inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)). After adjustment for sociodemographics, currently depressed men, but not women, had higher levels of CRP (1.33 versus 0.92 mg l−1, P<0.001, Cohens d=0.32) and IL-6 (0.88 versus 0.72 pg ml−1, P=0.01, Cohens d=0.23) than non-depressed peers. Associations reduced after considering lifestyle and disease indicators — especially body mass index — but remained significant for CRP. After full adjustment, highest inflammation levels were found in depressed men with an older age of depression onset (CRP, TNF-α). Furthermore, inflammation was increased in men using serotonin–norepinephrine reuptake inhibitors (CRP, IL-6) and in men and women using tri- or tetracyclic antidepressants (CRP), but decreased among men using selective serotonin reuptake inhibitors (IL-6). In conclusion, elevated inflammation was confirmed in depressed men, especially those with a late-onset depression. Specific antidepressants may differ in their effects on inflammation.