Phenotypic Risk Factors Research Articles

Replication and Predictive Value of SNPs Associated with Melanoma and Pigmentation Traits in a Southern European Case-Control Study

BackgroundGenetic association studies have revealed numerous polymorphisms conferring susceptibility to melanoma. We aimed to replicate previously discovered melanoma-associated single-nucleotide polymorphisms (SNPs) in a Greek case-control population, and examine their predictive value.MethodsBased on a field synopsis of genetic variants of melanoma (MelGene), we genotyped 284 patients and 284 controls at 34 melanoma-associated SNPs of which 19 derived from GWAS. We tested each one of the 33 SNPs passing quality control for association with melanoma both with and without accounting for the presence of well-established phenotypic risk factors. We compared the risk allele frequencies between the Greek population and the HapMap CEU sample. Finally, we evaluated the predictive ability of the replicated SNPs.ResultsRisk allele frequencies were significantly lower compared to the HapMap CEU for eight SNPs (rs16891982 – SLC45A2, rs12203592 – IRF4, rs258322 – CDK10, rs1805007 – MC1R, rs1805008 - MC1R, rs910873 - PIGU, rs17305573- PIGU, and rs1885120 - MTAP) and higher for one SNP (rs6001027 – PLA2G6) indicating a different profile of genetic susceptibility in the studied population. Previously identified effect estimates modestly correlated with those found in our population (r = 0.72, P<0.0001). The strongest associations were observed for rs401681-T in CLPTM1L (odds ratio [OR] 1.60, 95% CI 1.22–2.10; P = 0.001), rs16891982-C in SCL45A2 (OR 0.51, 95% CI 0.34–0.76; P = 0.001), and rs1805007-T in MC1R (OR 4.38, 95% CI 2.03–9.43; P = 2×10−5). Nominally statistically significant associations were seen also for another 5 variants (rs258322-T in CDK10, rs1805005-T in MC1R, rs1885120-C in MYH7B, rs2218220-T in MTAP and rs4911442-G in the ASIP region). The addition of all SNPs with nominal significance to a clinical non-genetic model did not substantially improve melanoma risk prediction (AUC for clinical model 83.3% versus 83.9%, p = 0.66).ConclusionOverall, our study has validated genetic variants that are likely to contribute to melanoma susceptibility in the Greek population.

Multivariable Modeling of Phenotypic Risk Factors for First-Onset TMD: The OPPERA Prospective Cohort Study

Multivariable Modeling of Phenotypic Risk Factors for First-Onset TMD: The OPPERA Prospective Cohort Study

P 14: Hypertriglyceridemic waist phenotype in type 2 diabetes: association with higher hs-CRP and lower antioxidative enzyme activity

Background and aim It was previously suggested that hypertriglyceridemic waist (HTgW) phenotype (waist girth ≥90 cm in men and ≥85 cm in women, and triglyceride (Tg) levels ≥2.0 mmol/l) could identify visceral obesity and higher risk for atherosclerosis, but the relationship between HTgW phenotype and different atherosclerosis risk factors has not yet been elucidated. The aim of this study was to analize (a) hs-CRP levels, (b) lipid levels and (c) antioxidant enzyme glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities in the following groups of subjects: 30 patients with type 2 diabetes (T2D) and HTgW (group A), 24 T2D patients with abdominal obesity (higher waist) and normal Tg (group B) and 20 non obese T2D patients without HTgW (group C). Methods CRP levels were detected by Elisa method, GSH-Px and SOD activity were detected by spectrophotometry, total cholesterol (Ch), HDL-Ch, LDL-Ch and Tg levels by enzymatic methods and the insulin resistance (IR) was assessed by using HOMA-IR (calculated from basal insulin levels determined by RIA and fasting glucose levels determined by glucosooxidase method). Results We found significantly higher hs-CRP level in group A compared to group B (6,97+/-2,01 vs 4,72+/-2,01 mg/l; p Conclusions Our results signify that presence of HTgW phenotype in T2D, as a marker of visceral obesity, is strongly associated with marked atherosclerosis risk profile, especially at the level of inflammation, reverse cholesterol metabolism and antioxidative enzyme activity. The results also suggest that in this phenotype detected higher IR might be exerting its atherogenic effect partly on the level of the changes in antioxidative defence.

Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: A case–control study

BackgroundDespite the implementation of cardiac monitoring guidelines, clozapine-induced myocarditis continues to cause deaths in Australia, and the risk is a barrier to prescription of this effective drug for the treatment of schizophrenia. This study was designed to identify clinical and phenotypic risk factors for clozapine-induced myocarditis. MethodPossible cases of clozapine related myocarditis occurring between June 1993 and November 2009 and a comparative group of controls taking clozapine for at least 45days without cardiac disease were documented from the patients' medical records. Results105 cases, with time to onset of 10–33days, and 296 controls were included in the study. In multivariate analysis, the risk of myocarditis increased by 26% for each additional 250mg of clozapine administered in the first nine days of clozapine titration (odds ratio 1.26; 95% confidence interval 1.02–1.55; p=0.03) and concomitant sodium valproate more than doubled the risk (2.59; 1.51–4.42; 0.001). Further, each successive decade in age was associated with a 31% increase in risk (1.31; 1.07–1.60; 0.009).Nevertheless, 33 cases received less than 920mg of clozapine during the first nine days of dose titration, did not take sodium valproate and were aged less than 40years; and nine control patients received sodium valproate and more than 920mg of clozapine in the first nine days without developing myocarditis. ConclusionsClozapine should be initiated by slow dose titration and sodium valproate is best avoided, if clinically feasible, during this period. All patients commencing clozapine should be monitored for myocarditis up to Day 28.

15q11.2 microdeletion and FMR1 premutation in a family with intellectual disabilities and autism

Genomic rearrangements of chromosome 15q11–q13 are responsible for diverse phenotypes including intellectual disabilities and autism. 15q11.2 deletion, implicating common PWS/AS breakpoints BP1–BP2, has been described in patients with delayed motor and speech development and behavioural problems. Here we report the clinical and molecular characterisation of a maternally inherited BP1–BP2 deletion in two siblings with intellectual, motor and speech delay, autistic syndrome disorder and several dysmorphic features. One of the patients was also a carrier of an FMR1 allele in the low premutation range. The four genes within the deletion were under-expressed in all deletion carriers but FMR1 mRNA levels remained normal. Our results suggest that BP1-BP2 deletion could be considered as a risk factor for neuropsychological phenotypes and that it presents with variable clinical expressivity.

Interactive effect of genetic susceptibility with height, body mass index, and hormone replacement therapy on the risk of breast cancer

BackgroundBreast cancer today has many established risk factors, both genetic and environmental, but these risk factors by themselves explain only part of the total cancer incidence. We have investigated potential interactions between certain known genetic and phenotypic risk factors, specifically nine single nucleotide polymorphisms (SNPs) and height, body mass index (BMI) and hormone replacement therapy (HRT).MethodsWe analyzed samples from three different study populations: two prospectively followed Swedish cohorts and one Icelandic case–control study. Totally 2884 invasive breast cancer cases and 4508 controls were analysed in the study. Genotypes were determined using Mass spectrometry-Maldi-TOF and phenotypic variables were derived from measurements and/or questionnaires. Odds Ratios and 95% confidence intervals were calculated using unconditional logistic regression with the inclusion of an interaction term in the logistic regression model.ResultsOne SNP (rs851987 in ESR1) tended to interact with height, with an increasingly protective effect of the major allele in taller women (p = 0.007) and rs13281615 (on 8q24) tended to confer risk only in non users of HRT (p-for interaction = 0.03). There were no significant interactions after correction for multiple testing.ConclusionsWe conclude that much larger sample sets would be necessary to demonstrate interactions between low-risk genetic polymorphisms and the phenotypic variables height, BMI and HRT on the risk for breast cancer. However the present hypothesis-generating study has identified tendencies that would be of interest to evaluate for gene-environment interactions in independent materials.

