Zhuqing Shi

NorthShore University HealthSystem

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Brian T. Helfand

NorthShore University HealthSystem

Jianfeng Xu

NorthShore University HealthSystem

Jun Wei

NorthShore University HealthSystem

Jianfeng Xu

NorthShore University HealthSystem

S. Lilly Zheng

NorthShore University HealthSystem

William B. Isaacs

Johns Hopkins University

Rong Na

Chinese University of Hong Kong

W. Kyle Resurreccion

NorthShore University HealthSystem

Kathleen A. Cooney

Duke University

Hongjie Yu

Fudan University

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NorthShore University HealthSystem

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University of Chicago

Fudan University

Johns Hopkins University

Institute of Seismology

Johns Hopkins Medicine

Northwestern University

State Key Laboratory of Genetic Engineering

Chinese Academy of Medical Sciences & Peking Union Medical College

Harvard University

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Utility of Polygenic Scores for Differentiating Diabetes Diagnosis Among Patients With Atypical Phenotypes of Diabetes

The Journal of Clinical Endocrinology & Metabolism (2023)

Liana K. Billings Zhuqing Shi Jun Wei Andrew S. Rifkin S. Lilly Zheng

Misclassification of diabetes type occurs in people with atypical presentations of type 1 diabetes (T1D) or type 2 diabetes (T2D). Although current clinical guidelines suggest clinical variables and treatment response as ways to help differentiate diabetes type, they remain insufficient for people with atypical presentations.This work aimed to assess the clinical utility of 2 polygenic scores (PGSs) in differentiating between T1D and T2D.Patients diagnosed with diabetes in the UK Biobank were studied (N = 41 787), including 464 (1%) and 15 923 (38%) who met the criteria for classic T1D and T2D, respectively, and 25 400 (61%) atypical diabetes. The validity of 2 published PGSs for T1D (PGST1D) and T2D (PGST2D) in differentiating classic T1D or T2D was assessed using C statistic. The utility of genetic probability for T1D based on PGSs (GenProb-T1D) was evaluated in atypical diabetes patients.The joint performance of PGST1D and PGST2D for differentiating classic T1D or T2D was outstanding (C statistic = 0.91), significantly higher than that of PGST1D alone (0.88) and PGST2D alone (0.70), both P less than .001. Using an optimal cutoff of GenProb-T1D, 23% of patients with atypical diabetes had a higher probability of T1D and its validity was independently supported by clinical presentations that are characteristic of T1D.PGST1D and PGST2D can be used to discriminate classic T1D and T2D and have potential clinical utility for differentiating these 2 types of diseases among patients with atypical diabetes.

10.1210/clinem/dgad456

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Increased genetic risk for β-cell failure is associated with β-cell function decline in people with prediabetes

Liana K. Billings Kathleen A. Jablonski Qing Pan Paul W. Franks Ronald Goldberg

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the influence of T2D pPS on diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin or placebo arms. Associations were tested using general linear models and Cox regression adjusted for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at one year follow-up adjusted for baseline measures (effect per pPS standard deviation (SD) -0.04, P=9.6 x 10-7; -8.45 uU/mg, P=5.6 x 10-6, respectively) and with increased diabetes incidence adjusted for BMI at nominal significance (HR 1.10 per SD, P=0.035). The liver/lipid pPS was associated with reduced one-year baseline-adjusted triglyceride levels (effect per SD -4.37, P=0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the β-cell cluster pPS had worsening in measures of β-cell function.

Prediabetes

10.2337/figshare.25833832

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Risk assessment of venous thromboembolism in inflammatory bowel disease by inherited risk in a population-based incident cohort

World Journal of Gastroenterology (2023)

