Lipoprotein(a) in Youth and Prediction of Major Cardiovascular Outcomes in Adulthood.

BACKGROUND: Elevated lipoprotein(a) [Lp(a)] is a common risk factor for cardiovascular disease outcomes with unknown mechanisms. We examined its potential role in identifying youths who are at increased risk of developing adult atherosclerotic cardiovascular disease (ASCVD). METHODS: Lp(a) levels measured in youth 9 to 24 years of age were linked to adult ASCVD and carotid intima-media thickness in the YFS (Cardiovascular Risk in Young Finns Study), in which 95 of the original 3596 participants (2.7%) recruited as children have been diagnosed with ASCVD at a median of 47 years of age. Results observed in YFS were replicated with the use of data for White participants from the BHS (Bogalusa Heart Study). In BHS, 587 White individuals had data on youth Lp(a) (measured at 8-17 years of age) and information on adult events, including 15 cases and 572 noncases. Analyses were performed with the use of Cox proportional hazard regression. RESULTS: In YFS, those who had been exposed to high Lp(a) level in youth [defined as Lp(a) ≥30 mg/dL] had ≈2 times greater risk of developing adult ASCVD compared with nonexposed individuals (hazard ratio, 2.0 [95% CI, 1.4-2.6]). Youth risk factors, including Lp(a), low-density lipoprotein cholesterol, body mass index, and smoking, were all independently associated with higher risk. In BHS, in an age- and sex-adjusted model, White individuals who had been exposed to high Lp(a) had 2.5 times greater risk (95% CI, 0.9-6.8) of developing adult ASCVD compared with nonexposed individuals. When also adjusted for low-density lipoprotein cholesterol and body mass index, the risk associated with high Lp(a) remained unchanged (hazard ratio, 2.4 [95% CI, 0.8-7.3]). In a multivariable model for pooled data, individuals exposed to high Lp(a) had 2.0 times greater risk (95% CI, 1.0-3.7) of developing adult ASCVD compared with nonexposed individuals. No association was detected between youth Lp(a) and adult carotid artery thickness in either cohort or pooled data. CONCLUSIONS: Elevated Lp(a) level identified in youth is a risk factor for adult atherosclerotic cardiovascular outcomes but not for increased carotid intima-media thickness.

Associations of retinal microvascular caliber with large arterial function and structure: A population-based study of 11 to 12 year-olds and midlife adults.

OBJECTIVE: We examined associations between retinal microvascular and large arterial phenotypes to explore relationships between the micro- and macro-vasculature in childhood and midlife. METHODS: Participants were 1288 children (11-12 years, 50.9% female) and 1264 adults (mean age 44 years, 87.6% female) in a cross-sectional population-based study. Exposures were retinal arteriolar and venular caliber quantified from retinal images. Outcomes included arterial function (pulse wave velocity; carotid arterial elasticity) and structure (carotid intima-media thickness). Multivariable regression models were performed adjusting for age, sex, and family socioeconomic position. RESULTS: In children, one standard deviation wider arteriolar caliber was associated with slower pulse wave velocity (-0.15 SD, 95% CI -0.21, -0.09) and higher elasticity (0.13 SD, 95% CI 0.06, 0.20); per SD wider venular caliber was associated with faster pulse wave velocity (0.09 SD, 95% CI 0.03, 0.15) and lower elasticity (-0.07 SD, 95% CI -0.13, -0.01). The size of adult associations was approximately double. Wider arteriolar caliber was associated with smaller carotid intima-media thickness (-0.09 SD, 95% CI -0.16, -0.03) in adults but not children. Venular caliber and carotid intima-media thickness showed little evidence of association. CONCLUSIONS: Narrower retinal arterioles and wider venules are associated with large arterial function as early as mid-childhood. Associations strengthen by midlife and also extend to arterial structure, although effect sizes remain small.

Do body mass index and waist-to-height ratio over the preceding decade predict retinal microvasculature in 11-12 year olds and midlife adults?

