Original Article Oncol Res Treat 2014;37:106–110 DOI: 10.1159/000360206
Received: July 1, 2013 Accepted: January 29, 2014 Published online: February 21, 2014
THADA Gene Polymorphism and Prostate Cancer Risk: A Meta-Analysis Fan Zhaoa Yong Xub Kuo Yangb Ming Liua Dong Weic Yaoguang Zhangc Xiaohong Shia Fan Yangd Xin Wangc Siying Lianga Chengxiao Zhaoe Xin Chenc Liang Suna Xiaoquan Zhua Nana Wang Juan Hui Yurong Zhang Ling Zhuf Yige Yanga Lei Tanga Jianye Wangc Ze Yanga a
Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing; bDepartment of Urology, Second Hospital of Tianjin Medical University, Tianjin; cDepartment of Urology and Beijing Hospital, Chinese Ministry of Health, Beijing; dThe Fifth School of Clinical Medicine, Peking University, Beijing; ePeking Union Medical College and Chinese Academy of Medical Sciences, Graduate School, Beijing; fPhysical Examination Center, Beijing Hospital, Ministry of Health, Beijing, China
Introduction
Association · Meta-analysis · Prostatic neoplasms · THADA · Polymorphism Summary Background: The single nucleotide polymorphism (SNP) rs1465618 in THADA at 2p21 has been identified as being associated with prostate cancer (PCa) risk in Europeans; however, it is not clear whether the SNP is related to PCa risk in multiple populations. We investigated the association of rs1465618 in THADA with PCa in a Chinese population and carried out a meta-analysis in multiple populations, testing the relevance of this SNP for PCa risk. Patients and Methods: We genotyped the SNP using high resolution melting (HRM) analysis and assessed its association with PCa risk in a case-control study of 289 PCa patients and 288 controls in a Chinese population. A meta-analysis was carried out with 36,313 PCa patients and 36,485 controls to evaluate the association of rs1465618 with PCa risk in multiple populations. Results: rs1465618 in THADA was significantly associated with PCa risk (p = 0.026; odds ratio (OR) 1.327, 95% confidence interval (CI) 1.035–1.700). Furthermore, the rs1465618 variant genotype was associated with PCa aggressiveness (p = 0.044; OR = 2.053, 95% CI = 1.015–6.602) in the Chinese population. The meta-analysis showed that rs1465618 was significantly associated with PCa risk in multiple populations (p = 1.0×10–8; OR = 1.127, 95% CI = 1.085–1.171). Conclusion: Our results showed that rs1465618 in THADA may be a shared susceptibility variant for PCa in multiple populations. THADA gene polymorphisms may impact PCa susceptibility and progression. Fan Zhao, Yong Xu, Kuo Yang, and Ming Liu contributed equally to this work.
© 2014 S. Karger GmbH, Freiburg 2296-5270/14/0373-0106$39.50/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com
Accessible online at: www.karger.com/ort
Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men, and causes more than 250,000 deaths annually [1, 2]. Although PCa is the most common non-cutaneous tumor in developed countries, its etiology remains poorly understood [3, 4]. Identifying risk factors for PCa is critically important for the development of potential interventions and the expansion of our understanding of the biology of this disease. It is known that age, race, and family history are major PCa risk factors [5–7]. Approximately 42% of PCa risk can be explained by heritable genetic factors [8, 9]. Recently, genome-wide association studies have identified more than 40 single nucleotide polymorphisms (SNPs) which are significantly associated with PCa risk in European populations [10–20]. The association of the SNP rs1465618 in THADA with PCa risk was reported in a few research cohorts [13, 21–23], but it is not clear if this could be a PCa-associated shared genetic variant among multiple populations. Herein, we investigated the association of rs1465618 in THADA with PCa risk in a Chinese population. We also performed a metaanalysis of published studies and our study, which may provide evidence of an association of rs1465618 in THADA with PCa risk among multiple populations.
