Linda Mustelin

A Comprehensive Evaluation of Potential Lung Function Associated Genes in the SpiroMeta General Population Sample

Rationale Lung function measures are heritable traits that predict population morbidity and mortality and are essential for the diagnosis of chronic obstructive pulmonary disease (COPD). Variations in many genes have been reported to affect these traits, but attempts at replication have provided conflicting results. Recently, we undertook a meta-analysis of Genome Wide Association Study (GWAS) results for lung function measures in 20,288 individuals from the general population (the SpiroMeta consortium). Objectives To comprehensively analyse previously reported genetic associations with lung function measures, and to investigate whether single nucleotide polymorphisms (SNPs) in these genomic regions are associated with lung function in a large population sample. Methods We analysed association for SNPs tagging 130 genes and 48 intergenic regions (+/−10 kb), after conducting a systematic review of the literature in the PubMed database for genetic association studies reporting lung function associations. Results The analysis included 16,936 genotyped and imputed SNPs. No loci showed overall significant association for FEV1 or FEV1/FVC traits using a carefully defined significance threshold of 1.3×10−5. The most significant loci associated with FEV1 include SNPs tagging MACROD2 (P = 6.81×10−5), CNTN5 (P = 4.37×10−4), and TRPV4 (P = 1.58×10−3). Among ever-smokers, SERPINA1 showed the most significant association with FEV1 (P = 8.41×10−5), followed by PDE4D (P = 1.22×10−4). The strongest association with FEV1/FVC ratio was observed with ABCC1 (P = 4.38×10−4), and ESR1 (P = 5.42×10−4) among ever-smokers. Conclusions Polymorphisms spanning previously associated lung function genes did not show strong evidence for association with lung function measures in the SpiroMeta consortium population. Common SERPINA1 polymorphisms may affect FEV1 among smokers in the general population.

Physical activity reduces the influence of genetic effects on BMI and waist circumference: a study in young adult twins

Objective:Both obesity and exercise behavior are influenced by genetic and environmental factors. However, whether obesity and physical inactivity share the same genetic vs environmental etiology has rarely been studied. We therefore analyzed these complex relationships, and also examined whether physical activity modifies the degree of genetic influence on body mass index (BMI) and waist circumference (WC).Methods:The FinnTwin16 Study is a population-based, longitudinal study of five consecutive birth cohorts (1975–1979) of Finnish twins. Data on height, weight, WC and physical activity of 4343 subjects at the average age of 25 (range, 22–27 years) years were obtained by a questionnaire and self-measurement of WC. Quantitative genetic analyses based on linear structural equations were carried out by the Mx statistical package. The modifying effect of physical activity on genetic and environmental influences was analyzed using gene-environment interaction models.Results:The overall heritability estimates were 79% in males and 78% in females for BMI, 56 and 71% for WC and 55 and 54% for physical activity, respectively. There was an inverse relationship between physical activity and WC in males (r=−0.12) and females (r=−0.18), and between physical activity and BMI in females (r=−0.12). Physical activity significantly modified the heritability of BMI and WC, with a high level of physical activity decreasing the additive genetic component in BMI and WC.Conclusions:Physically active subjects were leaner than sedentary ones, and physical activity reduced the influence of genetic factors to develop high BMI and WC. This suggests that the individuals at greatest genetic risk for obesity would benefit the most from physical activity.