BACKGROUND/OBJECTIVES: Microvascular changes may contribute to obesity-associated cardiovascular disease. We examined whether body mass index (BMI) and waist-to-height ratio (WHtR) (1) at multiple earlier time points and (2) decade-long trajectories predicted retinal microvascular parameters in mid-childhood/adulthood. METHODS: Participants/design: 1288 11-12 year olds (51% girls) and 1264 parents (87% mothers) in the population-based Child Health CheckPoint (CheckPoint) module within the Longitudinal Study of Australian Children (LSAC). LSAC exposure measures: biennial BMI z-score and WHtR for children at five time points from age 2-3 to 10-11 years and self-reported parent BMI at six time points from child age 0-1 years to 10-11 years. CheckPoint outcome measures: retinal arteriolar and venular caliber. ANALYSES: BMI/WHtR trajectories were identified by group-based trajectory modeling; linear regression models estimated associations between BMI/WHtR at each time point/trajectories and later retinal vascular caliber, adjusted for age, sex, and family socioeconomic status. RESULTS: In time point analyses, higher child BMI/WHtR from age 4 to 5 years was associated with narrower arteriolar caliber at the age of 11-12 years, but not venular caliber. For example, each standard deviation higher in BMI z-score at 4-5 years was associated with narrower arteriolar caliber at 11-12 years (standardized mean difference (SMD): -0.05, 95% confidence interval (CI): -0.10 to 0.01); by 10-11 years, associations had doubled to -0.10 (95% CI: -0.16 to -0.05). In adults, these finding were similar, except the magnitude of BMI and arteriolar associations were similar across all time points (SMD: -0.11 to -0.13). In child and adult BMI trajectory analyses, less favorable trajectories predicted narrower arteriolar (p-trend < 0.05), but not venular (p-trend > 0.1), caliber. Compared with those in the average BMI trajectory, SMDs in arterial caliber for children and adults in the highest trajectory were -0.25 (95% CI: -0.44 to -0.07) and -0.42 (95% CI: -0.73 to -0.10), respectively. Venular caliber showed late associations with child WHtR, but not with BMI in children or adults. CONCLUSIONS: Associations of decade-long high BMI trajectories with narrowed retinal arteriolar caliber emerge in children, and are clearly evident by midlife. Adiposity appears to exert its early adverse life course impacts on the microcirculation more via arteriolar than venular mechanisms.

Cardiovascular health and retinal microvascular geometry in Australian 11-12 year-olds.

Traditional retinal microvascular parameters (smaller arteriolar and greater venular caliber) are associated with cardiovascular risk factors, pre-clinical vascular phenotypes and clinical cardiovascular events in adults. Although novel retinal microvascular geometric parameters showed analogous associations in adults, less is known whether these parameters are associated with cardiovascular health from childhood. In a population-based cross-sectional study in children (n = 1126, mean age 11.4 years, 50.3% girls), we examined associations of cardiovascular risk factors and pre-clinical arterial phenotypes with retinal geometric parameters. Cardiovascular parameters included body mass index (BMI), an inflammatory marker (GlycA), low-density lipoprotein and high-density lipoprotein (HDL) cholesterol, systolic (SBP) and diastolic blood pressure, large artery functional (pulse wave velocity, PWV and carotid arterial elasticity) and structural (carotid intima-media thickness) phenotypes. Retinal geometric parameters (fractal dimension (Df) and tortuosity) were quantified from retinal images. Multivariable regression models were performed and adjusted for potential confounders. Higher values for BMI, SBP and PWV showed weak associations with lower (i.e. worse) arteriolar but not venular Df (standardized mean difference (SMD) ranging from -0.07 to -0.09, 95% CIs -0.15 to -0.01). Higher HDL was associated with greater arteriolar Df (SMD 0.07, 95% CI 0.01 to 0.13). Only higher SBP was associated with higher (i.e. worse) arteriolar but not venular tortuosity (SMD 0.09, 95% CI 0.02 to 0.16). In generally healthy children, some risk factors and pre-clinical arterial phenotypes show small associations with retinal geometric parameters. In childhood, emerging relationships between microvascular parameters and cardiometabolic risk may be better described by retinal vascular caliber than by geometric parameters.

