Polymorphisms in the CRP gene moderate an association between depressive symptoms and circulating levels of C-reactive protein

Although many studies have found psychological depression associated with higher circulating levels of C-reactive protein (CRP), not all findings are consistent. Since DNA sequence variation in the CRP gene has also been shown to predict plasma CRP levels, we hypothesized that plasma CRP may covary with depressive symptomatology as a function of allelic variation in the CRP gene. We tested this hypothesis in 868 healthy community volunteers of European ancestry. Depressive symptomatology was measured using the Center for Epidemiological Studies-Depression (CESD) scale, and plasma CRP was assayed from whole blood. Three polymorphisms [rs1417938 (A/T), rs1800947 (C/G) and rs1205 (C/T)] were genotyped and three-locus haplotypes were generated. Regression models adjusting for demographic and lifestyle-related covariates showed no direct association of CESD depression scores with CRP. In regression models adjusting for age, gender, education, smoking status and statin use, one CRP haplotype (T-G-C) was associated with CRP level (p = 0.014) and a second haplotype (A-G-T) showed marginal association (p = 0.064, respectively). Neither haplotype was related to depressive symptoms. However, plasma CRP was predicted by the interaction of A-G-T haplotype with depressive symptomatology (p = 0.009). Higher CESD scores were associated positively with CRP levels among individuals with the A-G-T haplotype (p = 0.004). In secondary analyses, body mass index was found to partially account for the moderating effects of the A-G-T haplotype on the association of depression with circulating CRP. In conclusion, we found that haplotypic variation in the CRP locus moderates an association of depressive symptoms with circulating CRP, which is partially mediated by BMI.     

Aromatase (CYP19A1) gene variants,sex steroid levels,and late‐life depression

Background : Sex differences in psychiatric disorders are common and could involve sex steroids. Aromatase, the product of the CYP19A1 gene, is the key enzyme in the conversion of androgen to estrogen. Whether CYP19A1 variants could be associated with depression differently in men and women has not been examined. Methods : This population‐based study included 405 men and 602 women aged ≥65 years. A clinical level of depression (DEP) was defined as having a score ≥16 on the Center for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini‐International Neuropsychiatric Interview and according to DSM‐IV criteria. Seven single‐nucleotide polymorphisms (SNPs) spanning the CYP19A1 gene were genotyped and circulating levels of estradiol and testosterone were determined. Multivariable analyses were adjusted for age, body mass index, ischemic pathologies, cognitive impairment, and anxiety. Results : Five SNPs were associated with DEP in women specifically and this varied according to a history of major depression (p‐values .01 to .0005). Three SNPs were associated with an increased risk of late‐life DEP in women without a history of major depression, while two SNPs were associated with a decreased DEP risk in women with a history of major depression and were also associated with higher estradiol levels. Conclusions : Variants of the CYP19A1 gene appear to be susceptibility factors for late‐life depression in a sex‐specific manner. The polymorphisms decreasing the risk of recurrent depression in postmenopausal women also influence estradiol levels.     

11β-Hydroxylase (CYP11B1) gene variants and new-onset depression in later life

BackgroundCumulative exposure to high glucocorticoid levels is detrimental for the brain and may have particular implications in later life. A feature of late-life depression is increased cortisol secretion. Variants in the CYP11B1 gene, which codes for the enzyme responsible for cortisol synthesis, could influence risk of late-life depression, but this hypothesis has not been examined. We investigated the associations between variants in the CYP11B1 gene and late-life depression, taking into account history of depression and potential sex-specific effects.MethodsWe assessed depression in 1007 community-dwellers aged 65 years or older (60% women) at baseline and over a 14-year follow-up. A clinical level of depression was defined as a score of ≥ 16 on the Centre for Epidemiology Studies Depression scale or a diagnosis of current major depression based on the Mini-International Neuropsychiatric Interview and according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). We examined incident and recurrent depression in participants without or with a history of major depression, respectively. We genotyped 5 single-nucleotide polymorphisms (SNPs) spanning CYP11B1. We used multivariable analyses to adjust for age, body mass index, cardiovascular ischemic pathologies, hypertension, cognitive impairment and anxiety.ResultsIn women, rs6471580 and rs7016924 were associated with a 50% lower rate of incident (new-onset) late-life depression, and rs11783855 was associated with a 2.4-fold higher rate of late-life depression. These associations remained after correction for multiple testing, but we found no associations for recurrent depression in women or men.LimitationsThis study focused on the major gene involved in corticosteroid biosynthesis, but other genes may also be implicated in this pathway.ConclusionVariants of the CYP11B1 gene appear to be susceptibility factors for late-life depression in a sex-specific manner.     