Metabolic phenotype and cardiovascular risk factors in the first degree relatives of Chinese women with polycystic ovary syndrome

To test the hypothesis that the first degree relatives of Chinese women with polycystic ovarian syndrome (PCOS) have higher risk of cardiovascular disease than those without PCOS.The metabolic phenotype and risks of cardiovascular disease were evaluated in 110 family members of 35 women with PCOS and 85 unrelated healthy control subjects without family history of diabetes and PCOS ( four age- and weight-matched subgroups ).The prevalence of impaired glucose tolerance was 51.4％ in mothers and 57.5％ in fathers with their daughters suffering from PCOS.The first degree relatives of PCOS women had significantly higher serum fasting insulin level,homeostasis model assessment for insulin resistance,insulin area under the curve,and lower insulin sensitivity index in all subgroups than the control subjects( P＜0.05 ).The control subjects had significantly elevated high molecular weight-adiponectin levels and decreased high sensitive-C reactive protein levels compared to the first degree relatives of PCOS women in all subgroups.Parents and brothers,but not sisters,of women with PCOS had significantly higher total cholesterol and low density lipoprotein-cholesterol ( P＜ 0.05 ),as well as triglyceride levels ( P＜ 0.05 ),compared with control subjects.The first degree relatives of PCOS women had features of insulin resistance and increased risk of cardiovascular disease. Key words: Polycystic ovarian syndrome ; First degree relatives ; Insulin resistance ; Cardiovascular disease

Abstract 5500: Phenotypic risk factors for malignant melanoma in-situ in US women and men

Abstract Malignant melanoma in-situ (MMIS) has been associated with the risk of invasive melanoma, either through invasive transformation or as a marker for de novo invasive melanoma. However, while risk of invasive melanoma has been extensively studied, very little data exists on phenotypic risk factors of MMIS. Objectives: In this study, we evaluated the risk of MMIS according to host phenotypic characteristics amongst a large population of US women and men. Methods: We used data from three prospective cohort studies, the Nurse's Health Study 1 and 2 (NHS, NHS2), and the Health Professionals Follow-up Study (HPFS). Data were collected via biennial questionnaires from 44,998 males and 205,153 females over a 28, 20 and 22 year period for NHS1, NHS2, and HPFS, respectively. 1,097 melanoma in-situ lesions were identified and confirmed via pathology reports. Risk factors were family history of melanoma, number of atypical (&amp;gt;3mm) nevi on an extremity, childhood/adolescent sunburn reaction, number of childhood/adolescent sunburns and natural hair color at age 21. Age-adjusted and multivariate regression analysis was performed. Further sub-analysis in NHS evaluated MMIS risk based on Fitzpatrick skin type. Results: Individuals with a family history of melanoma had increased risk of MMIS in all three studies, NHS mvRR 1.51 (95% CI 1.13-2.02), NHS2 RR 1.95 (95% CI 1.42-2.69), HPFS RR 2.72 (95% CI 1.61-4.59). Three or more moles on the extremity were also associated with increased risk of MMIS, NHS RR 1.62 (95% CI 1.19-2.21), NHS2 RR 1.63 (95% CI 1.08-2.45), HPFS RR 1.93 (95% CI 1.21-3.08). In individuals with 6 or more moles on an extremity, the relative risk increased to reflect threefold risk, NHS mvRR 2.77 (95% CI 2.02-3.78), NHS2 mvRR 2.95 (95% CI 2.25-3.88), HPFS mvRR 2.79 (95% CI 1.75-4.46) (P for trend &amp;lt;0.0001). Among women, but not men, red hair was a significant risk factor, NHS mvRR 1.55 (95% CI 1.09-2.21), NHS2 mvRR 2.10 (95% CI 1.34-3.30) as was ≥3 childhood sunburns, NHS mvRR 1.54 (95% CI 1.13-2.09), NHS2 mvRR 1.41 (95% CI 1.00-1.98). Fitzpatrick skin type was determined in NHS and was associated with significant increased risk of MMIS, Type I mvRR 1.97 (95% CI 1.34-2.89), Type II mvRR 1.61 (95% CI 1.19-2.17), Type III 1.47 (95% CI 1.08-1.98) (P for trend =0.0009). Conclusions: In this study of US women and men, family history of melanoma and more than three moles on an extremity were significantly associated with increased risk of MMIS, similar to our previous findings for invasive melanoma. Moreover, increasing number of moles was associated with increasing relative risk. For women, red hair color, frequent childhood sunburns and Fitzpatrick skin type I, II and III were associated with an increased risk of MMIS. Elucidating these risk factors and their relative contribution for MMIS risk may be helpful in identifying individuals with specific phenotypic risk factors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5500. doi:1538-7445.AM2012-5500