Socioeconomic position over the life course from childhood and smoking status in mid-adulthood: results from a 25-year follow-up study.

BACKGROUND: It remains unclear how life course socioeconomic position (SEP) variations impact later smoking status. We aimed to investigate the associations using a novel methodology - a structured regression framework and to explore the potential underlying mechanisms. METHODS: Data were from an Australian national cohort (n = 1489). SEP was measured in childhood (aged 7-15 years), young- (aged 26-36 years) and mid-adulthood (aged 31-41 years), including highest parental occupation in childhood and self-occupation in young- and mid-adulthood. Smoking status was self-reported in mid-adulthood. Four smoking-related variables in childhood including exposure to parental smoking, smoking experimentation, self-rated importance to be a non-smoker and intention to smoke were tested as potential mediators. A structured life course modelling approach was used to select the best-fit life course model(s). The log multinomial model was used to estimate the smoking risk in mid-adulthood with never smokers as the excluded category. RESULTS: 63.6% of participants were classified as stable non-manual occupation across the life course from childhood. The sensitive period and the accumulation model described the data equally as well as the saturated model. In the sensitive period model, compared to the non-manual group, those who had highest parental occupation of manual had a 21% lower risk of being former smokers and a 32% greater risk of being current smokers in mid-adulthood, and those who were occupied manually in mid-adulthood reported a 55% greater risk of being current smokers in mid-adulthood. In the accumulation model, compared to those who consistently reported non-manual occupations across the life course, those with manual occupations for longer had higher risk of being current smokers in mid-adulthood, with a 43% risk increase per time point in a manual occupation. Exposure to parental smoking and intention to smoke during childhood explained up to 40.2% of the excess risk of being current smokers in mid-adulthood associated with manual occupations in the sensitive period and the accumulation model. CONCLUSIONS: Childhood, young- and mid-adulthood are all important, but SEP in childhood and mid-adulthood may be of more importance in determining mid-adulthood smoking status. Exposure to parental smoking and intention to smoke in childhood seems to moderately mediate the associations.

DHA mediates the protective effect of fish consumption on new episodes of depression among women.

In a longitudinal cohort study of young Australian adults, we reported that for women higher baseline levels of fish consumption were associated with reduced incidence of new depressive episodes during the 5-year follow-up. Fish are high in both n-3 fatty acids and tyrosine. In this study, we seek to determine whether n-3 fatty acids or tyrosine explain the observed association. During 2004-2006, a FFQ (nine fish items) was used to estimate weekly fish consumption among 546 women aged 26-36 years. A fasting blood sample was taken and high-throughput NMR spectroscopy was used to measure 233 metabolites, including serum n-3 fatty acids and tyrosine. During 2009-2011, new episodes of depression since baseline were identified using the lifetime version of the Composite International Diagnostic Interview. Relative risks were calculated using log-binomial regression and indirect effects estimated using the STATA binary_mediation command. Potential mediators were added to separate models, and mediation was quantified as the proportion of the total effect due to the mediator. The n-3 DHA mediated 25·3 % of the association between fish consumption and depression when fish consumption was analysed as a continuous variable and 16·6 % when dichotomised (reference group: <2 serves/week). Tyrosine did not mediate the association (<0·1 %). Components in fish other than n-3 fatty acids and tyrosine might be beneficial for women's mental health.

Worsening Dietary and Physical Activity Behaviors Do Not Readily Explain Why Smokers Gain Weight After Cessation: A Cohort Study in Young Adults.

