Integration of a polygenic risk score of kidney function with cumulative cisplatin dose and time variables for the prediction of serum platinum levels.

12063 Background: Platinum levels are measurable in the serum for decades after cisplatin therapy and higher levels may be related to chemotherapy-induced toxicities. Since cisplatin is cleared exclusively by the kidney, we hypothesized that a genetic predictor of kidney function, an estimated glomerular filtration rate polygenic risk score (eGFR PRS), would significantly associate with serum platinum levels and could improve prediction models. Methods: Within a large well-characterized, multicenter clinical cohort of cisplatin-treated testicular cancer survivors (TCS), we conducted analyses on all patients with genetic data and serum platinum levels. Genotyping was performed on the HumanOmniExpressExome chip and standard QC measures were included. Serum platinum concentrations were quantified by inductively coupled plasma mass spectrometry. For all TCS, time since therapy (TIME) and cumulative cisplatin dose were collected. The eGFR PRS was developed from the Chronic Kidney Disease Genetics (CKDGen) consortium meta-analysis summary statistics using PRS-CS. Using principal component analysis, we restricted the analysis to TCS of genetically determined European ancestry, then calculated the genome-wide PRS for all participants. We performed Cox regression analyses to evaluate prediction models of serum platinum that included cumulative dose and TIME, as well as a model including eGFR PRS. Data are presented as median(interquartile range). Results: 901 patients were included in our analysis with a median diagnosis age of 31 (26 - 38) years, cumulative cisplatin dose of 400 (300-400) mg/m2, and time since first cisplatin dose of 4.6 (2.3-9.5) years. The median serum platinum level for all TCS was 305 (121-981) ng/L. When stratified into quartiles by eGFR PRS, TCS in the lowest quartile had a median serum platinum level of 316 (139-1014) ng/L while TCS in the highest had a median of 268 (106-731) ng/L. Comparison of two Cox regression models for serum platinum prediction, one including only cumulative dose and TIME as predictors and a second including dose, TIME, eGFR PRS, and an eGFR PRS*TIME interaction term, we determined the model including eGFR PRS had a lower AIC (14350 vs 16180) suggesting a more parsimonious model. Further, eGFR PRS was a significant independent predictor of serum platinum levels (p = 0.02) and the impact of eGFR PRS varies over time (eGFR PRS*TIME, p = 0.05). Conclusions: The genetic predictor of kidney function circumvents the use of renal function measures that may have been impaired by initial cisplatin administration. It is a significant independent predictor of serum platinum levels and consistent with expectation: TCS with higher genetically predicted kidney function had lower serum platinum levels. Our results suggest kidney function inferred by genetics may improve the prediction of serum platinum levels.

Associations of genetic variants at TAP1 and TAP2 with pulmonary tuberculosis risk among the Chinese population

Tuberculosis (TB) is a common infectious disease, and the present study aims to explore the associations of single nucleotide polymorphisms (SNPs) at rs1135216 and rs1057141 of transporter-associated antigen processing (TAP1) and rs2228396 of TAP2 with pulmonary tuberculosis (PTB) risk. A case–control study including 168 smear-positive PTB cases and 251 controls was conducted. Genotyping of the SNPs at rs1135216, rs1057141 and rs2228396 was performed, and their associations with PTB risk were analysed with SPSS software version 19.0. After conducting stratification for age, a significant association was detected for rs1057141 with increased PTB risk (OR = 0.17, 95% CI 0.04–0.79) among those aged ≥60 years. For those aged <60 years, a marginally significant association was detected between rs1135216 TC/CC and PTB risk (OR = 1.97, 95% CI 0.93–4.19). Haplotype analysis revealed that the haplotype AT at rs1135216 and rs2228396, as well as AAT at rs1057141, rs1135216 and rs2228396, was associated with increased PTB risk, and the ORs were 2.83 (95% CI 1.30–6.14) and 2.89 (95% CI 1.34–6.27), respectively. Rs1057141 is a genetic predictor of reduced PTB risk for those aged ≥60 years, while rs1135216 might be a potential genetic predictor for those aged <60 years. Haplotype AT at rs1135216 and rs2228396, as well as AAT at rs1057141, rs1135216 and rs2228396, is a genetic marker that may predict PTB risk.

ABCG2 GENE POLYMORPHISM IN PATIENTS WITH GOUT IN ZABAIKALSKY KRAI

Aim. To study the frequency distribution of alleles and genotypes of the C421A locus (rs2231142, Q141K) of the ABCG2 gene in patients with gout and to evaluate their association with the risk of the disease development.Methods. 80 patients (69 men and 11 women) with gout (mean age 54.8±12.4 years) were examined. Gout was diagnosed according to the ACR/EULAR classification criteria, 2015. The material for the study was DNA isolated from leukocytes of the whole peripheral blood. All patients were genotyped to detect polymorphism of the C421A locus (rs2231142, Q141K) of the ABCG2 gene. Statistical data processing was performed using Statistica 10.0 statistical software package.Results. The results of the study of the C421A polymorphism (rs2231142, Q141K) of the ABCG2 gene demonstrated a high frequency of mutant A (χ2 = 5.58, p = 0.018, OR = 3.5, CI95% = 1.16–10.52) genotypes C/A (χ2 = 5.03, p = 0.024, OR = 3.5, CI95% = 1.11–10.98) among patients with gout compared with the control group. This fact indicates the significance of the ABCG2 gene rs2231142 locus in the development of gout and allows us to consider the carriage of the minor (A) allele and the C/A genotype as a molecular genetic factor in the development of the disease. The carriage of the wild-type allele (C) and the C/C genotype has a protective character, reducing the risk of developing the disease by 3.5 times.Conclusion. ABCG2 C421A (rs2231142, Q141K) is associated with a high risk of developing gout among population of Zabaikalsky Krai. ABCG2 gene polymorphism can be considered as a genetic predictor of a higher risk of developing gout.

Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma

Key Points ATL subtypes are further classified into molecularly distinct subsets with different prognosis by genetic profiling. PD-L1 amplifications are a strong genetic predictor for worse outcome in both aggressive and indolent ATL.