Nicholas W.J. Wainwright

Social Adversity, the Serotonin Transporter (5-HTTLPR) Polymorphism and Major Depressive Disorder

BACKGROUND Recent evidence has suggested that the short allele of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR of the human serotonin gene [SLC6A4]) is associated with increased risk of depressive disorder but only among individuals exposed to social adversity. We report an investigation designed to replicate this finding. METHODS Data were available from a non-clinical sample of 4,175 adult men and women, ages 41-80 years, selected from participants in the European Prospective Investigation into Cancer and Nutrition in Norfolk (EPIC-Norfolk, United Kingdom) study. Evidence of past-year prevalent episodic major depressive disorder (MDD), defined by restricted DSM-IV diagnostic criteria, was assessed through questionnaire. Adverse experiences in childhood and in adulthood (during the five years preceding assessment) were also assessed through self-report. The 5-HTTLPR variant was genotyped according to published protocols. RESULTS One-year prevalent MDD criteria were met by 298 study participants. The experience of social adversity (both in childhood and adulthood) was strongly associated with increased rates of past-year prevalent MDD. No gene by environment (GxE) interactions between the 5-HTTLPR genotype, social adversity, and MDD were observed. CONCLUSIONS This study has not replicated a previous finding of a GxE interaction between the 5-HTTLPR genotype, social adversity, and depression.

Depression and ischemic heart disease mortality: evidence from the EPIC-Norfolk United Kingdom prospective cohort study.

OBJECTIVE The authors investigated the association between major depressive disorder, including its clinical course, and mortality from ischemic heart disease. METHOD This was a prospective cohort study of 8,261 men and 11,388 women 41-80 years of age who were free of clinical manifestations of heart disease and participated in the Norfolk, U.K., cohort of the European Prospective Investigation Into Cancer. The authors conducted a cross-sectional assessment of major depressive disorder during the period 1996-2000 and ascertained subsequent deaths from ischemic heart disease through linkage with data from the U.K. Office for National Statistics. RESULTS As of July 31, 2006, 274 deaths from ischemic heart disease were recorded over a total follow-up of 162,974 person-years (the median follow-up period was 8.5 years). Participants who had major depression during the year preceding baseline assessment were 2.7 times more likely to die from ischemic heart disease over the follow-up period than those who did not, independently of age, sex, smoking, systolic blood pressure, cholesterol, physical activity, body mass index, diabetes, social class, heavy alcohol use, and antidepressant medication use. This association remained after exclusion of the first 6 years of follow-up data. Consideration of measures of major depression history (including recency of onset, recurrence, chronicity, and age at first onset) revealed recency of onset to be associated most strongly with ischemic heart disease mortality. CONCLUSIONS Major depression was associated with an increased risk of ischemic heart disease mortality. The association was independent of established risk factors for ischemic heart disease and remained undiminished several years after the original assessment.

Psychological distress, major depressive disorder, and risk of stroke

Background: Studies have suggested that mood status is associated with an increased risk of stroke, though mostly based on measures of depression defined by symptoms alone rather than diagnostic criteria representative of clinically important distress and impairment. We investigated this association based upon a large population-based prospective cohort study. Methods: Baseline assessment of major depressive disorder (MDD) and of mental health well-being (defined by the Mental Health Inventory, MHI-5) was completed by 20,627 stroke-free participants, aged 41 to 80 years, in the United Kingdom European Prospective Investigation into Cancer–Norfolk study. Results: During 8.5 years of follow-up, 595 incident (fatal and nonfatal) stroke endpoints were recorded. Neither past year nor lifetime MDD was associated with stroke. A one SD decrease in MHI-5 scale score (representing greater emotional distress) was associated with an 11% increased risk of stroke after adjustment for age, sex, cigarette smoking, systolic blood pressure, cholesterol, obesity, preexisting myocardial infarction, diabetes, social class, education, hypertension treatment, family history of stroke, and antidepressant medication use (hazard ratio 1.11, 95% CI 1.00 to 1.22). This association was consistent for men and for women, for fatal and nonfatal stroke, and conformed to a dose-response relationship. Conclusions: Findings from this large prospective cohort study suggest that increased psychological distress is associated with elevated stroke risk. Episodic major depressive disorder was not associated with incident stroke in this study.

Healthy lifestyle choices: could sense of coherence aid health promotion?