INTRODUCTION: The relationship between smoking cessation and weight gain is well established but the underlying mechanisms remain poorly understood. We aimed to determine whether postcessation weight gain was mediated by changing health behaviors. METHODS: A total of 281 smokers self-reported their demographic, smoking, and lifestyle characteristics in 2004-2006 (aged 26-36) and 2009-2011 (aged 31-41). Behaviors considered as potential mediators of weight gain were changes in consumption of breakfast, discretionary foods (servings/d), fruit and vegetables (servings/d), alcohol (g/d), takeaway food (times/wk), Diet Guideline Index score, leisure time physical activity (PA, min/wk), total PA (min/wk), time spent sitting (min/d), and TV viewing (h/d). RESULTS: In total, 124 smokers quit smoking during 5 years follow-up. After adjustment for age, sex, baseline body mass index, education, and follow-up length, smoking cessation was associated with average excess weight gain of 2.09kg (95% CI = 0.35-3.83). Compared with continuing smokers, quitters reported a higher Diet Guideline Index score and less consumption of alcohol at baseline and follow-up (all p < .05). In addition, there was a tendency towards healthier dietary and PA behaviors over 5 years among quitters than continuing smokers except for time spent sitting, although these differences did not reach statistical significance. Adjustment for changes in these behaviors made little difference to the magnitude of postcessation weight gain (ß: 2.32kg, 95% CI = 0.54-4.10). CONCLUSIONS: The weight gain associated with smoking cessation was not explained by worsening dietary and PA behaviors. Future research is needed to elucidate the complex mechanisms and particularly ways it may be prevented. IMPLICATIONS: Fear of weight gain often discourages smokers from trying to quit but guidance on ways to most effectively avoid weight gain is lacking. It is important to identify what causes postcessation weight gain and the ways it may be prevented. The current study explored the effects of several changing dietary and PA behaviors on the relationship between smoking cessation and weight gain in 281 young Australian smokers. We found that quitters tended to adopt healthier dietary and PA behaviors than continuing smokers, so these behaviors did not readily explain the postcessation weight gain. Further investigations of other potential mechanisms are needed.

Polymorphisms affecting vitamin D-binding protein modify the relationship between serum vitamin D (25[OH]D3) and food allergy.

BACKGROUND: There is evolving evidence that vitamin D insufficiency may contribute to food allergy, but findings vary between populations. Lower vitamin D-binding protein (DBP) levels increase the biological availability of serum vitamin D. Genetic polymorphisms explain almost 80% of the variation in binding protein levels. OBJECTIVE: We sought to investigate whether polymorphisms that lower the DBP could compensate for adverse effects of low serum vitamin D on food allergy risk. METHODS: From a population-based cohort study (n = 5276) we investigated the association between serum 25-hydroxyvitamin D3 (25[OH]D3) levels and food allergy at age 1 year (338 challenge-proven food-allergic and 269 control participants) and age 2 years (55 participants with persistent and 50 participants with resolved food allergy). 25(OH)D3 levels were measured using liquid chromatography-tandem mass spectrometry and adjusted for season of blood draw. Analyses were stratified by genotype at rs7041 as a proxy marker of DBP levels (low, the GT/TT genotype; high, the GG genotype). RESULTS: Low serum 25(OH)D3 level (≤50 nM/L) at age 1 years was associated with food allergy, particularly among infants with the GG genotype (odds ratio [OR], 6.0; 95% CI, 0.9-38.9) but not in those with GT/TT genotypes (OR, 0.7; 95% CI, 0.2-2.0; P interaction = .014). Maternal antenatal vitamin D supplementation was associated with less food allergy, particularly in infants with the GT/TT genotype (OR, 0.10; 95% CI, 0.03-0.41). Persistent vitamin D insufficiency increased the likelihood of persistent food allergy (OR, 12.6; 95% CI, 1.5-106.6), particularly in those with the GG genotype. CONCLUSIONS: Polymorphisms associated with lower DBP level attenuated the association between low serum 25(OH)D3 level and food allergy, consistent with greater vitamin D bioavailability in those with a lower DBP level. This increases the biological plausibility of a role for vitamin D in the development of food allergy.

