Submissiveness: protection or risk?

THE LANCET

the BMJ’s Editor stated recently that “advertising must be immediately recognisable as such, and we never sell advertising linked to editorial material”.5 That is good, but not enough to protect readers from misleading promotion. We wonder about the effectiveness of a short letter reporting a serious adverse event with Coversyl compared with a longstanding international promotional campaign about Coversyl’s safety. We believe that medical journals have responsibilities that go beyond rejecting offensive advertising. If the BMJ and The Lancet do not want to spend time and money reviewing drug advertisements, we suggest that they inform their readers of their policy and publish warnings on each advertisement. *Agnès Vitry, Peter Mansfield Medical Lobby for Appropriate Marketing, PO Box 172, Daw Park, SA 5041, Australia

1 2 3 4

5

Frankel DH. Servier criticised on perindopril campaign. Lancet 1996; 347: 183. Vitry A, Mansfield P. Promotion of Coversyl by Servier. Lancet 1996; 347: 1411. MacFadyen RJ. Br Heart J 1991; 66: 206–11. Bagger JP. Adverse event with first-dose perindopril in congestive heart failure. Lancet 1997; 349: 1671–72. Editor. Advertisements for donepezil (Aricept) in the BMJ. Br Med J 1997; 14: 1555–56.

Submissiveness: protection or risk? SIR—M C Whiteman and colleagues (Aug 23, p 541)1 conclude that the personality trait of submissiveness might protect women in particular from nonfatal myocardial infarction (p=0·002). In the case of men this protective function was lower (p=0·023). They state that submissiveness protects neither sex from fatal myocardial infarctions, and continue: “there were no differences in personality scores for non-cardiovascular deaths (data not shown)”. The difficulty begins at this point. It is possible that submissiveness does protect from non-fatal myocardial infarction but represents an increased risk for other diseases such as infection Target indices

Leucocytes (cells/µL) CD4 (cells/␮L) CD20 (cells/␮L) CD14 (cells/␮L) CD13 (cells/␮L) HLA-DR (cells/␮L) IL-2 (pg/mL) sIL-2R (pg/mL)

or carcinoma. Data on other diseases are not provided, which is very relevant, as our data imply. 2 Of 69 healthy medical students, 31 were classed as dominant and 15 as submissive, assessed by means of the Freiburg personality inventory,3 which determined nervousness, aggressiveness, calmness, depression, excitability, sociability, dominance, inhibitedness, frankness, extraversion, emotionality, and self-perception. We compiled a comprehensive immunological profile for all volunteers: leucocytes, blood mononuclear cells (lymphocytes, monocytes) expressing CD3, CD4, CD8, CD20, CD16, CD14/CD13, HLA-DR, as well as the cytokines and soluble cytokine receptors interleukin (IL)-1␣, IL-1␤, IL-1 receptor antagonist, IL-6, tumour necrosing factor-␣, IL-2, soluble IL-2 receptor, IL-4, interferon-␥, IL-10, T-cell growth factor-␤1 in peripheral blood. We showed clear relations between the personality traits of dominance and submissiveness and several essential cellular and function indices (table). The multivariate PC test by Läuter,4 with the immunological indices for the mean comparison dominant versus submissive volunteers, gave a p value of p=0·027. The corresponding standard T2 test by Hotelling yielded p=0·065. According to our hypothesis, dominant personality, being creative, active, and life-affirming, should also offer increased resistance from the immunological viewpoint, indicated by functional and morphological immunological indices. In real life, for instance, people with these traits might be characterised by having fewer complaints and shorter courses or decreased frequencies of diseases. Nevertheless, there are high-risk personalities who should be psychologically submissive and, as indicated by cell and cytokine indices pointing to a dysfunctional or sluggish immune response, offer lower resistance which, in turn, are presumed to determine how the individual copes with life.

Mean values

p*

Dominant (n=31)

Submissive (n=15)

6600 1086·4 296·5 457·9 463·1 596·2 196·6 1693·2

5100 911·6 232·1 367·9 328·7 455·7 74·8 1512·9

0·0035 0·0498 0·0732 0·0847 0·0089 0·0251 0·0644 0·0865

CD4=T-helper cells, CD20=B-cells, CD14/CD13=monocytes, HLA-DR=human leucocyte locus A system, IL=interleukin, sIL-2R=soluble IL-2 receptor. *Welch test.