Background: A research framework based on the personal characteristic defined by a sense of coherence (SOC) focuses on the effective use of resources to maintain good health. Objectives: To test the hypothesis that individual differences in SOC are associated with healthier lifestyle choices independently of social class and education. Design and setting: Cross sectional. Population based cohort study recruited through 35 general practice registers. Reported dietary intakes of alcohol, fruit and vegetables, fibre, saturated fat, non-discretionary salt (sodium), and total sugars were assessed by food frequency questionnaire. Current cigarette smoking, physical inactivity, and SOC were assessed through questionnaires. Participants: 7863 men and 10 424 women. Residents of Norfolk (UK). Results: Compared with participants with the weakest SOC, those with the strongest were 28% less likely to be current smokers (odds ratio 0.72 (95% confidence interval (CI), 0.58 to 0.89)), 36% less likely to be physically inactive (0.64 (0.55 to 0.75)), and reportedly consumed on average 63 g/day more fruit and vegetables (95% CI, 46 to 80), and 1.2 g/day more fibre (0.8 to 1.6). These associations were independent of age, sex, social class, and education. For physical inactivity and consumption of fruit, vegetables, and fibre, these differences exceeded those observed between the extremes of social class and education. Conclusions: Individual differences in SOC are associated with healthy lifestyle choices independently of social class and education, and may therefore aid the design of future health promotion interventions.

Mastery, sense of coherence, and mortality: Evidence of independent associations from the epic-norfolk prospective cohort study.

This study investigated the association between 2 distinct personal coping resources (mastery and sense of coherence) and all-cause, cardiovascular, and cancer mortality. During follow-up (up to 6 years), 994 deaths were recorded among 20,323 participants, ages 41 to 80 years, in the European Prospective Investigation into Cancer Study in the United Kingdom. A strong sense of mastery was associated with lower rates of mortality from all causes, cardiovascular disease, and cancer, after adjusting for age, sex, and prevalent chronic physical disease. The association with all-cause mortality was observed for both men and women and remained following further adjustment for cigarette smoking, social class, hostility, neuroticism, and extroversion. Analysis of the joint association between mastery and sense of coherence revealed both personal coping dispositions to be independently associated with lower rates of all-cause mortality. In addition, these data suggested that the association for mastery was specific to cardiovascular mortality, whereas the association for sense of coherence was specific to cancer mortality. These results may aid future study of coping resources as determinants of persistent well-being.

Life Stress, Emotional Health, and Mean Telomere Length in the European Prospective Investigation into Cancer (EPIC)-Norfolk Population Study

We investigated the association between psychological stress, emotional health, and relative mean telomere length in an ethnically homogeneous population of 4,441 women, aged 41-80 years. Mean telomere length was measured using high-throughput quantitative real-time polymerase chain reaction. Social adversity exposure and emotional health were assessed through questionnaire and covariates through direct measurement and questionnaire. This study found evidence that adverse experiences during childhood may be associated with shorter telomere length. This finding remained after covariate adjustment and showed evidence of a dose-response relationship with increasing number of reported childhood difficulties associated with decreasing relative mean telomere length. No associations were observed for any of the other summary measures of social adversity and emotional health considered. These results extend and provide support for some previous findings concerning the association of adverse experience and emotional health histories with shorter telomere length in adulthood. Replication of these findings in longitudinal studies is now essential.

Adaptation to Social Adversity Is Associated With Stroke Incidence: Evidence From the EPIC-Norfolk Prospective Cohort Study

Background and Purpose— Laboratory-based studies have suggested that individual differences in cardiovascular reactivity and stress adaptive capacity are associated with stroke incidence. We test the hypothesis that sense of coherence (SOC), a marker of social stress adaptive capacity, is associated with incident stroke in a population-based prospective cohort study. Methods— A total of 20 629 participants, aged 41 to 80 years, in the UK European Prospective Investigation into Cancer (EPIC)-Norfolk study, who had not previously experienced a stroke, completed assessments that included SOC and details of their experience of life events during adulthood. An index of adaptation was constructed from responses to questions concerning over 80 000 adverse life events. Results— During 145 000 person-years of follow-up (mean 7.1 years), 452 participants experienced either a fatal or nonfatal stroke event. A strong (as opposed to a weak) SOC was associated with a reduced rate of stroke incidence (rate ratio 0.76; 95% CI, 0.60 to 0.96) after adjustment for age, sex, pre-existing myocardial infarction, diabetes, hypertension treatment, family history of stroke, cigarette smoking, systolic blood pressure, obesity, social class, education, hostility and depression. No sex difference in this association was observed. Measures of social adversity occurrence and impact were not associated with stroke incidence, whereas faster reported adaptation to adverse event exposure was associated with a reduced rate of stroke incidence (rate ratio 0.89; 95% CI, 0.81 to 0.98; per standard deviation change in adaptation score, adjusted for age and sex). Conclusions— Stress adaptive capacity is a potentially important candidate risk factor for stroke.