Association between adolescent emotional problems and metabolic syndrome: the modifying effect of C-reactive protein gene (CRP) polymorphisms

Depression is associated with the development of the metabolic syndrome, and both depression and metabolic syndrome are associated with markers of systemic inflammation, such as C-reactive protein (CRP). We examined associations between affective status in adolescence and adulthood, and the metabolic syndrome at age 53 years in a large representative British birth cohort. We also investigated whether two CRP gene polymorphisms (rs1205 and rs3093068) were associated with affective status and the metabolic syndrome, and whether the association between affective status and the metabolic syndrome was modified by these CRP polymorphisms. Women, but not men, with emotional problems in adolescence were more likely to have the metabolic syndrome (OR = 1.53, 95% CI: 1.04, 2.26), although this sex difference was not statistically significant (p = 0.22). The CRP SNPs were not associated with affective status or the metabolic syndrome, but the association of adolescent emotional problems with the metabolic syndrome was stronger in those who were homozygous for the major allele (C) of rs1205 (OR = 1.83, 95% CI: 1.17, 2.86) than in carriers of the T allele (OR = 1.01, 95% CI: 0.66, 1.55) (p = 0.05 for gene by affective status interaction). This interaction was stronger when considering adolescent emotional problems as a continuous variable (p = 0.003). Adolescent emotional problems play an important role in the development of the metabolic syndrome later in life, particularly in those homozygous for the major allele of CRP rs1205. These findings may highlight new ways of identifying people with emotional problems at high risk of developing the metabolic syndrome, which is of great importance for the management of the physical health of these patients.     

Association between CRP gene polymorphism 717A/G,C-reactive protein and neurological deficit in ischemic stroke

Inflammatory components play an important role in the pathogenesis of arteriosclerosis, one of the main causes of stroke. Blood C-reactive protein (CRP) level is connected with the severity of neurological deficit and disability after stroke. Production of CRP depends on CRP gene polymorphism. This study enrolled 125 patients with ischemic stroke. CRP 717A/G polymorphism was tested in all patients along with an assay of CRP levels measured on the first and tenth day after stroke onset. Neurological deficit on admission and before discharge from hospital was evaluated according to National Institutes of Health Stroke Scale (NIHSS), and then associated with CRP levels and the CRP polymorphism. The CRP 717AA genotype was the most frequent, observed in 53.6% of patients; AG genotype in 40%, and GG genotype in 6.4%. Carriers of the 717GG genotype had a significantly higher CRP level on the first day after stroke versus heterozygotes (p = 0.023). The improvement in neurological state evaluated with the NIHSS was significantly better in CRP 717AA patients in comparison with other CRP 717 genotypes (p = 0.035). A higher level of CRP on the first day after ischemic stroke was slightly associated with the CRP 717AG genotype. The CRP 717AA genotype promotes improvement of neurological state in patients with ischemic stroke.     

GWAS-Supported <Emphasis Type="Italic">CRP</Emphasis> Gene Polymorphisms and Functional Outcome of Large Artery Atherosclerotic Stroke in Han Chinese

Elevated C-reactive protein (CRP) levels increase the risk of poor functional disability in patients with ischemic stroke (IS). This study aimed to investigate the association between CRP gene polymorphisms and 3-month functional disability of large artery atherosclerotic (LAA) stroke in Han Chinese. Patients with first-ever LAA IS were prospectively enrolled in Nanjing Stroke Registry Program between August 2013 and October 2015. Five single-nucleotide polymorphisms (SNPs) (rs876537, rs2794520, rs3093059, rs7553007 and rs11265260) in CRP gene related to CRP levels in Asian by genome-wide association study were genotyped. The functional outcome at 3 months after the index stroke was assessed by the modified Rankin scale. Associations between genotypes and functional outcome of LAA IS were analyzed with logistic regression model. A total of 690 eligible patients (507 males) were evaluated. SNPs rs11265260 (multivariate-adjusted, p?=?0.022), rs2794520 (multivariate-adjusted, p?=?0.036) and rs3093059 (multivariate-adjusted, p?=?0.027) were significantly associated with elevated CRP in acute IS. Two SNPs, rs3093059 (dominant model: adjusted OR 2.49; 95% CI 1.55–4.00; recessive model: adjusted OR 3.67; 95% CI 1.22–11.03) and rs11265260 (dominant model: adjusted OR 2.51; 95% CI 1.56–4.02; recessive model: adjusted OR 4.70; 95% CI 1.63–13.56) independently predicted 3-month poor outcome of first-ever LAA IS, after adjusting for covariates. In addition, haplotype analysis indicated that haplotype GCTGC (adjusted OR 1.76; 95% CI 1.05–2.95; p?=?0.031) increased the poor outcome risk. SNPs rs3093059 and rs11265260 in CRP gene may influence the 3-month functional outcome of first-ever LAA IS in Han Chinese.     