Univariate comparison of means of various immunological indices for dominant versus submissive personality traits

1478

We would be interested to know whether certain non-cardiovascular diseases are correlated with the personality trait of submissiveness among Whiteman and colleagues’ patients. Our first results from healthy volunteers seem to imply that submissive volunteers have a less activated immune system than dominant volunteers. *Frank P Meyer, Uwe Tröger, Siegfried Ansorge, Jürgen Läuter Institutes of *Clinical Pharmacology, Experimental Internal Medicine, and Biometrics and Medical Informatics, Otto-von-Guericke-Universität Magdeburg, D-39120 Magdeburg, Germany 1

3

3

4

Whiteman MC, Deary IJ, Lee AJ, Fowkes FGR. Submissiveness and protection from coronary heart disease in the general population: Edinburgh Artery Study. Lancet 1997; 350: 541–45. Meyer FP, Tröger U, Ansorge S, et al. ‘Dominance’ personality trait and immune system in healthy volunteers. Hum Psychopharmacol (in press). Fahrenberg J, Selg H. Das Freiburger Persönlichkeitsinventar (FPI). Handanweisung. Göttingen: Hogrefe, 1970. Läuter J. Exact t and F tests for analyzing studies with multiple endpoints. Biometrics 1996; 52: 964–70.

SIR—The study by M C Whiteman and colleagues 1 did not provide enough information for readers to assess any contribution of potential confounders (apart from age and sex) to the main effect. I would like to have seen a table showing the relation between other cardiovascular risk factors and submissiveness or hostility at baseline. Even if there are no associations between submissiveness or hostility and established cardiovascular risk factors in these data, this is an important fact that should be aired. Whiteman and co-workers’ work was presented as if it were a casecontrol study. The Edinburgh Artery Study is a rigorously designed prospective cohort study, sampled from the general population. Because research on putative links between personality and cardiovascular disease is at a comparatively early stage of development, more baseline data that compared personality profiles with other risk factors would have been particularly welcome. Since the study population is small, the issue of statistical power may have driven both the choice of analytic method and the attention given to specificity of outcome. Small studies are necessary as epidemiologists refine their measurements, 2,3 but as with all observational investigations, the interpretation depends critically on

Vol 350 • November 15, 1997

THE LANCET

how potential confounders are handled.4 In this complicated territory, identifying causal pathways and confounding factors is not straightforward, as Whiteman et al acknowledge, but explicit decisions about whether or not to adjust for other variables can only be made when baseline relations between variables are known. I submit that it would have been helpful if potential associations between the main exposures—submissiveness and hostility—and other baseline variables besides age and sex had received more attention. Mark N Upton Department of General Practice, Glasgow University, Woodside Health Centre, Glasgow G20 7LR, UK 1

2

3

4

Whiteman MC, Deary IJ, Lee AJ, Fowkes FGR. Submissiveness and protection from coronary heart disease in the general population: Edinburgh Artery Study. Lancet 1997; 350: 541–45. Schulte PA. Methodologic issues in the use of biologic markers in epidemiologic research. Am J Epidemiol 1987; 126: 1006–16. Phillips AN, Davey Smith G. The design of prospective epidemiological studies: more subjects or better measurements? J Clin Epidemiol 1993; 46: 1203–11. Brennan P, Croft P. Interpreting the results of observational research: chance is not such a fine thing. BMJ 1994; 309: 727–30.

Authors’ reply SIR—We agree with Frank Meyer and colleagues that submissiveness may have different relations with other diseases. The Edinburgh Artery Study is a cohort study designed to measure the prevalence and incidence of cardiovascular and peripheral vascular disease and their risk factors. 1 Stringent criteria for defining events and extensive follow-up procedures have been undertaken to ensure the high quality of data, and are described

