F 
these four pathways in smoking-related carcinogenesis. We will investigate them in our future studies. In summary, this study conducted a two-stage pathway analysis in GWAS of lung cancer in Han Chinese using GSEA method, and identified four pathways (achPathway, metPathway, At1rPathway and rac1Pathway) associated with lung cancer risk. These findings may be an important supplement for GWAS and provide new insights into biology of lung cancer.Supporting InformationTable S1. The rank of pathways based on combined dataset of Nanjing and Beijing studies. Table S2. Sensitivity analysis of pathway analysis for genes defined by SNPs within 20 kb upstream or downstream. Table S3. Gene overlaps between 4 indentified pathways for all genes defined by BioCarta database or genes with significant representative SNPs (P,0.05)a. (a) The bottom-left of the symmetric matrix is the number of overlap genes between pair-wise pathways and their total gene number. The top-right part is the overlap rate between pair-wise pathways ( ). Table S4. Genes with 
significant representative SNPs (P#0.01) contributed to multiple pathways. (a) Derived from logistic regression model with adjustment for age, gender, packyear of smoking and principal components in combined dataset of Nanjing and Beijing studies. Table S5. The results of sensitivity analysis for 4 identified pathway after removing significant overlapping genes (PAK1, PIK3R1, PTK2 and PTK2B). (DOCX)File SPathway Analysis for GWAS of Lung CancerAcknowledgmentsThe authors thank all of the study subjects, research staff and students who participated in this work. We also appreciate two anonymous reviewers for their valuable suggestions for this manuscript.Author ContributionsConceived and designed the experiments: RZ ZH HS FC. Performed the experiments: MC C. Wu C. Wang LH TW DL. Analyzed the data: RZ YZ JD JG CQ JB. Wrote the paper: RZ YZ MC GJ.
The retinal pigment epithelium (RPE) provides nutrients, growth factors and ions to the photoreceptors, removes waste products of retinal metabolism and is essential for photoreceptor survival and, hence, for Linolenic acid methyl ester web vision. RPE dysfunction is associated with aging and multiple inherited retinal degenerative diseases. One such disease, choroideremia (CHM), is an X-linked chorioretinal degeneration caused by functional defects in CHM/REP1, a chaperone protein for Rab GTPases [1], which are critical regulators of membrane trafficking [2]. Loss of function of Rab Escort Protein-1 (REP1) in CHM results in reduced Rab GTPase prenylation, a lipid modification that is absolutely required for Rab membrane Anlotinib site binding and function [1]. Loss of function of REP1 in CHM is functionally compensated by a related protein, REP2 [3]. However, this compensation is only partial as a subset of Rabs are underprenylated in peripheral lymphoblasts of CHMpatients and in mouse models of CHM [4,5]. Given that Rab GTPases regulate multiple steps in membrane traffic pathways including vesicle budding, movement and fusion with the destination compartment, the partial loss of function of multiple Rabs is predicted to affect multiple intracellular trafficking pathways. One of the partially affected Rabs in CHM is Rab27a, which is required for melanosome movement into the apical processes of RPE cells [6,7]. However the pathology of CHM cannot be explained solely by compromised Rab27a function as the ashen mouse, which lacks functional Rab27a, does not reproduce the retinal degeneration observed in CHM patient.F these four pathways in smoking-related carcinogenesis. We will investigate them in our future studies. In summary, this study conducted a two-stage pathway analysis in GWAS of lung cancer in Han Chinese using GSEA method, and identified four pathways (achPathway, metPathway, At1rPathway and rac1Pathway) associated with lung cancer risk. These findings may be an important supplement for GWAS and provide new insights into biology of lung cancer.Supporting InformationTable S1. The rank of pathways based on combined dataset of Nanjing and Beijing studies. Table S2. Sensitivity analysis of pathway analysis for genes defined by SNPs within 20 kb upstream or downstream. Table S3. Gene overlaps between 4 indentified pathways for all genes defined by BioCarta database or genes with significant representative SNPs (P,0.05)a. (a) The bottom-left of the symmetric matrix is the number of overlap genes between pair-wise pathways and their total gene number. The top-right part is the overlap rate between pair-wise pathways ( ). Table S4. Genes with significant representative SNPs (P#0.01) contributed to multiple pathways. (a) Derived from logistic regression model with adjustment for age, gender, packyear of smoking and principal components in combined dataset of Nanjing and Beijing studies. Table S5. The results of sensitivity analysis for 4 identified pathway after removing significant overlapping genes (PAK1, PIK3R1, PTK2 and PTK2B). (DOCX)File SPathway Analysis for GWAS of Lung CancerAcknowledgmentsThe authors thank all of the study subjects, research staff and students who participated in this work. We also appreciate two anonymous reviewers for their valuable suggestions for this manuscript.Author ContributionsConceived and designed the experiments: RZ ZH HS FC. Performed the experiments: MC C. Wu C. Wang LH TW DL. Analyzed the data: RZ YZ JD JG CQ JB. Wrote the paper: RZ YZ MC GJ.
The retinal pigment epithelium (RPE) provides nutrients, growth factors and ions to the photoreceptors, removes waste products of retinal metabolism and is essential for photoreceptor survival and, hence, for vision. RPE dysfunction is associated with aging and multiple inherited retinal degenerative diseases. One such disease, choroideremia (CHM), is an X-linked chorioretinal degeneration caused by functional defects in CHM/REP1, a chaperone protein for Rab GTPases [1], which are critical regulators of membrane trafficking [2]. Loss of function of Rab Escort Protein-1 (REP1) in CHM results in reduced Rab GTPase prenylation, a lipid modification that is absolutely required for Rab membrane binding and function [1]. Loss of function of REP1 in CHM is functionally compensated by a related protein, REP2 [3]. However, this compensation is only partial as a subset of Rabs are underprenylated in peripheral lymphoblasts of CHMpatients and in mouse models of CHM [4,5]. Given that Rab GTPases regulate multiple steps in membrane traffic pathways including vesicle budding, movement and fusion with the destination compartment, the partial loss of function of multiple Rabs is predicted to affect multiple intracellular trafficking pathways. One of the partially affected Rabs in CHM is Rab27a, which is required for melanosome movement into the apical processes of RPE cells [6,7]. However the pathology of CHM cannot be explained solely by compromised Rab27a function as the ashen mouse, which lacks functional Rab27a, does not reproduce the retinal degeneration observed in CHM patient.