Obesity, confidant support and functional health: cross-sectional evidence from the EPIC-Norfolk cohort

OBJECTIVE: To investigate the association between body mass index (BMI) and functional health according to age and the support available from a close confidant.DESIGN: A cross-sectional population-based study.PARTICIPANTS: A total of 20 921 participants in the European Prospective Investigation into Cancer and Nutrition, aged 41–80 y resident in Norfolk, England.MEASUREMENTS: Standardised clinic-based assessment of BMI, self-reported functional health status assessment (according to the anglicised Short Form 36 (SF-36) Health Survey questionnaire) and the availability (and quality) of a close confiding relationship.RESULTS: Self-reported physical functioning declined steadily with increasing age. Obesity (BMI ≥30) was strongly associated with self-reported physical functional health, equivalent to being 11 y older for men and 16 y older for women (after adjustment that included prevalent chronic physical conditions and cigarette smoking). This adverse effect of obesity on physical functional health was found to increase with age for both men and women. Perceived inadequacy of a confiding relationship was associated with reduced physical functional capacity, equivalent to being 4 y older for men and 5 y older for women. For those with markedly inadequate confidant relationships, the impact of obesity on physical functional capacity was approximately constant by age. For those not critical of the adequacy of their confiding relationships, the impact of obesity was least for those younger but rose to equivalent levels as those with markedly inadequate confidant relationships among older participants.CONCLUSIONS: The availability of a close confidant relationship (perceived as uncritical and characterised by the absence of shared negative interactions) may delay the impact of obesity in reducing physical functional capacity.

Psychosocial aetiology of chronic disease: a pragmatic approach to the assessment of lifetime affective morbidity in an EPIC component study

OBJECTIVES The Health and Life Experiences Questionnaire (HLEQ) was developed for use in a prospective cohort study of 25 000 men and women living in Norfolk and forms a component study of the European Prospective Investigation into Cancer and Nutrition (EPIC). The HLEQ includes an assessment of mood status over the life course allowing a limited capacity for the imposition of diagnostic criteria to enable eventual evaluation of mental health status for chronic disease outcomes. This paper reports estimates of HLEQ Major Depressive Disorder (MDD) prevalence and compares them with those obtained through interviewer-based methods. In addition evidence for the impact of recall, clustering or cohort effects on these estimates are examined. PARTICIPANTS 3491 eligible respondents to EPIC in Norfolk, aged 45–74 years, recruited from the first five general practices who completed the HLEQ. MAIN RESULTS MDD prevalence estimates were found to be closely comparable to those obtained recently (by interview) in the UK and to those lifetime MDD rates determined through international studies. Risk of MDD onset was found to vary with age as expected from earlier studies using interviewer-based assessments. Limited evidence was found to show that the distribution of first onset MDD episodes were compressed during the immediate pre-assessment period. Results were also consistent with previous evidence demonstrating the raised risk of MDD among women and of the decline in gender differences with advancing age. CONCLUSIONS These results suggest that estimates of putative MDD diagnostic status, derived through the HLEQ, and of associated demographic risk are similar to those derived by more intensive and costly assessment methods. Implications for the future study of MDD both as an outcome and as a risk factor for chronic disease are discussed.

Lipoprotein(a) and Risk of Coronary, Cerebrovascular, and Peripheral Artery Disease The EPIC-Norfolk Prospective Population Study

Objective—Although the association between circulating levels of lipoprotein(a) [Lp(a)] and risk of coronary artery disease (CAD) and stroke is well established, its role in risk of peripheral arterial disease (PAD) remains unclear. Here, we examine the association between Lp(a) levels and PAD in a large prospective cohort. To contextualize these findings, we also examined the association between Lp(a) levels and risk of stroke and CAD and studied the role of low-density lipoprotein as an effect modifier of Lp(a)-associated cardiovascular risk. Methods and Results—Lp(a) levels were measured in apparently healthy participants in the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort. Cox regression was used to quantify the association between Lp(a) levels and risk of PAD, stroke, and CAD outcomes. During 212 981 person-years at risk, a total of 2365 CAD, 284 ischemic stroke, and 596 PAD events occurred in 18 720 participants. Lp(a) was associated with PAD and CAD outcomes but not with ischemic stroke (hazard ratio per 2.7-fold increase in Lp(a) of 1.37, 95% CI 1.25–1.50, 1.13, 95% CI 1.04–1.22 and 0.91, 95% CI 0.79–1.03, respectively). Low-density lipoprotein cholesterol levels did not modify these associations. Conclusion—Lp(a) levels were associated with future PAD and CAD events. The association between Lp(a) and cardiovascular disease was not modified by low-density lipoprotein cholesterol levels.