Acquired obesity and poor physical fitness impair expression of genes of mitochondrial oxidative phosphorylation in monozygotic twins discordant for obesity

Defects in expression of genes of oxidative phosphorylation in mitochondria have been suggested to be a key pathophysiological feature in familial insulin resistance. We examined whether such defects can arise from lifestyle-related factors alone. Fourteen obesity-discordant (BMI difference 5.2 +/- 1.8 kg/m(2)) and 10 concordant (1.0 +/- 0.7 kg/m(2)) monozygotic (MZ) twin pairs aged 24-27 yr were identified among 658 MZ pairs in the population-based FinnTwin16 study. Whole body insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp technique. Transcript profiles of mitochondrial genes were compared using microarray data of fat biopsies from discordant twins. Body composition of twins was determined using DEXA and maximal oxygen uptake (Vo(2max)) and working capacity (W(max)) using a bicycle ergometer exercise test with gas exchange analysis. The obese cotwins had lower insulin sensitivity than their nonobese counterparts (M value 6.1 +/- 2.0 vs. 9.2 +/- 3.2 mg x kg LBM(-1) x min(-1), P < 0.01). Transcript levels of genes involved in the oxidative phosphorylation pathway (GO:0006119) in adipose tissue were lower (P < 0.05) in the obese compared with the nonobese cotwins. The obese cotwins were also less fit, as measured by Vo(2max) (50.6 +/- 6.5 vs. 54.2 +/- 6.4 ml x kg LBM(-1) x min(-1), for obese vs. nonobese, P < 0.05), W(max) (3.9 +/- 0.5 vs. 4.4 +/- 0.7 W/kg LBM, P < 0.01) and also less active, by the Baecke leisure time physical activity index (2.8 +/- 0.5 vs. 3.3 +/- 0.6, P < 0.01). This implies that acquired poor physical fitness is associated with defective expression of the oxidative pathway components in adipose tissue mitochondria.

Epidemiology of eating disorders in Europe: prevalence, incidence, comorbidity, course, consequences, and risk factors

Purpose of review Eating disorders – anorexia nervosa, bulimia nervosa, and binge eating disorder – affect numerous Europeans. This narrative review summarizes European studies on their prevalence, incidence, comorbidity, course, consequences, and risk factors published in 2015 and the first half of 2016. Recent findings Anorexia nervosa is reported by <1–4%, bulimia nervosa <1–2%, binge eating disorder <1–4%, and subthreshold eating disorders by 2–3% of women in Europe. Of men, 0.3–0.7% report eating disorders. Incidences of anorexia appear stable, whereas bulimia may be declining. Although the numbers of individuals receiving treatment have increased, only about one-third is detected by healthcare. Over 70% of individuals with eating disorders report comorbid disorders: anxiety disorders (>50%), mood disorders (>40%), self-harm (>20%), and substance use (>10%) are common. The long-term course of anorexia nervosa is favorable for most, but a substantial minority of eating disorder patients experience longstanding symptoms and somatic problems. The risk of suicide is elevated. Parental psychiatric disorders, prenatal maternal stress, various family factors, childhood overweight, and body dissatisfaction in adolescence increase the risk of eating disorders. Summary Eating disorders are relatively common disorders that are often overlooked, although they are associated with high comorbidity and serious health consequences.

The DSM-5 diagnostic criteria for anorexia nervosa may change its population prevalence and prognostic value

The definition of anorexia nervosa was revised for the Fifth Edition of the Diagnostic and Statistical Manual (DSM-5). We examined the impact of these changes on the prevalence and prognosis of anorexia nervosa. In a nationwide longitudinal study of Finnish twins born 1975-1979, the women (N = 2825) underwent a 2-stage screening for eating disorders at mean age 24. Fifty-five women fulfilled DSM-IV criteria for lifetime anorexia nervosa. When we recoded the interviews using DSM-5 criteria, we detected 37 new cases. We contrasted new DSM-5 vs. DSM-IV cases to assess their clinical characteristics and prognosis. We also estimated lifetime prevalences and incidences and tested the association of minimum BMI with prognosis. We observed a 60% increase in the lifetime prevalence of anorexia nervosa using the new diagnostic boundaries, from 2.2% to 3.6%. The new cases had a later age of onset (18.8 y vs. 16.5, p = 0.002), higher minimum BMI (16.9 vs. 15.5 kg/m(2), p = 0.0004), a shorter duration of illness (one year vs. three years, p = 0.002), and a higher 5-year probability or recovery (81% vs. 67%, p = 0.002). Minimum BMI was not associated with prognosis. It therefore appears that the substantial increase in prevalence of anorexia nervosa is offset by a more benign course of illness in new cases. Increased diagnostic heterogeneity underscores the need for reliable indicators of disease severity. Our findings indicate that BMI may not be an ideal severity marker, but should be complemented by prognostically informative criteria. Future studies should focus on identifying such factors in prospective settings.