Abstract 4484: A novel objective, image-based phenotypic assay reveals higher α-radiation-induced γ-H2AX level in peripheral blood lymphocytes as a risk predictor for lung cancer

Abstract Intermediate phenotypic biomarker measures the summary results of genetic variations and may enhance predictive power in cancer risk assessment. In this study, we developed a novel objective, image-based phenotypic assay to measure α-radiation induced DNA double strand breaks (DSBs) in peripheral blood lymphocytes (PBLs) and used it as a potential biomarker for lung cancer risk prediction. γ-H2AX formation in the chromatin flanking DNA DSBs is one of the most sensitive DNA damage markers. In an ongoing lung cancer case-control study, the baseline and α-radiation-induced γ-H2AX immunofluorescence intensities in the PBLs from 403 untreated lung cancer patients and 307 controls subjects were assessed, and the ratio of the induced γ-H2AX level to the baseline γ-H2AX level was used as a variable to evaluate the sensitivity to mutagen challenge. The mean γ-H2AX ratio was significantly higher in cases than controls (case vs. control: 1.46±0.14 vs. 1.41±0.12, p &amp;lt; 0.001). A significantly decreasing trend in γ-H2AX ratio with age was observed for both cases (p for trend =0.003) and controls (p for trend =0.011). Dichotomized at the median level of the γ-H2AX ratio in controls, individuals with high ratio exhibited a significantly increased risk of lung cancer (OR=2.33, 95%CI: 1.67-3.23). There was also a dose-response relationship with lung cancer risk in tertile and quartile analysis (p for trend &amp;lt; 0.001 for both). Analysis of the joint effects of risk factors revealed an apparently elevated risk of lung cancer for subjects with a higher γ-H2AX ratio who were ever smokers, compared with subjects with a low ratio who were never smokers (OR=12.68, 95%CI: 6.84-23.51, p &amp;lt; 0.001). This is the first study applying relative quantification of the γ-H2AX level in PBL to assess the risk for developing lung cancer. Susceptibility to DNA DSBs might help to identify individuals at high risk for this cancer. α-radiation-induced DNA damage as determined with the new γ-H2AX assay could be a novel phenotypic risk factor of lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4484. doi:1538-7445.AM2012-4484

Sun damage in ultraviolet photographs correlates with phenotypic melanoma risk factors in 12-year-old children

Ultraviolet (UV) photography has been used to motivate sun safety in behavioral interventions. The relationship between sun damage shown in UV photographs and melanoma risk has not been systematically investigated. To examine the relationship between severity of sun damage in UV photographs and phenotypic melanoma risk factors in children. UV, standard visible and cross-polarized photographs were recorded for 585 children. Computer software quantified sun damage. Full-body nevus counts, skin color by colorimetry, facial freckling, hair and eye color were collected in skin examinations. Demographic data were collected in telephone interviews of parents. Among 12-year-old children, sun damage shown in UV photographs correlated with phenotypic melanoma risk factors. Sun damage was greatest for children who were non-Hispanic white and those who had red hair, blue eyes, increased facial freckling, light skin and greater number of nevi (all P values < .001). Results were similar for standard visible and cross-polarized photographs. Freckling was the strongest predictor of sun damage in visible and UV photographs. All other phenotypic melanoma risk factors were also predictors for the UV photographs. Differences in software algorithms used to score the photographs could produce different results. UV photographs portray more sun damage in children with higher risk for melanoma based on phenotype. Therefore sun protection interventions targeting those with greater sun damage on UV photographs will target those at higher melanoma risk. This study establishes reference ranges dermatologists can use to assess sun damage in their pediatric patients.