Andrew S. Rifkin Zhuqing Shi Jun Wei Siqun L. Zheng Brian T. Helfand

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the digestive tract with increasing prevalence globally. Although venous thromboembolism (VTE) is a major complication in IBD patients, it is often underappreciated with limited tools for risk stratification.To estimate the proportion of VTE among IBD patients and assess genetic risk factors (monogenic and polygenic) for VTE.Incident VTE was followed for 8465 IBD patients in the UK Biobank (UKB). The associations of VTE with F5 factor V leiden (FVL) mutation, F2 G20210A prothrombin gene mutation (PGM), and polygenic score (PGS003332) were tested using Cox hazards regression analysis, adjusting for age at IBD diagnosis, gender, and genetic background (top 10 principal components). The performance of genetic risk factors for discriminating VTE diagnosis was estimated using the area under the receiver operating characteristic curve (AUC).The overall proportion of incident VTE was 4.70% in IBD patients and was similar for CD (4.46%), UC (4.49%), and unclassified (6.42%), and comparable to that of cancer patients (4.66%) who are well-known at increased risk for VTE. Mutation carriers of F5/F2 had a significantly increased risk for VTE compared to non-mutation carriers, hazard ratio (HR) was 1.94, 95% confidence interval (CI): 1.42-2.65. In contrast, patients with the top PGS decile had a considerably higher risk for VTE compared to those with intermediate scores (middle 8 deciles), HR was 2.06 (95%CI: 1.57-2.71). The AUC for differentiating VTE diagnosis was 0.64 (95%CI: 0.61-0.67), 0.68 (95%CI: 0.66-0.71), and 0.69 (95%CI: 0.66-0.71), respectively, for F5/F2 mutation carriers, PGS, and combined.Similar to cancer patients, VTE complications are common in IBD patients. PGS provides more informative risk information than F5/F2 mutations (FVL and PGM) for personalized thromboprophylaxis.

Exosome

Tumor progression

10.3748/wjg.v29.i39.5494

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Assessing the Clinical Utility of Genetic Risk Scores for Targeted Cancer Screening

Research Square (Research Square) (2020)

Carly Conran Zhuqing Shi W. Kyle Resurreccion Rong Na Brian T. Helfand

Abstract Background: Genome-wide association studies have identified thousands of disease-associated single nucleotide polymorphisms (SNPs). A subset of these SNPs may be additively combined to generate genetic risk scores (GRSs) that confer risk for a specific disease. Although the clinical validity of GRSs to predict risk of specific diseases has been well established, there is still a great need to determine their clinical utility by applying GRSs in primary care for cancer risk assessment and targeted intervention. Methods: This clinical study involved 281 primary care patients without a personal history of breast, prostate or colorectal cancer who were 40-70 years old. DNA was obtained from a pre-existing biobank at NorthShore University HealthSystem. GRSs for colorectal cancer and breast or prostate cancer were calculated and shared with participants through their primary care provider. Additional data was gathered using questionnaires as well as electronic medical record information. A t-test or Chi-square test was applied for comparison of demographic and key clinical variables among different groups. Results: The median age of the 281 participants was 58 years and the majority were female (66.6%). One hundred one (36.9%) participants received 2 low risk scores, 99 (35.2%) received 1 low risk and 1 average risk score, 37 (13.2%) received 1 low risk and 1 high risk score, 23 (8.2%) received 2 average risk scores, 21 (7.5%) received 1 average risk and 1 high risk score, and no one received 2 high risk scores. Before receiving GRSs, younger patients and women reported significantly more worry about risk of developing cancer. After receiving GRSs, those who received at least one high GRS reported significantly more worry about developing cancer. There were no significant differences found between gender, age, or GRS with regards to participants’ reported optimism about their future health neither before nor after receiving GRS results. Conclusions: Genetic risk scores that quantify an individual’s risk of developing breast, prostate and colorectal cancers as compared with a race-defined population average risk have potential clinical utility as a tool for risk stratification and to guide cancer screening in a primary care setting.

10.21203/rs.3.rs-93488/v1

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Concept and benchmarks for assessing narrow‐sense validity of genetic risk score values

The Prostate (2019)