Associations between sports participation, cardiorespiratory fitness, and adiposity in young adult twins

Exercise behavior, cardiorespiratory fitness, and obesity are strongly influenced by genetic factors. By studying young adult twins, we examined to what extent these interrelated traits have shared genetic and environmental etiologies. We studied 304 twin individuals selected from the population-based FinnTwin16 study. Physical activity was assessed with the Baecke questionnaire, yielding three indexes: sport index, leisure-time index, and work index. In this study, we focused on sport index, which describes sports participation. Body composition was determined using dual-energy X-ray absorptiometry and cardiorespiratory fitness using a bicycle ergometer exercise test with gas exchange analysis. The Baecke sport index was associated with high maximal oxygen uptake adjusted for lean body mass (Vo(2max)[adj]) (r = 0.40), with low body fat percentage (BF%) (r = -0.44) and low waist circumference (WC) (r = -0.29). Heritability estimates for the key traits were as follows: 56% for sport index, 71% for Vo(2max)[adj], 77% for body mass index, 66% for WC, and 68% for BF%. The association between sport index and Vo(2max) was mostly explained by genetic factors (70%), as were both the association between sport index and BF% (71%) and that between sport index and WC (59%). Our results suggest that genetic factors explain a considerable part of the associations between sports participation, cardiorespiratory fitness, and obesity.

Incidence and weight trajectories of binge eating disorder among young women in the community

OBJECTIVE To assess the population prevalence and incidence of binge eating disorder (BED) among young women. METHOD In a nationwide longitudinal study of Finnish twins born 1975-1979, the women participated in five surveys from age 16 until their mid-thirties. At Wave 4 (mean age 24 years), the women (N = 2,825) underwent a 2-stage screening for eating disorders. We assessed the lifetime prevalence, incidence, and clinical characteristics of DSM-5 BED. RESULTS We detected 16 women who met DSM-5 criteria for BED, yielding a lifetime prevalence of 0.7% (95% confidence interval [CI] 0.4-1.2%). The incidence of BED among women between 10 and 24 years of age was 35 (95% CI 20-60) per 100,000 person-years. The mean age of onset of BED was 19 years (range 13-27 years). Of the cases, 13/16 (81%) were currently ill. Duration of illness at the time of assessment ranged from less than a year to 13 years (median 6 years). Of women with BED, only two had a history of other eating disorders, but six had lifetime major depressive disorder. Two-thirds of the women with BED belonged to the highest weight quartile at age 16, and their mean BMI at age 22-27 year was 26.2 kg/m(2) (range 22.1-32.5 kg/m(2)). DISCUSSION Incident BED as defined by DSM-5 was relatively rare among younger women and was often preceded by relative overweight. BED often occurred without a history of other eating disorders, but comorbidity with major depressive disorder was common.