Smoking status and health-related quality of life: a longitudinal study in young adults.

PURPOSE: The possibility that tobacco use affects health-related quality of life (HRQoL) has attracted interest. However, a lack of prospective evidence weakens the case for a causal relationship. The aim was to examine the longitudinal relationship between change in smoking status and change in HRQoL in young adults. METHODS: We conducted a population-based cohort study with data collected in 2004-2006 (aged 26-36) and 2009-2011 (aged 31-41). Exposure was change in self-reported smoking status during follow-up. Outcomes were changes in physical and mental HRQoL measured by SF-12. RESULTS: For physical HRQoL (n = 2080), quitters had a 2.12 (95 % confidence interval (CI) 0.73, 3.51) point improvement than continuing smokers, whereas former smokers who resumed smoking had a 2.08 (95 % CI 0.21, 3.94) point reduction than those who maintained cessation. Resumed smokers were 39 % (95 % CI 10, 75 %) more likely to have a clinically significant (>5 point) reduction of physical HRQoL than former smokers who maintained cessation. In contrast, quitters were 43 % (95 % CI 3, 98 %) more likely to have a clinically significant (>5 point) improvement in physical HRQoL than continuing smokers. Change in smoking status was not significantly associated with change in mental HRQoL (n = 1788). CONCLUSIONS: Smoking by young adults was cross-sectionally associated with lower physical HRQoL and longitudinally associated with reductions in physical HRQoL. The expectation of short- to medium-term gains in physical HRQoL as well as long-term health benefits may help motivate young adult smokers to quit.

MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: a pooled-analysis from the M-SKIP project.

The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 controls from 17 studies. We calculated a summary odds ratio (SOR) for the association of each of the nine most studied MC1R variants and of variants combined with CM by using random-effects models. Stratified analysis by phenotypic characteristics were also performed. Melanoma risk increased with presence of any of the main MC1R variants: the SOR for each variant ranged from 1.47 (95%CI: 1.17-1.84) for V60L to 2.74 (1.53-4.89) for D84E. Carriers of any MC1R variant had a 66% higher risk of developing melanoma compared with wild-type subjects (SOR; 95%CI: 1.66; 1.41-1.96) and the risk attributable to MC1R variants was 28%. When taking into account phenotypic characteristics, we found that MC1R-associated melanoma risk increased only for darker-pigmented Caucasians: SOR (95%CI) was 3.14 (2.06-4.80) for subjects with no freckles, no red hair and skin Type III/IV. Our study documents the important role of all the main MC1R variants in sporadic CM and suggests that they have a direct effect on melanoma risk, independently on the phenotypic characteristics of carriers. This is of particular importance for assessing preventive strategies, which may be directed to darker-pigmented Caucasians with MC1R variants as well as to lightly pigmented, fair-skinned subjects.

Longitudinal associations between fish consumption and depression in young adults.

Few studies have examined longitudinal associations between fish consumption and depression; none have defined depression using a diagnostic tool. We investigated whether fish consumption was associated with fewer new depression episodes in a national study of Australian adults. In 2004-2006, 1,386 adults aged 26-36 years (38% males) completed a 127-item (9 fish items) food frequency questionnaire. Fish intake was examined continuously (times/week) and dichotomously (reference group: <2 times/week). During 2009-2011, the lifetime version of the Composite International Diagnostic Interview was administered by telephone. New episodes of major depression/dysthymic disorder (since baseline) were defined using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. During follow-up, 160 (18.8%) women and 70 (13.1%) men experienced depression. For women, each additional weekly serving of fish consumed at baseline decreased the risk of having a new depressive episode by 6% (adjusted relative risk = 0.94, 95% confidence interval: 0.87, 1.01). Women who ate fish ≥2 times/week at baseline had a 25% lower risk of depression during follow-up than those who ate fish <2 times/week (adjusted relative risk = 0.75, 95% confidence interval: 0.57, 0.99). Reverse causation was also suggested but appeared to be restricted to persons with recent depression. Fish consumption was not associated with depression in men. These findings provide further evidence that fish consumption may be beneficial for women's mental health.