Ultraviolet photography as a skin cancer risk assessment and intervention tool

I n the Gamble et al study in this issue, the authors conducted a comprehensive study assessing the relationship between severity of sun damage in ultraviolet (UV) photographs with phenotypic melanoma risk factors in a large population of 12-yearold children. They found that indeed the severity of sun damage in UV photography correlates closely with phenotypic melanoma risk factors such as freckling and skin color, yet standard visible light photography did not. Skin cancer primary prevention needs to start with the younger-aged populations. As with other prevention strategies, the earlier in life preventive behaviors begin, the more likely they will be practiced in adulthood. Ultimately, UV photography could be used as a risk assessment tool in primary care physicians’ offices for younger patients and therefore aid in tailoring appropriate skin cancer prevention counseling efforts. There have been many other risk assessment tools developed, such as the risk of malignancy tool in ovarian cancer, or even the body mass index used so frequently in pediatric practices. Increased body mass index is associated with many health risks including various cancers. It is an example of a simple tool that only takes a couple minutes of nursing or medical assistant time (and is therefore low cost), yet it is highly predictive of many future health outcomes. UV photography could be quickly used in a similar fashion in dermatologists’ or general practitioners’ offices when the patient is checked in. However, there may be clinical practice barriers to its widespread use as a result of the costs of such equipment

Polymorphism in Osteopontin Gene (SPP1) Is Associated with Asthma and Related Phenotypes in a Puerto Rican Population

Recent studies have shown that osteopontin, a cytokine with suggested immunoregulatory functions, may contribute to pathogenesis of asthma. To determine whether single-nucleotide polymorphisms (SNPs) in SPP1, the gene encoding osteopontin, are associated with risk of asthma, we genotyped 6 known SNPs in SPP1 in the well-characterized Genetics of Asthma in Latino Americans population of 294 Mexican and 365 Puerto Rican parent-child asthma trios. The associations between SNPs and asthma or asthma-related phenotypes were examined by transmission disequilibrium tests as implemented in the family-based association test program. Three polymorphisms, 1 in exon 7 (rs1126616C) and 2 in the 3'-untranslated region (rs1126772A and rs9138A) of SPP1, were associated with diagnosis of asthma, severity of asthma, asthma in subjects with elevated immunoglobulin E (IgE) (IgE >100 IU/mL), and postbronchodilator FEV(1) in Puerto Ricans (P values=0.00007-0.04). The CC genotype of rs1126616 conferred an odds ratio of 1.7 (95% CI=[1.3, 2.3], P value adjusted for multiple comparisons=0.001) for asthma compared with the CT and TT genotypes. Furthermore, haplotype analysis identified rs1126616C-rs1126772A-rs9138A to be associated with an increased risk for asthma, severity of asthma, and asthma in subjects with elevated IgE (P=0.03). There was no association between the SPP1 SNPs and asthma outcomes in Mexicans. Our findings suggest that the SPP1 gene is a risk factor for asthma and asthma-related phenotypes in Puerto Ricans, and are consistent with previous animal and human studies on the role of osteopontin in pathogenesis of asthma.

Is ANK3 a specific risk factor for psychatric phenotypes?

Is ANK3 a specific risk factor for psychatric phenotypes?

Risk Assessment Model for Development of Advanced Age-Related Macular Degeneration

To design a risk assessment model for development of advanced age-related macular degeneration (AMD) incorporating phenotypic, demographic, environmental, and genetic risk factors. We evaluated longitudinal data from 2846 participants in the Age-Related Eye Disease Study. At baseline, these individuals had all levels of AMD, ranging from none to unilateral advanced AMD (neovascular or geographic atrophy). Follow-up averaged 9.3 years. We performed a Cox proportional hazards analysis with demographic, environmental, phenotypic, and genetic covariates and constructed a risk assessment model for development of advanced AMD. Performance of the model was evaluated using the C statistic and the Brier score and externally validated in participants in the Complications of Age-Related Macular Degeneration Prevention Trial. The final model included the following independent variables: age, smoking history, family history of AMD (first-degree member), phenotype based on a modified Age-Related Eye Disease Study simple scale score, and genetic variants CFH Y402H and ARMS2 A69S. The model did well on performance measures, with very good discrimination (C statistic = 0.872) and excellent calibration and overall performance (Brier score at 5 years = 0.08). Successful external validation was performed, and a risk assessment tool was designed for use with or without the genetic component. We constructed a risk assessment model for development of advanced AMD. The model performed well on measures of discrimination, calibration, and overall performance and was successfully externally validated. This risk assessment tool is available for online use.