Fatigued breast cancer survivors and gene polymorphisms in the inflammatory pathway

Chronic fatigue (CF) in breast cancer survivors (BCSs) has been associated with increased serum C-reactive protein-levels (CRP), pro-inflammatory cytokines and cytokine gene single nucleotide polymorphisms (SNPs). Still, there are few studies on these topics, and due to small study-cohorts the possibility to adjust for other conditions related to inflammatory processes, e.g. depression, has been limited.In 302 BCSs, examined approximately four years after treatment for breast cancer stage II/III, data on high sensitivity (hs)CRP, leukocytes and mRNA interleukin (IL)1β and IL6R expression, depression and chronic fatigue were available. Three years thereafter, 236 BCSs were re-examined. The associations between fatigue and SNPs in inflammation-related genes; IL1β (rs16944), IL6 (rs1800795), IL6receptor (rs4129267, rs4845617, rs2228145), CRP (rs2794521, rs3091244) were investigated, together with the relations between SNPs in IL6R,IL1β and CRP genes and mRNA blood expression levels of IL6R and IL1β and serum hsCRP-levels, respectively. All analyses were repeated after exclusion of depressed individuals and separating BCSs with persistent fatigue from never-fatigued individuals.Even after exclusion of depressed individuals neither the SNPs nor the mRNA IL1β and IL6R expression levels were associated with chronic or persistent fatigue. In the subset of persistent fatigued and never-fatigued individuals the CRP SNP (rs3091244) was associated with hsCRP level (p = 0.02). IL1β and IL6R mRNA expression levels were not related to the IL1β and IL6R genotypes.In a large cohort of BCSs the investigated SNPs in inflammation-related genes were not associated with fatigue, though subset analyses indicated an association between the CRP SNP (rs3091244) and serum hsCRP.     

C-reactive protein and depression in persons with Human Immunodeficiency Virus infection: The Positive Living with HIV (POLH) Study

BackgroundHuman Immunodeficiency Virus (HIV) infection has been frequently associated with chronic inflammation as well as depression. C-reactive protein (CRP) is positively associated with depression in people without HIV infection. We tested the hypothesis of an independent relationship between CRP and depression in a cohort of HIV-positive people.MethodsA cross-sectional survey was conducted among 316 HIV-positive people (181 men and 135 women) aged 18–60 years residing in the Kathmandu Valley, Nepal. The latex agglutination turbidimetric method was used to measure serum CRP concentrations and the Beck Depression Inventory (BDI)-I method was used to measure depression, with a cut off of ⩾20 indicating likely depression. The relationship between CRP concentrations and depression symptoms was assessed using both multiple linear regression analysis and multiple logistic regression analysis, with adjustment for potential socio-demographic, cardiovascular, life-style, and HIV-related clinical and treatment confounding factors.ResultsTwenty-six percent participants (men: 23%; women: 29%) met criteria for depression. In multiple regression analysis, the authors observed a linear relation between serum CRP concentrations and BDI score (beta for 1 unit change in ln(CRP) = 1.13, p = 0.001) in HIV-positive participants. In a logistic regression analysis, participants with serum CRP levels > 3 mg/L had a 2.3-fold higher odds of depression symptoms compared to those with serum CRP level ⩽ 3 mg/L (p = 0.005). In analyses stratified by sex, associations were stronger in men than in women. For example, CRP > 3 mg/L was associated with a 3.6-fold higher odds of depression in men (p = 0.002), while in women the odds ratio was 1.7 (p = 0.33).ConclusionWe found a linear relationship between serum CRP concentrations and depression symptoms score in HIV-positive people, and evidence that risk of depression is elevated among HIV-positive men with a high level of inflammation (CRP > 3 mg/L). Further prospective study to confirm the role of inflammation in depression among HIV-positive people is warranted.     