Association between multiple sclerosis risk-associated SNPs and relapse and disability--a prospective cohort study.

BACKGROUND: The modulating effects of the multiple sclerosis (MS) risk-associated single-nucleotide polymorphisms (SNPs) on MS clinical course are not well established. OBJECTIVES: The objective of this paper is to investigate whether known MS risk-associated SNPs were associated with clinical course, and whether these SNPs modified the 25(OH)D-relapse association. METHODS: Using a prospective cohort of 141 participants with relapsing-remitting MS and genotype data followed between 2002 and 2005, genotype-vitamin D interactions and the genetic predictors of relapse were assessed using survival analysis, and genetic predictors of 25(OH)D and disability progression were evaluated by multilevel mixed-effects linear regression. RESULTS: While no SNP reached statistical significance after multiple testing, five SNPs were associated with relapse, with significant cumulative genotype risk effects and two demonstrated significant allele dose-response. Two SNPs altered the 25(OH)D-relapse association with significant allele dose-response. Five SNPs modified levels of 25(OH)D, with significant cumulative genotype 'risk' effect, and three demonstrated significant allele dose-response. We found no consistent evidence for an association between any SNPs and disability. CONCLUSIONS: Our study provides evidence for an association between known MS risk-associated SNPs and relapse. Our findings indicate gene-environment interactions may be an important mechanism on MS clinical course, and provide support for the role of vitamin D in MS relapse.

Hypertension in an experimental model of systemic lupus erythematosus occurs independently of the renal nerves.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder with prevalent hypertension and renal injury. In this study, we tested whether the renal nerves contribute to the development of hypertension in an established mouse model of SLE (NZBWF1). Female SLE and control (NZW/LacJ) mice were subjected to either bilateral renal denervation or a sham procedure at 32 wk of age. Two weeks later, blood pressure was assessed in conscious mice using carotid artery catheters. Blood pressure was higher in SLE mice compared with controls, as previously reported; however, blood pressure was not altered in the denervated SLE or control mice. The development of albuminuria was markedly blunted in denervated SLE mice; however, glomerulosclerosis was increased. Renal denervation reduced renal cortical expression of monocyte-chemoattractant protein in SLE mice but did not significantly alter renal monocyte/macrophage infiltration. Renal cortical TNF-α expression was also increased in sham SLE mice, but this was not impacted by denervation. This study suggests that the renal nerves do not have a significant role in the pathogenesis of hypertension, but have a complex effect on the associated renal inflammation and renal injury.

Lower urinary tract symptoms in relation to region of birth in 95,393 men living in Australia: the 45 and Up Study.

PURPOSE: Lower urinary tract symptoms (LUTS) are very common among older men globally, but evidence regarding the relationship between LUTS and country of origin is limited. This study aimed to investigate the relationship between the prevalence of LUTS and region of birth in a large, ethnically diverse population of older men resident in New South Wales, Australia. METHODS: Data on LUTS, demographic and behavioural factors were collected by postal questionnaire from 2006 to 2009 and analysed for 95,393 men aged 45 and over from the 45 and Up Study, who had not had previous prostate surgery. Logistic regression was used to investigate the association between region of birth and moderate/severe LUTS, ascertained using a modified International Prostate Symptom Score, adjusting for age, income, education, alcohol consumption and smoking. RESULTS: Overall, 18,530 (19.4 %) men had moderate or severe LUTS. Compared to Australian-born men, prevalence of moderate/severe LUTS was significantly higher in men born in the Middle East & North Africa, Southeast Asia and North America regions (adjusted odds ratios (OR) = 1.43; 95 % CI = 1.23-1.66, OR = 1.25; 1.10-1.42, OR = 1.26; 1.05-1.52, respectively), whereas men from the UK & Ireland had significantly lower prevalence (OR = 0.85; 0.80-0.90). Patterns of association were generally similar for storage- and voiding-related types of LUTS. However, participants born in Sub-Saharan Africa showed a significantly elevated prevalence of moderate/severe voiding symptoms (1.22; 1.03-1.45) but not storage symptoms, compared to Australian-born respondents. CONCLUSION: The prevalence of LUTS and of specific subtypes of LUTS varies according to region of birth.