Patients and Methods Study Population The study sample consisted of 289 pathologically confirmed PCa patients and 288 healthy age-matched controls. All subjects were permanent residents of Beijing and Tianjin in China. Clinical characteristic were obtained by review of the medical records. Aggressive PCa was defined as prostate-specific antigen (PSA) ≥ 20 ng/ml, Gleason score ≥ 8, or patho-
Prof. Ze Yang Key Laboratory of Geriatrics Beijing Hospital 1 Dahua Road, Dong Dan Beijing 100730, China [email protected]
Downloaded by: NYU Medical Center Library 198.143.38.2 - 6/23/2015 10:40:48 AM
Keywords
logical tumor stage C/D. Healthy controls with PSA 99% concordance for all successfully genotyped SNPs.
was defined as p ≤ 0.05. All p values were two-sided. The pooled OR and 95% CI for the SNP in multiple populations were calculated in fixed and random effects methods by Comprehensive Meta-Analysis V2 software (Biostat, Englewood, NJ, USA). We assessed heterogeneity among study populations with Q-statistic and I2 statistic p values.
Results Characteristics of the Study Population Clinical characteristics of the patients and health controls in this study are presented in table 1. The average age of patients and controls was 71.6 ± 9.9 years and 70.5 ± 7.6 years, respectively. The proportion of cases with available PSA, tumor stage, Gleason score, and disease aggressiveness were 74.4, 46.8, 49.8, and 53.3%, respectively.
Statistical Analysis Departure from Hardy-Weinberg equilibrium was assessed for this SNP in case and control groups using Pearson’s χ2 test. SNP allele frequencies between cases and controls were evaluated using Pearson’s χ2 test. The association of rs1465618 in THADA with PCa risk was estimated by odds ratio (OR) and 95% confidence interval (95% CI) from unconditional logistic regression analysis with adjustment for age. Significance
Association between rs1465618 in THADA and PCa Risk in Chinese Population Allele frequencies and genotype distributions of rs1465618 in THADA are shown in table 2. The observed genotype frequency in controls and cases conformed to the Hardy-Weinberg equilibrium. The distribution of rs1465618 polymorphisms was significantly different between cases and controls (p = 0.026; OR = 1.327, 95% CI = 1.035–1.700). There was no
Table 1. Clinical and epidemiologic characteristics of prostate cancer cases and controls
Table 3. Association between rs1465618 in THADA and clinicopathological characteristics of prostate cancer patients
Variables a
Age , mean ± SD, years BMIb, mean ± SD
Cases
Controls
71.6 ± 9.9 31.25 ± 4.86
70.5 ± 7.6 22.25 ± 8.48
n (%) PSA, ng/ml
Received: July 1, 2013 Accepted: January 29, 2014 Published online: February 21, 2014
THADA Gene Polymorphism and Prostate Cancer Risk: A Meta-Analysis Fan Zhaoa Yong Xub Kuo Yangb Ming Liua Dong Weic Yaoguang Zhangc Xiaohong Shia Fan Yangd Xin Wangc Siying Lianga Chengxiao Zhaoe Xin Chenc Liang Suna Xiaoquan Zhua Nana Wang Juan Hui Yurong Zhang Ling Zhuf Yige Yanga Lei Tanga Jianye Wangc Ze Yanga a
Key Laboratory of Geriatrics, Beijing Hospital and Beijing Institute of Geriatrics, Ministry of Health, Beijing; bDepartment of Urology, Second Hospital of Tianjin Medical University, Tianjin; cDepartment of Urology and Beijing Hospital, Chinese Ministry of Health, Beijing; dThe Fifth School of Clinical Medicine, Peking University, Beijing; ePeking Union Medical College and Chinese Academy of Medical Sciences, Graduate School, Beijing; fPhysical Examination Center, Beijing Hospital, Ministry of Health, Beijing, China
Introduction
Association · Meta-analysis · Prostatic neoplasms · THADA · Polymorphism Summary Background: The single nucleotide polymorphism (SNP) rs1465618 in THADA at 2p21 has been identified as being associated with prostate cancer (PCa) risk in Europeans; however, it is not clear whether the SNP is related to PCa risk in multiple populations. We investigated the association of rs1465618 in THADA with PCa in a Chinese population and carried out a meta-analysis in multiple populations, testing the relevance of this SNP for PCa risk. Patients and Methods: We genotyped the SNP using high resolution melting (HRM) analysis and assessed its association with PCa risk in a case-control study of 289 PCa patients and 288 controls in a Chinese population. A meta-analysis was carried out with 36,313 PCa patients and 36,485 controls to evaluate the association of rs1465618 with PCa risk in multiple populations. Results: rs1465618 in THADA was significantly associated with PCa risk (p = 0.026; odds ratio (OR) 1.327, 95% confidence interval (CI) 1.035–1.700). Furthermore, the rs1465618 variant genotype was associated with PCa aggressiveness (p = 0.044; OR = 2.053, 95% CI = 1.015–6.602) in the Chinese population. The meta-analysis showed that rs1465618 was significantly associated with PCa risk in multiple populations (p = 1.0×10–8; OR = 1.127, 95% CI = 1.085–1.171). Conclusion: Our results showed that rs1465618 in THADA may be a shared susceptibility variant for PCa in multiple populations. THADA gene polymorphisms may impact PCa susceptibility and progression. Fan Zhao, Yong Xu, Kuo Yang, and Ming Liu contributed equally to this work.