Common haplotypes of the C-reactive protein gene and circulating leptin levels influence the interindividual variability in serum C-reactive protein levels. The Segovia study

C-reactive protein (CRP) is a marker of systemic inflammation significantly associated with an increased risk of cardiovascular disease in the general population. The aim of our current work was to study those clinical and genetic variables potentially associated with interindividual variability in serum CRP levels. A random sample of 844 participants (450 women, mean age 55 years) from a study carried out on the general Spanish population (The Segovia Study) was studied. Our results showed that age, gender, waist circumference, leptin, impaired glucose tolerance and smoking were the clinical variables significantly associated with variations in serum CRP levels. Among those, leptin showed the strongest association, explaining 11% of the interindividual variability in circulating CRP levels (p<0.001). To study the effect of genetic variants on serum CRP levels, 10 SNPs within the CRP locus were genotyped in 756 participants. Four of these SNPs (rs1417938, rs1800947, rs1130864, rs1205) were significantly associated with CRP levels after adjustment for clinical variables. Among the common haplotypes inferred from eight SNPs, two (CCATGCCT, p=0.025; CTATCCTT, p=0.004) explained 2.9% of the total variation in serum CRP. The results here reported show that 2.9% of the total variation in circulating CRP levels seems to be explained by genetics variations within CRP locus. Furthermore, serum leptin levels are strongly associated with serum CRP levels in our Spanish population.     

Risk factors of stroke and −717A > G (rs2794521) CRP gene polymorphism among stroke patients in West Pomerania province of Poland

Background and purposeSome of the risk factors of ischaemic stroke influence the development of atherosclerosis, which is a significant cause of vascular incidents. An inflammatory component plays a role in pathogenesis of both atherosclerosis and atrial fibrillation, the most important risk factor of embolic strokes. C-reactive protein (CRP) concentration in blood reflects the inflammatory process. Concentration of this protein depends on the CRP gene polymorphism. The aim of the study was to assess the relationship between selected risk factors of stroke and variant of −717A > G (rs2794521) CRP gene polymorphism in population of West Pomerania Province of Poland.Materials and methodsThere were 125 consecutive patients with ischaemic stroke analysed, who met the inclusion and exclusion criteria. In all patients, −717A > G CRP gene polymorphism was genotyped and analysed in relation to selected stroke risk factors.ResultsPrevalence of type 2 diabetes was lower in patients with AA genotype of −717A > G CRP gene polymorphism than in patients with other alleles (p = 0.017). Subjects with GG genotype had significantly higher concentration of CRP comparing to AG genotype (p = 0.023). No correlation was found between −717A > G CRP gene polymorphism and the lipid profile and other selected risk factors of stroke.ConclusionsIn patients with ischaemic stroke in West Pomerania Province, the GG genotype of −717A > G CRP gene polymorphism is associated with significantly higher CRP concentration in relation to AG genotype. Patients with AA genotype may be characterised by lower prevalence of type 2 diabetes.     

Longitudinal interactions of estrogen receptor alpha gene rs9340799 with social-environmental factors on depression in adolescents after Wenchuan earthquake

Inconsistent relationships were reported between rs9340799 on estrogen receptor alpha gene (ESR1) and depression in previous studies. The present study was to explore the longitudinal changes of prevalence and severity of depression in 439 Chinese Han adolescents with different genotypes of ESR1 rs9340799 at 6, 12 and 18 months after the 2008 Wenchuan earthquake. Social-environmental factors were collected by questionnaires from 465 high school students. Variants of rs9340799 were genotyped by polymerase chain reaction-restriction fragment length polymorphism analyses and verified by DNA sequencing. Depression symptoms were assessed by Beck Depression Inventory (BDI). The results showed the female AA homozygotes had higher prevalence of depression at 12 months and higher BDI scores at 18 months than the female G allele carriers. Significantly decreased prevalence of depression was observed only in the female AA homozygotes at 18 months when compared with that at 6 or 12 months. Consecutive decreases in BDI scores were observed only in the female AA homozygotes. The AA genotype was one of the risk factors at 12 months and predictors of BDI scores at 18 months. These results firstly suggest different interactions may occur in a gender and time dependent manner among rs9340799 and other potential factors of depression or predictors of its severity, and influence the development and natural rehabilitation of depression.     