Gene-environment interaction in problematic substance use: interaction between DRD4 and insecure attachments.

To investigate the combined effect of an exon III variable number tandem repeat in the dopamine receptor gene (DRD4) and insecure attachment style on risk for tobacco, cannabis and alcohol use problems in young adulthood. It was hypothesized that (1) individuals with 5, 6, 7 or 8 repeats (labelled 7R+) would be at increased risk for problematic drug use, and (2) risk for drug use would be further increased in individuals with 7R+ repeats who also have a history of insecure parent-child attachment relations. Data were drawn from the Victorian Adolescent Health Cohort Study, an eight-wave longitudinal study of adolescent and young adult development. DRD4 genotypes were available for 839 participants. Risk attributable to the combined effects of 7R+ genotype and insecure attachments was evaluated within a sufficient causes framework under the assumptions of additive interaction using a two-by-four table format with a common reference group. 7R+ alleles were associated with higher tobacco, cannabis and alcohol use (binging). Insecure attachments were associated with higher tobacco and cannabis use but lower alcohol use. For tobacco, there was evidence of interaction for anxious but not avoidant attachments. For cannabis, there was evidence of interaction for both anxious and avoidant attachments, although the interaction for anxious attachments was more substantial. There is no evidence of interaction for binge drinking. Results are consistent with a generic reward deficit hypothesis of drug addiction for which the 7R+ disposition may play a role. Interaction between 7R+ alleles and attachment insecurity may intensify risk for problematic tobacco and cannabis use.

Polygenic Risk Scores and the Risk of Childhood Overweight/Obesity in Association With the Consumption of Sweetened Beverages: A Population-Based Cohort Study.

Background: Sugar-sweetened beverage (SSB) and non-nutritive sweetened beverage (NNSB) consumption is associated with obesity and are targets for population-level dietary interventions. In children (<16 years), we evaluate whether SSB or NNSB consumption is associated with subsequent (2 years later) overweight and/or obesity, and the effect of consumption on subsequent overweight/obesity differs by BMI polygenic risk score (BMI-PRS). Methods: The nationally representative Longitudinal-Study-of-Australian-Children had biennial data collection from birth (n = 5107) until age 14/15 years (n = 3127). At age 11/12 years, a comprehensive biomedical assessment, including PRS assessment, was undertaken (n = 1422). Parent- or self-reported beverage consumption (SSBs: soft drinks, energy drinks, and/or juice; NNSBs: diet drinks) was measured as any/none over previous 24 hours. BMI-PRS was derived using published results (high PRS ≥75th percentile). At ages 4/5-14/15 children were classified as having obesity, overweight/obesity, or not having overweight/obesity using BMI z-score (CDC cut points). Results: SSB consumption had limited association with subsequent overweight/obesity. NNSB consumption was associated with ∼8% more children with subsequent overweight/obesity at most ages. In older children with high BMI-PRS, associations between NNSB consumption and subsequent overweight/obesity strengthened with age [at age 14-15 for high BMI-PRS, difference in proportion with overweight/obesity among NNSB consumers vs. nonconsumers = 0.38 (95% confidence interval: 0.22 to 0.55, p ≤ 0.001)]. There was limited association between SSB consumption and BMI-PRS. Conclusion: NNSB consumption was associated with increased risk of overweight/obesity for children with greater genetic risk at older ages (12-15 years). Focused intervention among children with high genetic risk could target NNSB consumption; however, reverse causality (children with genetic risk and/or high BMI consume more NNSBs) cannot be excluded.