Subjective Response to Alcohol Challenge: A Quantitative Review

Individual differences in subjective response to alcohol, as measured by laboratory-based alcohol challenge, have been identified as a candidate phenotypic risk factor for the development of alcohol-use disorders (AUDs). Two models have been developed to explain the role of subjective response to alcohol, but predictions from the 2 models are contradictory, and theoretical consensus is lacking. This investigation used a meta-analytic approach to review the accumulated evidence from alcohol-challenge studies of subjective response as a risk factor. Data from 32 independent samples (total N = 1,314) were aggregated to produce quantitative estimates of the effects of risk-group status (i.e., positive family history of AUDs or heavier alcohol consumption) on subjective response. As predicted by the Low Level of Response Model (LLRM), family history-positive groups experienced reduced overall subjective response relative to family history-negative groups. This effect was most evident among men, with family history-positive men responding more than half a standard deviation less than family history-negative men. In contrast, consistent with the Differentiator Model (DM), heavier drinkers of both genders responded 0.4 standard deviations less on measures of sedation than did the lighter drinkers but nearly half a standard deviation more on measures of stimulation, with the stimulation difference appearing most prominent on the ascending limb of the blood alcohol concentration curve. The accumulated results from 3 decades of family history comparisons provide considerable support for the LLRM. In contrast, results from typical consumption comparisons were largely consistent with predictions of the DM. The LLRM and DM may describe 2 distinct sets of phenotypic risk, with importantly different etiologies and predictions for the development of AUDs.

Maternal Smoking and Congenital Heart Defects in the Baltimore-Washington Infant Study

OBJECTIVE: We investigated associations between maternal cigarette smoking during the first trimester and the risk of congenital heart defects (CHDs) among the infants. METHODS: The Baltimore-Washington Infant Study was the first population-based case-control study of CHDs conducted in the United States. Case and control infants were enrolled during the period 1981–1989. We excluded mothers with overt pregestational diabetes and case mothers whose infants had noncardiac anomalies (with the exception of atrioventricular septal defects with Down syndrome) from the analysis, which resulted in 2525 case and 3435 control infants. Self-reported first-trimester maternal cigarette consumption was ascertained via an in-person interview after delivery. Associations for 26 different groups of CHDs with maternal cigarette consumption were estimated by using logistic regression models. Odds ratios (ORs) corresponded to a 20-cigarette-per-day increase in consumption. RESULTS: We observed statistically significant positive associations between self-reported first-trimester maternal cigarette consumption and the risk of secundum-type atrial septal defects (OR: 1.36 [95% confidence interval (CI): 1.04–1.78]), right ventricular outflow tract defects (OR: 1.32 [95% CI: 1.06–1.65]), pulmonary valve stenosis (OR: 1.35 [95% CI: 1.05–1.74]), truncus arteriosus (OR: 1.90 [95% CI: 1.04–3.45]), and levo-transposition of the great arteries (OR: 1.79 [95% CI: 1.04–3.10]). A suggestive association was observed for atrioventricular septal defects among infants without Down syndrome (OR: 1.50 [95% CI: 0.99–2.29]). CONCLUSIONS: These findings add to the existing body of evidence that implicates first-trimester maternal cigarette smoking as a modest risk factor for select CHD phenotypes.

Is Ankyrin a genetic risk factor for psychiatric phenotypes?

BackgroundGenome wide association studies reported two single nucleotide polymorphisms in ANK3 (rs9804190 and rs10994336) as independent genetic risk factors for bipolar disorder. Another SNP in ANK3 (rs10761482) was associated with schizophrenia in a large European sample. Within the debate on common susceptibility genes for schizophrenia and bipolar disorder, we tried to investigate common findings by analyzing association of ANK3 with schizophrenia, bipolar disorder and unipolar depression.MethodsWe genotyped three single nucleotide polymorphisms (SNPs) in ANK3 (rs9804190, rs10994336, and rs10761482) in a case-control sample of German descent including 920 patients with schizophrenia, 400 with bipolar affective disorder, 220 patients with unipolar depression according to ICD 10 and 480 healthy controls. Sample was further differentiated according to Leonhard's classification featuring disease entities with specific combination of bipolar and psychotic syndromes.ResultsWe found no association of rs9804190 and rs10994336 with bipolar disorder, unipolar depression or schizophrenia. In contrast to previous findings rs10761482 was associated with bipolar disorder (p = 0.015) but not with schizophrenia or unipolar depression. We observed no association with disease entities according to Leonhard's classification.ConclusionOur results support a specific genetic contribution of ANK3 to bipolar disorder though we failed to replicate findings for schizophrenia. We cannot confirm ANK3 as a common risk factor for different diseases.