Levels of C-reactive protein (CRP) in elderly patients with unipolar depression – case control analysis

Aim: C-reactive protein (CRP) is the major acute-phase plasma protein. Studies show that patients with depression have elevated levels of CRP. The aim of the study was to determine differences in CRP serum level in elderly patients with unipolar depression (DEP) compared with non-depressed elderly patients (nonDEP) using case-control analysis.

Methods: Serum level of CRP was measured in 404 (DEP: n?=?202, nonDEP: n?=?202) Caucasian inpatients aged ≥60 (350 women, 86.7%; mean age?=?76.7 years).

Results: Mean CRP level in the study groups was: DEP 2.67?±?2.56?mg/dL, nonDEP 2.41?±?2.19?mg/dL, the difference was not significant (p?=?0.96). The overall rate of being above the high level of CRP (set at 3.0?mg/L) was 33.2% for DEP and 29.2% for nonDEP groups (p?=?0.39). It was also found that, in the whole study group, CRP level was not correlated with age (p?=?0.10).

Conclusions: Elderly patients with depression have no increased CRP levels. A high percentage (～30%) of all subjects had a CRP level >3?mg/L, which is the cut-off point for increased cardiovascular risk.     

Depression inhibits the anti-inflammatory effects of leisure time physical activity and light to moderate alcohol consumption

Light to moderate alcohol consumption and leisure time physical activity (LTPA) are independently associated with lower levels of high sensitivity C-reactive protein (CRP), a predictor of cardiometabolic risk. In contrast, depression, ranging from low mood disturbance to major depressive disorder, has been associated with elevated CRP. To test the hypothesis that depression attenuates the anti-inflammatory effects of LTPA and alcohol consumption, the current study tested the moderating effect of severity of depressive symptomatology on the relation of alcohol consumption and LTPA to CRP in 222 healthy adult men and women (18–65 years of age). Given the known effects of gender on inflammation, we also examined the effects of gender on the tested interactions. Depression was assessed using the Beck Depression Inventory. Frequency of alcohol consumption, hours of LTPA per week and other coronary risk/protective factors were assessed via self-report and structured interview. Fasting blood samples were used to measure CRP and lipids. As predicted, the interaction between LTPA and depressive symptomatology was significant (F = 5.29, p < .03) such that lower CRP was associated with the combination of decreased depressive symptomatology and increased LTPA. Among those with increased depressive symptoms, increased LTPA was not associated with higher CRP. Similarly, depression interacted with alcohol consumption in predicting CRP in men but not women (F = 5.03, p < .008) such that for men light to moderate alcohol consumption was associated with lower CRP but only among those with decreased depressive symptoms. Light to moderate alcohol consumption was not associated with lower CRP in those with increased depressive symptom severity. The pattern of the interactions between anti-inflammatory activities such as light to moderate alcohol consumption and LTPA and psychological distress as indexed by severity of depressive symptomatology suggests an important new avenue for future research.     

Dysbindin (DTNBP1) – A role in psychotic depression?

Previous studies yielded evidence for dysbindin (DTNBP1) to impact the pathogenesis of schizophrenia on the one hand and affective disorders such as bipolar or major depressive disorder (MDD) on the other. Thus, in the present study we investigated whether DTNBP1 variation was associated with psychotic depression as a severe clinical manifestation of MDD possibly constituting an overlapping phenotype between affective disorders and schizophrenia.A sample of 243 Caucasian inpatients with MDD (SCID-I) was genotyped for 12 SNPs spanning 92% of the DTNBP1 gene region. Differences in DTNBP1 genotype distributions across diagnostic subgroups of psychotic (N = 131) vs. non-psychotic depression were estimated by Pearson Chi² test and logistic regression analyses adjusted for age, gender, Beck Depression Inventory (BDI) and the Global Assessment of Functioning Scale (GAF).Overall, patients with psychotic depression presented with higher BDI and lower GAF scores expressing a higher severity of the illness as compared to depressed patients without psychotic features. Four DTNBP1 SNPs, particularly rs1997679 and rs9370822, and the corresponding haplotypes, respectively, were found to be significantly associated with the risk of psychotic depression in an allele-dose fashion.In summary, the present results provide preliminary support for dysbindin (DTNBP1) gene variation, particularly SNPs rs1997679 and rs9370822, to be associated with the clinical phenotype of psychotic depression suggesting a possible neurobiological mechanism for an intermediate trait on the continuum between affective disorders and schizophrenia.     