© 2014 S. Karger GmbH, Freiburg 2296-5270/14/0373-0106$39.50/0 Fax +49 761 4 52 07 14 [email protected] www.karger.com
Accessible online at: www.karger.com/ort
Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men, and causes more than 250,000 deaths annually [1, 2]. Although PCa is the most common non-cutaneous tumor in developed countries, its etiology remains poorly understood [3, 4]. Identifying risk factors for PCa is critically important for the development of potential interventions and the expansion of our understanding of the biology of this disease. It is known that age, race, and family history are major PCa risk factors [5–7]. Approximately 42% of PCa risk can be explained by heritable genetic factors [8, 9]. Recently, genome-wide association studies have identified more than 40 single nucleotide polymorphisms (SNPs) which are significantly associated with PCa risk in European populations [10–20]. The association of the SNP rs1465618 in THADA with PCa risk was reported in a few research cohorts [13, 21–23], but it is not clear if this could be a PCa-associated shared genetic variant among multiple populations. Herein, we investigated the association of rs1465618 in THADA with PCa risk in a Chinese population. We also performed a metaanalysis of published studies and our study, which may provide evidence of an association of rs1465618 in THADA with PCa risk among multiple populations.
Patients and Methods Study Population The study sample consisted of 289 pathologically confirmed PCa patients and 288 healthy age-matched controls. All subjects were permanent residents of Beijing and Tianjin in China. Clinical characteristic were obtained by review of the medical records. Aggressive PCa was defined as prostate-specific antigen (PSA) ≥ 20 ng/ml, Gleason score ≥ 8, or patho-
Prof. Ze Yang Key Laboratory of Geriatrics Beijing Hospital 1 Dahua Road, Dong Dan Beijing 100730, China [email protected]
Downloaded by: NYU Medical Center Library 198.143.38.2 - 6/23/2015 10:40:48 AM
Keywords
logical tumor stage C/D. Healthy controls with PSA 99% concordance for all successfully genotyped SNPs.
was defined as p ≤ 0.05. All p values were two-sided. The pooled OR and 95% CI for the SNP in multiple populations were calculated in fixed and random effects methods by Comprehensive Meta-Analysis V2 software (Biostat, Englewood, NJ, USA). We assessed heterogeneity among study populations with Q-statistic and I2 statistic p values.
Results Characteristics of the Study Population Clinical characteristics of the patients and health controls in this study are presented in table 1. The average age of patients and controls was 71.6 ± 9.9 years and 70.5 ± 7.6 years, respectively. The proportion of cases with available PSA, tumor stage, Gleason score, and disease aggressiveness were 74.4, 46.8, 49.8, and 53.3%, respectively.
Statistical Analysis Departure from Hardy-Weinberg equilibrium was assessed for this SNP in case and control groups using Pearson’s χ2 test. SNP allele frequencies between cases and controls were evaluated using Pearson’s χ2 test. The association of rs1465618 in THADA with PCa risk was estimated by odds ratio (OR) and 95% confidence interval (95% CI) from unconditional logistic regression analysis with adjustment for age. Significance
Association between rs1465618 in THADA and PCa Risk in Chinese Population Allele frequencies and genotype distributions of rs1465618 in THADA are shown in table 2. The observed genotype frequency in controls and cases conformed to the Hardy-Weinberg equilibrium. The distribution of rs1465618 polymorphisms was significantly different between cases and controls (p = 0.026; OR = 1.327, 95% CI = 1.035–1.700). There was no
Table 1. Clinical and epidemiologic characteristics of prostate cancer cases and controls
Table 3. Association between rs1465618 in THADA and clinicopathological characteristics of prostate cancer patients
Variables a
Age , mean ± SD, years BMIb, mean ± SD
Cases
Controls
71.6 ± 9.9 31.25 ± 4.86
70.5 ± 7.6 22.25 ± 8.48
n (%) PSA, ng/ml