Genetic Influences on Physical Activity in Young Adults. A Twin Study

PURPOSE The aim of this study was to investigate genetic and environmental influences on different aspects of physical activity in young adult twins. METHODS We studied 1274 Finnish twins with a mean age of 22.4 yr, from the population-based FinnTwin12 study. Physical activity was assessed with the Baecke Questionnaire, yielding four indexes: the sport index, leisure time activity index, work index, and total score. Quantitative genetic analyses based on linear structural equations were used to estimate the contribution of genetic and environmental factors on these physical activity traits. RESULTS The overall heritability estimates were 64% (95% confidence interval (CI) = 0.56%-0.70%) for sports activity, 41% (95% CI = 0.31%-0.51%) for leisure time activity excluding sports, 56% (95% CI = 0.48%-0.63%) for physical activity at work, and 54% (95% CI = 0.45%-0.62%) for total physical activity. Unique environmental factors accounted for the rest of the trait variances. We did not find evidence for common environmental or dominant genetic influences. The heritability estimates did not differ between men and women, and no sex-specific genetic factors were found. Sports activity and leisure time activity excluding sports were associated (r = 0.27), and additive genetic factors explained 57% of their association. CONCLUSIONS Our results suggest that genetic factors contribute significantly to physical activity levels in young adults and that sports activity is under stronger genetic influence than leisure time physical activity excluding sports. We also concluded that physical activity at work does not seem to be associated with sports activities or other leisure time physical activity at this age.

Long-term outcome in anorexia nervosa in the community.

OBJECTIVE Few studies have assessed outcomes of anorexia nervosa (AN) outside clinical settings. We aimed to assess mortality, recovery, and socio-demographic outcomes of AN in a community sample. METHOD Women in the nationwide FinnTwin16 cohort (born 1975-1979) were followed for 10 years after baseline diagnostic assessment (mean age at follow-up 34 years, N = 2188). We compared women with lifetime DSM-IV AN (N = 40) with unaffected women from the same cohort. RESULTS None of the women with AN had died and 88% were weight-recovered (BMI ≥ 18.5 kg/m(2) ), but their mean BMI (22.0 kg/m(2) ) was lower than among unaffected women (24.0 kg/m(2) , p = 0.008). University degrees (38 vs. 29%, p = 0.26), sickness absence during the past year (median 5 vs. 3 days, p = 0.21), or unemployment or disability pension (5 vs. 4%, p = 0.62) did not significantly differ between AN probands and their unaffected peers. More women with AN were still studying (15 vs. 4%, p = 0.003), and half of them had children, as compared to 66% of unaffected women (p = 0.05). DISCUSSION The long-term prognosis of AN in the community appears promising. Weight-restoration is common and socio-demographic outcomes are generally favorable. However, women with a history of AN may be less likely to have children.

Do psychological harms result from being labelled with an unexpected diagnosis of abdominal aortic aneurysm or prostate cancer through screening? A systematic review

Objective A potential psychological harm of screening is unexpected diagnosis—labelling. We need to know the frequency and severity of this harm to make informed decisions about screening. We asked whether current evidence allows an estimate of any psychological harm of labelling. As case studies, we used two conditions for which screening is common: prostate cancer (PCa) and abdominal aortic aneurysm (AAA). Design Systematic review with narrative synthesis. Data sources and eligibility criteria We searched the English language literature in PubMed, PsychINFO and Cumulative Index of Nursing and Allied Health Literature (CINAHL) for research of any design published between 1 January 2002 and 23 January 2017 that provided valid data about the psychological state of people recently diagnosed with early stage PCa or AAA. Two authors independently used explicit criteria to review and critically appraise all studies for bias, applicability and the extent to which it provided evidence about the frequency and severity of harm from labelling. Results 35 quantitative studies (30 of PCa and 5 of AAA) met our criteria, 17 (48.6%) of which showed possible or definite psychological harm from labelling. None of these studies, however, had either appropriate measures or relevant comparisons to estimate the frequency and severity of psychological harm. Four PCa and three AAA qualitative studies all showed clear evidence of at least moderate psychological harm from labelling. Seven population-based studies found increased suicide in patients recently diagnosed with PCa. Conclusions Although qualitative and population-based studies show that at least moderate psychological harm due to screening for PCa and AAA does occur, the current quantitative evidence is insufficient to allow a more precise estimation of frequency and severity. More sensitive measures and improved research designs are needed to fully characterise this harm. In the meantime, clinicians and recommendation panels should be aware of the occurrence of this harm.