Diabetes,depressive symptoms,and inflammation in older adults: Results from the Health,Aging, and Body Composition Study

Objective

Up-regulated levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) are common to both type 2 diabetes mellitus (T2DM) and elevated depressive symptoms, yet little attention has been given to the biological mechanisms associated with these co-morbidities. This study examined the association between inflammation and both T2DM and elevated depressive symptoms.

Methods

Baseline data were analyzed from 3009 adults, aged 70–79, participating in the Health, Aging, and Body Composition Study. Diabetes was assessed per self-report, medication use, fasting glucose and/or glucose tolerance tests. Elevated depressive symptoms were categorized using the Center for Epidemiologic Studies Depression scale (cut-score ≥ 20). Log-transformed IL-6, TNF-α, and CRP were analyzed using ANCOVA.

Results

Participants with T2DM and elevated depressive symptoms (T2DM + DEP n = 14) demonstrated significantly (p < .05) higher IL-6 compared to (T2DM Only n = 628), (DEP Only n = 49), and (No T2DM or DEP n = 2067) groups following covariate adjustment. Similarly, participants with T2DM + DEP (n = 14) had significantly (p < .05) higher CRP, after covariate adjustment, compared to DEP Only (n = 50) and No T2DM or DEP groups (n = 2153). No association was observed for TNF-α.

Conclusions

These findings provide evidence that inflammation is associated with T2DM and elevated depressive symptoms. Participants with T2DM + DEP demonstrated the highest IL-6 levels compared to all other groups. Greater CRP levels were also observed in T2DM, but not elevated depressive symptoms, which may suggest that differential associations between T2DM and depressive symptoms exist for various inflammatory markers. Further investigation into these associations could aid in understanding the biological pathways underlying both T2DM and depressive symptoms.     

Depressogenic vulnerability and gender-specific patterns of neuro-immune dysregulation: What the ratio of cortisol to C-reactive protein can tell us about loss of normal regulatory control

We examined whether the ratio of cortisol (CORT) to high-sensitivity C-reactive protein (hsCRP), an index that captures the integrity of homeostatic regulation between the hypothalamic–pituitary–adrenal (HPA) axis and inflammatory processes, is associated with vulnerability to depression in a gender specific manner and whether glucocorticoid receptor (GR) sensitivity plays a role in these associations. Fasting blood samples were collected between 08:45 and 09:15 and assayed for CORT, hsCRP, and leukocyte count in 213 healthy, medication-free men and women. The NEO-Personality Inventory was used to assess neuroticism, extraversion and anxiety. We used the Hamilton Depression Interview to assess depressive symptoms, the Buss–Perry anger subscale to measure anger, and the Pittsburgh Sleep Quality Index to evaluate subjective sleep quality and its components. Log-transformed CORT/CRP values were analyzed using multiple regression with Holms’ adjusted p-values and age, body mass index (BMI), and race as covariates. GR sensitivity was estimated using the log-transformed ratio of neutrophils (N)-to-monocytes (M). The log-transformed ratio of CORT/CRP did not differ between men and women but was significantly and negatively associated with age and BMI. Severity of depressive symptoms, extraversion, anxiety, and sleep quality were associated with the CORT/CRP ratio in a gender-specific manner. For women, decreasing CORT/CRP ratios, suggestive of an insufficient release of CORT coupled with a heightened inflammatory state, were associated with increasing severity of depressive symptoms, decreasing quality of sleep, increasing frequency of sleep disturbance, and decreasing extraversion. For men, increasing frequency of daytime disturbance and levels of anxiety were associated with increasing CORT/CRP ratio, suggestive of an enhanced release of CORT relative to attenuated levels of hsCRP. For both genders, increasing anger was associated with decreasing CORT/CRP ratios. Although results suggested GR downregulation in women but not men, such differences did not mediate the observed associations. With the use of the CORT/CRP ratio, we showed that vulnerability factors for depression are associated with a loss of normal regulatory controls resulting in gender-specific patterns of neuro-immune dysregulation. That GR downregulation did not influence these associations suggests that the loss of regulatory controls in at risk individuals is primarily at the level of the hormone. Beyond the individual contribution of each component of the CORT/CRP ratio, disruption of normal neuroimmune regulatory feedback provides a plausible biological framework useful in understanding biobehavioral vulnerabilities to depression in a gender specific manner. The CORT/CRP ratio may be a viable biomarker not only for delineating risk for MDD but also progression and treatment responses among patients with MDD; possibilities that are testable in future studies.     