The association between parity and knee cartilage in young women.

OBJECTIVES: There have been no reported studies of the association between parity and cartilage in young individuals. The aim of this study was to describe the association between parity, cartilage volume and cartilage defects in women aged 31-41 years. METHODS: Cross-sectional study of 144 women, mean age 36 years and BMI 25 kg/m(2), who were participants in an established prospective study. Parity was assessed using a questionnaire. Knee (medial tibial, lateral tibial and patellar) cartilage volume, cartilage defects (grade 0-4 depending on the severity of cartilage thickness loss at tibial and patellar sites) and tibial bone area were assessed using T1-weighted fat-suppressed MRI. RESULTS: The prevalence of cartilage defects (grade ≥2) in this population was 13%. Parity was associated with a higher risk of cartilage defects at the patellar [prevalence ratio (PR) per birth 1.52, 95% CI 1.05, 2.21; PR parous vs nulliparous 1.93, 95% CI 0.66, 5.65], but not tibial sites, after adjustment for confounders including age, BMI, smoking, physical activity, knee injury and tibial bone area. This association between parity and patellar cartilage defects was stronger for those women who had three or more births (vs nulliparous, PR 5.27, 95% CI 1.39, 20.01). There were no significant associations between parity and cartilage volume. CONCLUSION: Parity was associated with knee cartilage defects primarily at the patellar site in this sample of young women. This association was more apparent with increasing number of live births, suggesting a possible adverse effect of parity on knee cartilage.

Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project: study design and methods for pooling results of genetic epidemiological studies.

BACKGROUND: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. DESIGN AND METHODS: Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling. DISCUSSION: Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields.

Pulmonary emboli from therapeutic sodium hyaluronate.

A patient presented with shortness of breath and pleuritic pain shortly after bilateral knee synovial injections with sodium hyaluronate (HA). He was discharged after a brief hospitalization without a diagnosis when no Doppler or radiologic evidence of deep vein thrombosis or pulmonary emboli was found. Radiologic studies found patchy ground glass opacities that were predominantly peripheral in disposition, with prominent septal lines in the lungs; a subsequent pulmonary function test showed a reduced diffusing capacity of the lung for carbon monoxide (D(LCO)). These results prompted a lung biopsy that revealed multiple emboli composed of HA and fibrin in medium size pulmonary arteries, enlarged lymphatic vessels, and a bone marrow embolus. This is the first report of HA emboli following therapeutic HA injections and demonstrates that pulmonary function tests can be used to infer the reduction in pulmonary vascular area consequent to pulmonary emboli, and so can contribute to the detection of pulmonary emboli in unusual presentations.

Effect of including environmental data in investigations of gene-disease associations in the presence of qualitative interactions.

Complex diseases are likely to be caused by the interplay of genetic and environmental factors. Despite this, gene-disease associations are frequently investigated using models that focus solely on a marginal gene effect, ignoring environmental factors entirely. Failing to take into account a gene-environment interaction can weaken the apparent gene-disease association, leading to loss in statistical power and, potentially, inability to identify genuine risk factors. If a gene-environment interaction exists, therefore, a joint analysis allowing the effect of the gene to differ between groups defined by the environmental exposure can have greater statistical power than a marginal gene-disease model. However, environmental data are subject to measurement error. Substantial losses in statistical power for detecting gene-environment interactions can arise from measurement error in the environmental exposure. It is unclear, however, what effect measurement error may have on the power of the joint analysis. We consider the potential benefits, in terms of statistical power, of collecting concurrent environmental data within large cohorts in order to enhance gene detection. We further consider whether these benefits remain in the presence of misclassification in both the gene and the environmental exposure. We find that when an effect of the gene is apparent only in the presence of the environmental exposure, the joint analysis has greater power than a marginal gene-disease analysis. This comparative increase in power remains in the presence of likely levels of misclassification of either the gene or environmental exposure.