Genome-wide Association Study Of Pulmonary Tuberculosis In Chinese Han Population

Objectives: To find host susceptibility loci and genes associated with tuberculosis(TB)in Chinese Han population by genome-wide association study.To replicate and validate host susceptibility variants of published GWAS significant SNPs in African and European populations.To explain the biological correlation of single nucleotide polymorphisms location and surrounding genes according to verified statistically significant associated loci.Methods: The study population included subjects included 5149 cases of patients with pulmonary TB from TB control centers all over China and in 7042 healthy controls from Medical Centers of Changzheng Hospital,Beijing 301 Hospital.In the first stage of the study,we initially conducted a GWAS included individuals of 1853 TB(cases)and 3115 healthy controls recruited from China.Using Omni Zhong Hua-8 version1.0 Bead Chips on ISCAN platform.We genotyped 900,015 SNPs in total of both cases and controls.We conducted genome-wide association analysis by using bioinformatics tools.In the second stage of the study,we conducted a genome-wide genotyping included individuals of 725 TB(cases)and 3927 healthy controls recruited from China.Using Illumina Core Exome chips on ISCAN platform.We conducted genome-wide association analysis by using bioinformatics tools.Then we conducted genotype imputation in this dataset trying to validate promising SNPs in stage1.In the third stage of the study,we attempted to replicate promising SNPs form step1 and published TB associated SNPs of GWAS studies in African and European populations.We conducted this genotyping in an independent cohort of 2571 individuals from China by using Sequenom i Plex.In order to confirm the result of stage 1,we used controls in 3,927 Core Exome control cohort as common controls(variants imputed if not directly genotyped).Finally,We conducted meta-analysis of three stages in searching susceptibility gene associated with TB by multiple statistical methods and bioinformatics tools.Results:In the first stage,we found no genome-wide significant loci(P <5 × 10-8),but we found possible trend of significant association in chromosome 6 and chromosome 22,therefore,we chose the 68 candidates SNP for subsequent verification.In the second stage,we conducted Core Exome micorarray type and meta-analysis with stage1.We discovered two genome-wide significant SNPs,which were rs117435254(Pmeta = 1.43 × 10-11)and rs7364237(Pmeta = 3.26 × 10-9).The third stage: We genotyped of the 68 candidate SNPs selected from the first phase and 26 published associated loci in the independent samples.The 26 GWAS reported SNPs have not been confirmed in this study population in meta-analysis of stage 2 and 3.Finally,we performed meta-analysis of three stages.Rs532098(Pmeta = 1.47 × 10-10)and rs9309112(Pmeta = 3.14 × 10-8)were found genome-wide significant.Conclusions: Our research revealed several possible TB host susceptibility loci in Chinese Han may exist.Rs117435254 is located in intron region of SF3A1 gene.Rs7364237 is located in intron region of PES1 gene.Rs532098 is located intragenic region of MHC region,Rs9309112 is located in intron region of LRPPRC gene.This study shows that SNPs or the gene it impact functionally may affect susceptibility to tuberculosis in the Chinese Han population.The previously reported 26 GWAS association loci have not been confirmed in our study population.It may indicate that differences in TB susceptibility may exist between different ethnic groups.It may also be explained by inadequate sample size of this study and weak power of current statistical methods,which are not enough to detect potential false negative results.These conclusions still need further confirmation by large-scale genetic studies with advanced methods and biological function studies.