BDNF promoter methylation and genetic variation in late-life depression

The regulation of the brain-derived neurotrophic factor (BDNF) is important for depression pathophysiology and epigenetic regulation of the BDNF gene may be involved. This study investigated whether BDNF methylation is a marker of depression. One thousand and twenty-four participants were recruited as part of a longitudinal study of psychiatric disorders in general population elderly (age⩾65). Clinical levels of depression were assessed using the Mini International Neuropsychiatric Interview for the diagnosis of major depressive disorder according to the Diagnostic and Statistical Manual of Mental Disorder IV criteria, and the Centre for Epidemiologic Studies Depression Scale (CES-D) for assessment of moderate to severe depressive symptoms. Buccal DNA methylation at the two most widely studied BDNF promoters, I and IV, was investigated using the Sequenom MassARRAY platform that allows high-throughput investigation of methylation at individual CpG sites within defined genomic regions. In multivariate linear regression analyses adjusted for a range of participant characteristics including antidepressant use, depression at baseline, as well as chronic late-life depression over the 12-year follow-up, were associated with overall higher BDNF methylation levels, with two sites showing significant associations (promoter I, Δ mean=0.4%, P=0.0002; promoter IV, Δ mean=5.4%, P=0.021). Three single-nucleotide polymorphisms (rs6265, rs7103411 and rs908867) were also found to modify the association between depression and promoter I methylation. As one of the largest epigenetic studies of depression, and the first investigating BDNF methylation in buccal tissue, our findings highlight the potential for buccal BDNF methylation to be a biomarker of depression.     

Methylation of the oxytocin receptor gene in clinically depressed patients compared to controls: The role of OXTR rs53576 genotype

The emerging field of epigenetics provides a biological basis for gene-environment interactions relevant to depression. We focus on DNA methylation of exon 1 and 2 of the oxytocin receptor gene (OXTR) promoter. The research aims of the current study were to compare OXTR DNA methylation of depressed patients with healthy control subjects and to investigate possible influences of the OXTR rs53576 genotype. The sample of the present study consisted of 43 clinically depressed women recruited from a psychosomatic inpatient unit and 42 healthy, female control subjects – mean age 30 years (SD = 9). DNA methylation profiles of the OXTR gene were assessed from leukocyte DNA by means of bisulfite sequencing. Depressed female patients had decreased OXTR exon 1 DNA methylation compared to non-depressed women. The association between depression and methylation level was moderated by OXTR rs53576 genotype. Exon 2 methylation was associated with OXTR rs53576 genotype but not with depression. Our findings suggest exon-specific methylation mechanisms. Exon 1 methylation appears to be associated with depressive phenotypes whereas exon 2 methylation is influenced by genotype. Previously reported divergent associations between OXTR genotype and depression might be explained by varying exon 1 methylation. In order to further understand the etiology of depression, research on the interplay between genotype, environmental influences and exon-specific methylation patterns is needed.     

Variation in the Uric Acid Transporter Gene SLC2A9 and Its Association with AAO of Parkinson’s Disease

Based on the observed inverse association between hyperuricemia and Parkinson’s disease (PD) risk, the natural antioxidant activity of uric acid has been suggested to play a protective role. SLC2A9 has been indicated as the most effective of all uric acid transporters, and SLC2A9 variants have been shown to influence circulating uric acid levels. With this study, we aimed to test the association between such SLC2A9 polymorphisms and age at onset (AAO) of PD. Variants rs733175, rs737267, rs1014290, and rs6449213 within SLC2A9 were genotyped in 664 PD individuals from three European centers. The effect of each polymorphism on AAO was estimated within each center using a linear regression model adjusted for gender and genotype at the other SNPs and assuming an additive genetic model. Results across centers were combined using inverse-variance weighted fixed-effect meta-analysis. The minor allele of rs1014290, previously shown to be associated with lower serum uric acid levels, was found to be associated with a lower AAO of PD (pooled estimate ?4.56 years; 95% CI ?8.13, ?1.00; p?=?0.012). The association remained significant after adjustment for multiple comparisons and was highly consistent across centers (heterogeneity, I ² 0%). No gender differences were observed. Our study suggests that SLC2A9 genetic variants influence age of onset of Parkinson’s disease.