Hongjie Yu Zhuqing Shi Yishuo Wu Chi‐Hsiung Wang Xiaoling Lin

Abstract Background While higher genetic risk score (GRS) has been statistically associated with increased disease risk (broad‐sense validity), the concept and tools for assessing the validity of reported GRS values from tests (narrow‐sense validity) are underdeveloped. Methods We propose two benchmarks for assessing the narrow‐sense validity of GRS. The baseline benchmark requires that the mean GRS value in a general population approximates 1.0. The calibration benchmark assesses the agreement between observed risks and estimated risks (GRS values). We assessed benchmark performance for three prostate cancer (PCa) GRS tests, derived from three SNP panels with increasing stringency of selection criteria, in a PCa chemoprevention trial where 714 of 3225 men were diagnosed with PCa during the 4‐year follow‐up. Results GRS from Panels 1, 2, and 3 were all statistically associated with PCa risk; P = 5.58 × 10 −3 , P = 1 × 10 −3 , and P = 1.5 × 10 −13 , respectively (broad‐sense validity). For narrow‐sense validity, the mean GRS value among men without PCa was 1.33, 1.09, and 0.98 for Panels 1, 2, and 3, respectively (baseline benchmark). For assessing the calibration benchmark, observed risks were calculated for seven groups of men with GRS values <0.3, 0.3–0.79, 0.8–1.19, 1.2‐1.49, 1.5‐1.99, 2‐2.99, and ≥3. The calibration slope (higher is better) was 0.15, 0.12, and 0.60, and the bias score (lower is better) between the observed risks and GRS values was 0.08, 0.08, and 0.02 for Panels 1, 2, and 3, respectively. Conclusion Performance differed considerably among GRS tests. We recommend that all GRS tests be evaluated using the two benchmarks before clinical implementation for individual risk assessment.

10.1002/pros.23821

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Journal of Heterocyclic Chemistry (2023)

Akkattu T. Biju Basker Sundararaju Tatiana Besset Jeffrey W. Bode Yün Chi

10.1002/jhet.4505

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Journal of Heterocyclic Chemistry (2023)

Akkattu T. Biju Basker Sundararaju Tatiana Besset Jeffrey W. Bode Yün Chi

10.1002/jhet.4507

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PD65-11 INCLUSION OF KLK3 GERMLINE NONSYNONYMOUS MUTATION I179T AS PART OF MULTIGENE PANEL TESTING FOR PREDICTING PROSTATE CANCER PROGRESSION

The Journal of Urology (2021)

Jianfeng Xu Zhuqing Shi Jun S. Wei Rong Na W. Kyle Resurreccion

You have accessJournal of UrologyProstate Cancer: Detection & Screening VII (PD65)1 Sep 2021PD65-11 INCLUSION OF KLK3 GERMLINE NONSYNONYMOUS MUTATION I179T AS PART OF MULTIGENE PANEL TESTING FOR PREDICTING PROSTATE CANCER PROGRESSION Jianfeng Xu, Zhuqing Shi, Jun Wei, Rong Na, W. Kyle Resurreccion, Chi-Hsiung Wang, Chris Sample, Misop Han, S. Lilly Zheng, Kathleen Cooney, Brian Helfand, and William Isaacs Jianfeng XuJianfeng Xu More articles by this author , Zhuqing ShiZhuqing Shi More articles by this author , Jun WeiJun Wei More articles by this author , Rong NaRong Na More articles by this author , W. Kyle ResurreccionW. Kyle Resurreccion More articles by this author , Chi-Hsiung WangChi-Hsiung Wang More articles by this author , Chris SampleChris Sample More articles by this author , Misop HanMisop Han More articles by this author , S. Lilly ZhengS. Lilly Zheng More articles by this author , Kathleen CooneyKathleen Cooney More articles by this author , Brian HelfandBrian Helfand More articles by this author , and William IsaacsWilliam Isaacs More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002109.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Clinical guidelines now include germline testing for prostate cancer (PCa). Currently, only 11 genes are routinely evaluated for rare pathogenic mutations (RPMs). Common variants in the KLK3 gene, despite being consistently associated with PCa progression, are not included in these recommendations. The objective of the current study is to assess the added value of a nonsynonymous mutation (I179T) in KLK3 to RPMs in 11 guideline-recommended genes for predicting PCa progression. METHODS: Retrospective analysis of two prospective cohorts: 1) PCa patients treated with radical surgery at the Johns Hopkins Hospital (JHH), average 7.9 years of follow-up, 2) PCa patients in the UK Biobank (UKB), average 9.3 years of follow-up. Subjects in the JHH cohort were selected from PCa patients who underwent radical prostatectomy, including all “progressors” (developed metastasis and/or died of PCa) and a subset of “non-progressors”. Subjects in the UKB cohort were all men diagnosed with PCa. Only Caucasian subjects were analyzed. RPMs of 11 genes from Whole Exon Sequencing and variants of KLK3 from SNP arrays. RESULTS: There were 1,943 (JHH) and 10,228 (UKB) PCa patients with mean ages of diagnosis at 59.01 years and 64.36 years, respectively. In the JHH cohort, 5.2% (95/1,843) of patients had RPMs in the 11 genes; hazard ratio (HR) (95% confidence interval [CI]) for progression was 2.69 (1.77-4.07), P<.001. In comparison, more patients [9.7% (189/1,943)] carried the KLK3 I179T mutation; HR was 1.55 (1.07-2.24), P=.02. Virtually the same results were found in the UKB cohort. Added value of KLK3 to 11 genes was demonstrated when RPMs of 11 genes and KLK3 I179T were analyzed jointly. In the combined cohort, compared to patients without any mutation (RPMs-/KLK3-), RPMs-/KLK3+ patients had modestly increased risk for progression [HR=1.43 (1.05-1.94), P=.02], and RPMs+/KLK3+ patients had greatly increased risk for progression; [HR 5.38 (2.95-9.81), P<.001]. CONCLUSIONS: These two vastly different cohorts consistently demonstrate the added value of KLK3 I179T to the 11 guideline-recommended genes for predicting PCa progression and provide a robust basis for its inclusion in germline testing for predicting PCa progression. Source of Funding: This study was partially supported by grants from Department of Defense (W81XWH-16-1-0764, W81XWH-16-1-0765, and W81XWH-16-1-0766). © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1157-e1157 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jianfeng Xu More articles by this author Zhuqing Shi More articles by this author Jun Wei More articles by this author Rong Na More articles by this author W. Kyle Resurreccion More articles by this author Chi-Hsiung Wang More articles by this author Chris Sample More articles by this author Misop Han More articles by this author S. Lilly Zheng More articles by this author Kathleen Cooney More articles by this author Brian Helfand More articles by this author William Isaacs More articles by this author Expand All Advertisement PDF downloadLoading ...

