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1 POLYMORPHISMS OF THE PSD3 GENE ARE ASSOCIATED WITH OBESITY IN TWO CAUCASIAN SAMPLES Gong S1, Xu C2, Wang L1, Li Y3, Owusu D1, Wang K1 1Biostatistics and Epidemiology, East Tennessee State University, TN 2Texas Tech University Health, El Paso, TX 3School of Medicine, Emory University, Atlanta, GA Outline Introduction Objectives Methods Analysis Results Conclusions Disclosure references Introduction 3 Current efforts of intensive research to alleviate obesity by diet, exercise, education, surgery, and drug therapies only have not well offered effective long-term solutions to the obesity epidemic. There is a need to explore the genetic and epigenetic mechanisms involved in obesity initiation and development. Introduction (cont.) 4 The genome-wide association studies (GWAS) approach has been successful in identifying loci harboring common forms of obesity susceptibility genes using single-nucleotide polymorphisms (SNPs). Genetic variants are increasingly recognized to be associated with obesity using candidate gene approaches in addition to GWAS (Loos, 2009; Hebebrand et al., 2010). Introduction (cont.) 5 The pleckstrin and Sec7 domain containing 3 gene (PSD3) is located at 8p22 and decreased expression of PSD3 has been detected in multiple types of cancer, suggesting that PSD3 is a potential tumor suppressor gene for cancer (Thomassen et al., 2009). PSD3 gene is associated with immune diseases such as systemic sclerosis (Jin et al., 2014). The real functions of the PSD3 gene remain to be further clarified especially its association with the obesity. Study Aims 6 To understand the association of PSD3 gene and obesity We specifically examined genetic associations of 163 SNPs within the PSD3 gene with obesity using the Marshfield sample (McCarty et al., 2005, 2008) and conducted the replication study using the Study of Addiction - Genetics and Environment (SAGE) sample (Bierut et al., 2010). -- Hypothesis: PSD3 gene polymorphisms play an important role in obesity. Methods 7 The Marshfield sample: The Marshfield sample is from the publicly available data from A GWAS on Cataract and HDL in the Personalized Medicine Research Project Cohort - Study Accession: phs000170.v1.p1 (dbGaP). Genotyping data using the Illumina Human660WQuad_v1_A are available for 3,564 individuals (1,442 obese and 2,122 controls). Methods (cont.) 8 The SAGE sample: GENEVA: Study of Addiction Genetics and Environment (SAGE) is a comprehensive GWAS using approximately 4,000 unrelated subjects of European and AfricanAmerican descent. In this study, We calculated the BMI based on height and weight measures. Obesity was determined as a body mass index (BMI) ≥ 30 (254 obese and 776 non-obese). We used the SAGE sample for replication study. Statistical analysis 9 Hardy-Weinberg equilibrium was tested for all the SNPs using the controls by using HAPLOVIEW software (Barrett et al., 2005). The minor allele frequency (MAF) was determined for each SNP using PLINK v1.07 (Purcell et al., 2007). Logistic regression analysis of obesity, adjusted for age and sex, was performed using PLINK v1.07. Results 10 Table 1. Descriptive characteristics of cases and controls Number Sex, N (%) Males Females Age, years Mean ± SD Range Cases Marshfield SAGE 1,442 254 Controls Marshfield SAGE 2,122 776 623(43%) 819(57%) 852(40%) 198(26%) 1,270(60%) 578(74%) 73(29%) 181(71%) 65.2 ±10.4 41.5±8.9 46-90 24-65 67.1±11.8 46-90 39.2±9.1 24-65 11 Genotype quality control and descriptive statistics The mean age for participants are 65.2 years for obese individuals and 67.1 for controls in Marshfield sample (P<0.0001 based on KruskalWallis Test), and 41.5 years for cases and 39.2 for controls in the SAGE sample (P=0.0004 based on Kruskal-Wallis Test). The range of age was 46-90 years for the Marshfield sample and 24-65 years for the SAGE sample. Table 2. SNPs within PSD3 gene associated with obesity in the Marshfield sample (P<0.05) 12 Association with obesity in the Marshfield sample 13 Single marker analysis showed that 20 SNPs in the Marshfield sample were associated with obesity (P < 0.05). SNP rs4921966 revealed strongest association with obesity (P = 3.97 x 10-6). Replication study in the SAGE sample 14 3 SNPs (rs11995692, rs7007413, and rs13256382) were associated with obesity in the SAGE sample (P < 0.05). 5 SNPs were associated with obesity with P<0.01 in the SAGE sample (rs11204003, rs11783114, rs1896201, rs11987871 and rs1025229 with P= 5.96 x10-5, 0.00525, 0.00699, 0.00819 and 0.0092, respectively). Table 3. Haplotype analysis of the PSD3 gene in the Marshfield sample 15 Frequencya Haplotype rs7007413 C T C rs11988239 G A G rs11995692 C C T aHaplotype rs11988239 A G G rs11995692 C T T rs748208 T C C P-valuec 0.44 0.45 0.1 0.85 1.23 0.87 0.00141 3.23E-05 0.0842 0.45 0.44 0.11 1.23 0.85 0.87 3E-05 0.00119 0.0802 0.30 0.16 0.54 1.18 1.15 0.81 0.00235 0.0362 6.97E-06 frequency in the sample. refers to the Odds ratio for each haplotype using PLINK. cP-value for the haplotype. bOR ORb Haplotype analysis in the Marshfield sample 16 We identified a haplotype block for 6 SNPs using HAPLOVIEW including rs11995692 and rs7007413 associated with obesity in both samples. The T-G haplotype from rs7007413 and rs11988239 (r2=0.64) revealed significant association with obesity in the Marshfield sample (P = 3.23 x 10-5). The T-C haplotype from rs11995692 and rs748208 (r2=0.44) revealed significant association with obesity in the Marshfield sample (P = 6.97 x 10-6). Figure 1. Linkage disequilibrium structure of six SNPs. The numbers indicate the r2 values between the corresponding two SNPs. 17 Discussion 18 We first hypothesized and carried out the study on the association of PSD3 with obesity. Totally, 20 SNPs showed significant association (P<0.05) with obesity in the Marshfield sample. Haplotype analysis further supported the single marker analysis results. Several SNPs were replicated in the SAGE sample. Discussion (cont.) 19 We provide the preliminary basis for future studies with focus on the effect of PSD3 particularly on the obesity risk using longitudinal designs and diverse population. Future studies focusing on obesity-related geneenvironment interactions are warranted. Limitations 20 Although two samples were used to increase the generalization, these findings may not be generalizable to other populations in different countries or ethnic groups (e.g., nonwhite). We only had two samples for the analysis, and need to replicate in additional samples. Our current findings might be spurious or subject to type I error. Conclusions 21 We firstly observed the associations between the PSD3 gene polymorphisms with obesity in two Caucasian samples, providing a basis for replication in other populations to elucidate the potential role of these genetic variants. Future functional study of this gene may help to better characterize the genetic architecture of obesity. Disclosure Originality Study is original ideas of the authors and it has not been published anywhere else Conflict of interest The authors declare that they have no conflict of interest Funding Authors received no funding for the current study References 23 Hebebrand J, Volckmar AL, Knoll N, Hinney A (2010) Chipping away the ‘missing heritability’: GIANT steps forward in the molecular elucidation of obesity—but still lots to go. Obes Facts 3:294–303. 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Breast Cancer Res Treat 113:239-249. Saar K, Geller F, Rüschendorf F, et al. (2003) Genome scan for childhood and adolescent obesity in German families. Pediatrics 111(2):321-7. Thank you 24 Questions