in several previous publications. 1–3 Our Lancet report3 describes the relation between baseline submissiveness or dominance and incident cardiovascular events in the 809 male and 793 female participants. Our study was not designed to gather such exhaustive information |on non-cardiovascular diseases. It would be ill-advised for us to attempt post-hoc analysis with noncardiovascular endpoints. Our data, as do Meyer’s, suggest that submissiveness or dominance is a trait that warrants further attention in epidemiological research, including its relation with non-cardiovascular diseases. In reply to Mark Upton, we adjusted fully for the potentially confounding baseline risk factors of smoking, alcohol consumption, social class, systolic and diastolic blood pressure, total and high-density lipoprotein cholesterol, triglycerides, body-mass index, and extent of baseline atherosclerosis (as assessed by the ankle-brachial pressure index).3 We explained our adjustments in the data analysis section of the methods and footnotes in the tables. Our aim was to describe the relation between personality and disease, not personality with risk factors, so their correlations were not presented separately. However, the table shows the correlation coefficients between hostility, submissiveness, and the baseline risk factors in men and women. We have also previously published the relations between personality, smoking, and alcohol consumption in the Edinburgh Artery Study.4 The data were not presented as a case-control study. The comparisons were made between those developing an event and all others in the population not developing that event. The risk of having an event over a 5-year period was calculated in relation to a standard deviation change in submissiveness scores as measured at

Hostility

Smoking Alcohol Social class Systolic blood pressure Diastolic blood pressure Total cholesterol HDL-cholesterol Triglycerides Body-mass index ABPI

Submissiveness

Men

Women

Men

Women

0·10* 0·11† 0·15† 0·08* 0·07 0·01 ⫺0·01 0·09* 0·08* ⫺0·02

0·07 0·09* 0·11† ⫺0·11 ⫺0·06 ⫺0·01 ⫺0·05 0·05 ⫺0·01 ⫺0·05

0·04 ⫺0·09* 0·01 0·02 ⫺0·06 ⫺0·01 0·04 ⫺0·05 ⫺0·11† 0·00

0·03 0·01 0·02 0·01 ⫺0·01 ⫺0·03 0·02 0·01 ⫺0·05 0·01

Smoking mesured in packyears (number of 20-cigarette packs smoked per day, multiplied by number of years as smoker). Alcohol=units consumed in previous week. Social class groups 1–5, 1 highest and 5 lowest. APBI=ankle brachial pressure index. *p⭐0·05; †p⭐0·01.

Pearson correlation coefficients between hostility, submissivenss, and baseline risk factors in 809 men and 783 women

Vol 350 • November 15, 1997

baseline in the whole population. This is a standard approach to data analysis in cohort studies. *M C Whiteman, I J Deary, A J Lee, F G R Fowkes Wolfson Unit for Prevention of Peripheral Vascular Diseases, Department of Public Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK 1

2

3

4

Fowkes FGR, Housley E, Cawood EHH, Macintryre CCA, Ruckley CV, Prescott RJ. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial diseases in the general population. Int J Epidemiol 1991; 20: 384–92. Leng GC, Lee AJ, Fowkes FGR, et al. Incidence, natural history and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol 1996; 25: 1172–81. Whiteman MC, Deary IJ, Lee AJ, Fowkes FGR. Submissiveness and protection from coronary heart disease in the general population: Edinburgh Artery Study. Lancet 1997; 350: 541–45. Whiteman MC, Fowkes FGR, Deary IJ, Lee AJ. Hostility, cigarette smoking and alcohol consumption in the general population. Soc Sci Med 1997; 44: 1089–96.

MTHFR 677C→T mutation and neural-tube defects S IR —David Wilcken’s Aug 30 commentary 1 examines the clinical relevance of the 677C→T 5,10 methylene-tetrahydrofolate reductase (MTHFR) mutation. He also estimates that in most white populations the frequency of the homozygous mutant genotype is about 11%, indirectly suggesting that the mutation frequency might not be population specific. However, in 1995 an Italian study reported a 16·3% frequency of this mutation.2 Three other studies have also reported high frequencies of the homozygous mutant genotype in unselected cohorts of Italian healthy, unrelated controls. 3–5 These results indicate a higher frequency than that reported by Wilcken for the deficient genotype in Italians, namely 18%. Many other studies have shown that the prevalence of the MTHFR mutant genotype can vary according to the population investigated—for example, Japanese 2%, Brazilian 4%, Irish 12·9%. In many of these studies, the sample size was small and selection biases are likely. However, because the four Italian studies were conducted in institutions geographically located in different areas of the country and in the frame of different investigational aims, overestimation due to the same type of bias is unlikely. Thus, the 11% rate for the MTHFR 677C→T mutation proposed by Wilcken is not consistent with the data available for Italians.

1479