10.1097/ju.0000000000002109.11

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Journal of Heterocyclic Chemistry (2023)

Akkattu T. Biju Basker Sundararaju Tatiana Besset Jeffrey W. Bode Yün Chi

10.1002/jhet.4508

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Germline mutations in PPFIBP2 are associated with lethal prostate cancer

The Prostate (2018)

Yishuo Wu Hongjie Yu Siqun L. Zheng Bing Feng Ashley L. Kapron

Background Few genes have germline mutations which predispose men to more aggressive prostate cancer (PCa). This study evaluated the contribution of germline loss of function (LOF) variants in PPFIBP2 to risk of lethal PCa. Methods A case‐case study of 1414 PCa patients with lethal PCa and low‐risk localized PCa was performed. Germline DNA samples from these patients were sequenced for PPFIBP2 . Mutation carrier rates and association with lethal PCa were analyzed using the Fisher exact test, logistic regression, and Kaplan‐Meier survival analysis. Results In the entire study population, eight patients, all of European ancestry, were identified as carrying PPFIBP2 pathogenic or likely pathogenic mutations. Seven (1.52%) of 462 lethal PCa patients were carriers compared with only one (0.12%) carrier in 810 low‐risk PCa patients, P = 0.0029. The estimated Odds Ratio (OR) of carrying PPFIBP2 mutation for lethal PCa was 13.8 in European American population. The PPFIBP2 loss‐of‐function mutation carrier rate in lethal PCa cases was also higher than in 33 370 non‐Finnish European individuals from the Exome Aggregation Consortium (ExAC) (carrier rate of 0.17%, P = 1.92 × 10 −5 ) and in 498 men with localized PCa from The Cancer Genome Atlas cohort (TCGA) cohort (carrier rate of 0%, P = 0.0058). Survival analysis in European American lethal cases revealed PPFIBP2 mutation status as an independent predictor of shorter survival after adjusting for age at diagnosis, PSA at diagnosis, and genetic background (hazard ratio = 2.62, P = 0.034). Conclusions While larger studies are needed, germline mutations in a novel gene, PPFIBP2 , differentiated risk for lethal PCa from low‐risk cases and were associated with shorter survival times after diagnosis.

10.1002/pros.23697

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