Browsing by Subject "Single nucleotide polymorphisms"

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    ItemOpen Access
    Potentially functional variants of ERAP1, PSMF1 and NCF2 in the MHC-I-related pathway predict non-small cell lung cancer survival.
    (Cancer immunology, immunotherapy : CII, 2021-03-02) Yang, Sen; Tang, Dongfang; Zhao, Yu Chen; Liu, Hongliang; Luo, Sheng; Stinchcombe, Thomas E; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Wang, Qiming; Wei, Qingyi

    Background

    Cellular immunity against tumor cells is highly dependent on antigen presentation by major histocompatibility complex class I (MHC-I) molecules. However, few published studies have investigated associations between functional variants of MHC-I-related genes and clinical outcomes of lung cancer patients.

    Methods

    We performed a two-phase Cox proportional hazards regression analysis by using two previously published genome-wide association studies to evaluate associations between genetic variants in the MHC-I-related gene set and the survival of non-small cell lung cancer (NSCLC) patients, followed by expression quantitative trait loci analysis.

    Results

    Of the 7811 single-nucleotide polymorphisms (SNPs) in 89 genes of 1185 NSCLC patients in the discovery dataset of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 24 SNPs remained statistically significant after validation in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. In a multivariate stepwise Cox model, three independent functional SNPs (ERAP1 rs469783 T > C, PSMF1 rs13040574 C > A and NCF2 rs36071574 G > A) remained significant with an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.77-0.89, P = 8.0 × 10-7], 0.86 (0.80-0.93, P = 9.4 × 10-5) and 1.31 (1.11-1.54, P = 0.001) for overall survival (OS), respectively. Further combined genotypes revealed a poor survival in a dose-response manner in association with the number of unfavorable genotypes (Ptrend < 0.0001 and 0.0002 for OS and disease-specific survival, respectively). Also, ERAP1 rs469783C and PSMF1 rs13040574A alleles were associated with higher mRNA expression levels of their genes.

    Conclusion

    These potentially functional SNPs of the MHC-I-related genes may be biomarkers for NSCLC survival, possibly through modulating the expression of corresponding genes.
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    ItemOpen Access
    Shared Inherited Genetics of Benign Prostatic Hyperplasia and Prostate Cancer.
    (European urology open science, 2022-09) Glaser, Alexander; Shi, Zhuqing; Wei, Jun; Lanman, Nadia A; Ladson-Gary, Skylar; Vickman, Renee E; Franco, Omar E; Crawford, Susan E; Lilly Zheng, S; Hayward, Simon W; Isaacs, William B; Helfand, Brian T; Xu, Jianfeng

    Background

    The association between benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remains controversial, largely due to a detection bias in traditional observational studies.

    Objective

    To assess the association between BPH and PCa using inherited single nucleotide polymorphisms (SNPs).

    Design setting and participants

    The participants were White men from the population-based UK Biobank (UKB).

    Outcome measurements and statistical analysis

    The association between BPH and PCa was tested for (1) phenotypic correlation using chi-square, (2) genetic correlation (r g) based on genome-wide SNPs using linkage disequilibrium score regression, and (3) cross-disease genetic associations based on known risk-associated SNPs (15 for BPH and 239 for PCa), individually and cumulatively using genetic risk score (GRS).

    Results and limitations

    Among 214 717 White men in the UKB, 24 623 (11%) and 14 311 (6.7%) had a diagnosis of BPH and PCa, respectively. Diagnoses of these two diseases were significantly correlated (χ2 = 1862.80, p < 0.001). A significant genetic correlation was found (r g = 0.16; 95% confidence interval 0.03-0.28, p = 0.01). In addition, significant cross-disease genetic associations for established risk-associated SNPs were also found. Among the 250 established genome-wide association study-significant SNPs of PCa or BPH, 49 were significantly associated with the risk of the other disease at p < 0.05, significantly more than expected by chance (N = 12, p < 0.001; χ2 test). Furthermore, significant cross-disease GRS associations were also found; GRSBPH was significantly associated with PCa risk (odds ratio [OR] = 1.26 [1.18-1.36], p < 0.001), and GRSPCa was significantly associated with BPH risk (OR = 1.03 [1.02-1.04], p < 0.001). Moreover, GRSBPH was significantly and inversely associated with lethal PCa risk in a PCa case-case analysis (OR = 0.58 [0.41-0.81], p = 0.002). Only White men were studied.

    Conclusions

    BPH and PCa share common inherited genetics, which suggests that the phenotypic association of these two diseases in observational studies is not entirely caused by the detection bias.

    Patient summary

    For the first time, we found that benign prostatic hyperplasia and prostate cancer are genetically related. This finding may have implications in disease etiology and risk stratification.