P007. Comprehensive analysis of phenotypic risk factors of melanoma in a central European population

Department of Dermatology, Division of General Dermatology, Medical University of Vienna, Vienna, Austria

Maternal Smoking and Congenital Heart Defects in the Baltimore-Washington Infant Study

We investigated associations between maternal cigarette smoking during the first trimester and the risk of congenital heart defects (CHDs) among the infants. The Baltimore-Washington Infant Study was the first population-based case-control study of CHDs conducted in the United States. Case and control infants were enrolled during the period 1981-1989. We excluded mothers with overt pregestational diabetes and case mothers whose infants had noncardiac anomalies (with the exception of atrioventricular septal defects with Down syndrome) from the analysis, which resulted in 2525 case and 3435 control infants. Self-reported first-trimester maternal cigarette consumption was ascertained via an in-person interview after delivery. Associations for 26 different groups of CHDs with maternal cigarette consumption were estimated by using logistic regression models. Odds ratios (ORs) corresponded to a 20-cigarette-per-day increase in consumption. We observed statistically significant positive associations between self-reported first-trimester maternal cigarette consumption and the risk of secundum-type atrial septal defects (OR: 1.36 [95% confidence interval (CI): 1.04-1.78]), right ventricular outflow tract defects (OR: 1.32 [95% CI: 1.06-1.65]), pulmonary valve stenosis (OR: 1.35 [95% CI: 1.05-1.74]), truncus arteriosus (OR: 1.90 [95% CI: 1.04-3.45]), and levo-transposition of the great arteries (OR: 1.79 [95% CI: 1.04-3.10]). A suggestive association was observed for atrioventricular septal defects among infants without Down syndrome (OR: 1.50 [95% CI: 0.99-2.29]). These findings add to the existing body of evidence that implicates first-trimester maternal cigarette smoking as a modest risk factor for select CHD phenotypes.

Gender-Specific Differences in Adipose Distribution and Adipocytokines Influence Adolescent Nonalcoholic Fatty Liver Disease Δ

Nonalcoholic fatty liver disease (NAFLD) is a predominantly adult-diagnosed disorder. Knowledge regarding the epidemiology, phenotype, and metabolic risk factors, during adolescence is limited. We sought to determine the prevalence, phenotype, and predictors of NAFLD in 1170 community-based adolescents in the Western Australian Pregnancy Cohort (Raine) Study (the Raine Cohort) who underwent a cross-sectional assessment that included questionnaires, anthropometry, cardiovascular examinations, blood tests, and abdominal ultrasound examinations. Among the 1170 adolescents assessed, the prevalence of NAFLD was 12.8%. Females compared with males had a significantly higher prevalence of NAFLD (16.3% versus 10.1%, P = 0.004) and central obesity (33.2% versus 9.9%, P < 0.05). The severity of hepatic steatosis was associated with the body mass index, waist circumference, subcutaneous adipose tissue thickness (SAT), serum leptin level, homeostasis model assessment for insulin resistance score (P < 0.001 for all), and serum alanine aminotransferase level (P < 0.005) in both genders, but it was associated with increasing visceral adipose tissue thickness (VAT; P < 0.001) and decreasing serum adiponectin levels (P < 0.05) in males alone. Males and females with NAFLD had similar amounts of SAT (P > 0.05); however, in comparison with females with NAFLD, males with NAFLD had greater VAT, a more severe metabolic phenotype with higher glucose levels and systolic blood pressure and lower adiponectin and high-density lipoprotein cholesterol levels (P < 0.001 for all), and greater measures of liver injury (alanine aminotransferase and aspartate aminotransferase, P < 0.001 for all). Similarly, metabolic syndrome was more common in males than females with NAFLD (24% versus 8%, P = 0.01). Suprailiac skinfold thickness predicted NAFLD independently of the body mass index, insulin resistance, and VAT. Gender differences in adolescent NAFLD are related to differences in adipose distribution and adipocytokines. The male phenotype of NAFLD is associated with more adverse metabolic features and greater visceral adiposity than the female phenotype despite the lower prevalence of NAFLD.