Research Article: Risk prediction of pulmonary tuberculosis using genetic and conventional risk factors in adult Korean population

Date Published: March 29, 2017

Publisher: Public Library of Science

Author(s): Eun Pyo Hong, Min Jin Go, Hyung-Lae Kim, Ji Wan Park, Sunil K. Ahuja.


A complex interplay among host, pathogen, and environmental factors is believed to contribute to the risk of developing pulmonary tuberculosis (PTB). The lack of replication of published genome-wide association study (GWAS) findings limits the clinical utility of reported single nucleotide polymorphisms (SNPs). We conducted a GWAS using 467 PTB cases and 1,313 healthy controls obtained from two community-based cohorts in Korea. We evaluated the performance of PTB risk models based on different combinations of genetic and nongenetic factors and validated the results in an independent Korean population comprised of 179 PTB cases and 500 healthy controls. We demonstrated the polygenic nature of PTB and nongenetic factors such as age, sex, and body mass index (BMI) were strongly associated with PTB risk. None of the SNPs achieved genome-wide significance; instead, we were able to replicate the associations between PTB and ten SNPs near or in the genes, CDCA7, GBE1, GADL1, SPATA16, C6orf118, KIAA1432, DMRT2, CTR9, CCDC67, and CDH13, which may play roles in the immune and inflammatory pathways. Among the replicated SNPs, an intergenic SNP, rs9365798, located downstream of the C6orf118 gene showed the most significant association under the dominant model (OR = 1.59, 95% CI 1.32–1.92, P = 2.1×10−6). The performance of a risk model combining the effects of ten replicated SNPs and six nongenetic factors (i.e., age, sex, BMI, cigarette smoking, systolic blood pressure, and hemoglobin) were validated in the replication set (AUC = 0.80, 95% CI 0.76–0.84). The strategy of combining genetic and nongenetic risk factors ultimately resulted in better risk prediction for PTB in the adult Korean population.

Partial Text

Pulmonary tuberculosis (PTB) is a prevalent infectious disease that is caused by Mycobacterium tuberculosis (M. tuberculosis). According to the Global Tuberculosis Report published by the World Health Organization in 2015, the estimated numbers of new tuberculosis cases and tuberculosis deaths worldwide reached almost 9.6 million and 1.1 million in 2014, respectively. The incidence and mortality rate of PTB reported in South Korea (86 patients and 3.8 deaths per 100,000 populations, respectively) are higher than those identified in other developed countries. (

Traditional risk factors such as gender (male), aging, low household income, cigarette smoking, alcohol consumption, and high blood pressure, which is one of the risk factors for DM, were consistently found to be associated with PTB risk [15, 21]. Specifically, male, increased age and low BMI were identified as strong predictors of PTB in Korean adult populations. Consistent with previous studies, blood pressure was positively correlated with BMI (β = 0.02, 95% CI 0.02–0.03, P = 6.4×10−9 and β = 0.04, 95% CI 0.03–0.05, P = 1.5×10−11 for SBP and DBP, respectively), while BMI was negatively associated and blood pressure was positively associated with PTB in the current study [2, 21]. Categorization of two continuous predictors, Hb and BUN, made them insignificant. These results support previous findings that categorization of continuous risk factors, especially dichotomization, reduces statistical power and leads to incomplete correction for confounding factors [22]. Thus, baseline BMI, SBP, DBP, HB, and BUN were investigated as continuous variables in multivariate logistic analysis. We cannot, however, rule out potential temporal bias in the estimation of causal effects of the nongenetic factors as prevalent cases were analyzed in the current study.




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