Browsing by Author "Li, Ming"
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Item A multicenter cross-sectional study in infants with congenital heart defects demonstrates high diagnostic yield of genetic testing but variable evaluation practices(Elsevier, 2023-04-29) Durbin, Matthew D.; Helvaty, Lindsey R.; Li, Ming; Border, William; Fitzgerald-Butt, Sara; Garg, Vidu; Geddes, Gabrielle C.; Helm, Benjamin M.; Lalani, Seema R.; McBride, Kim L.; McEntire, Alexis; Mitchell, Dana K.; Murali, Chaya N.; Wechsler, Stephanie B.; Landis, Benjamin J.; Ware, Stephanie M.; Pediatrics, School of MedicinePurpose: For patients with congenital heart disease (CHD), the most common birth defect, genetic evaluation is not universally accepted, and current practices are anecdotal. Here, we analyzed genetic evaluation practices across centers, determined diagnostic yield of testing, and identified phenotypic features associated with abnormal results. Methods: This is a multicenter cross-sectional study of 5 large children's hospitals, including 2899 children ≤14 months undergoing surgical repair for CHD from 2013 to 2016, followed by multivariate logistics regression analysis. Results: Genetic testing occurred in 1607 of 2899 patients (55%). Testing rates differed highly between institutions (42%-78%, P < .001). Choice of testing modality also differed across institutions (ie, chromosomal microarray, 26%-67%, P < .001). Genetic testing was abnormal in 702 of 1607 patients (44%), and no major phenotypic feature drove diagnostic yield. Only 849 patients were seen by geneticists (29%), ranging across centers (15%-52%, P < .001). Geneticist consultation associated with increased genetic testing yield (odds ratio: 5.7, 95% CI 4.33-7.58, P < .001). Conclusion: Genetics evaluation in CHD is diagnostically important but underused and highly variable, with high diagnostic rates across patient types, including in infants with presumed isolated CHD. These findings support recommendations for comprehensive testing and standardization of care.Item The Association Between Citrus Consumption and Skin Cancer: An Analysis of Risk and Nutrient-Gene Interaction(2020-12) Marley, Andrew Raymond; Han, Jiali; Sibg, Yiqing; Li, Xin; Li, Ming; Champion, Victoria L.Purpose. In the US, melanoma and non-melanoma skin cancer (NMSC) rates have increased substantially in recent decades. While many skin cancer risk factors have been established, the impact of dietary citrus, which is naturally abundant in photocarcinogenic psoralens, remains enigmatic. The purpose of this research was to investigate associations between citrus consumption and risks of melanoma and NMSC, and to conduct a genome-wide study to identify genetic variants that may modify this association. Methods. Participants from the UK Biobank were leveraged for these analyses. Citrus consumption was collected via five rounds of 24-hour recall questionnaires, with complete citrus data available for n=210,126 participants. Ascertainment of melanoma and NMSC cases were identified by international classification of disease codes via linkage with national registries. Logistic regression was used to estimate odds ratios and 95% confidence intervals for the associations between citrus consumption and skin cancer outcomes. Individual citrus products were assessed for independent associations with skin cancer risk, and established skin cancer risk factors were tested for interaction. Joint 2-degree-of-freedom (df) and 1-df tests were used to assess interaction between total citrus consumption and genetic variants. Results. After controlling for covariates, high total citrus consumption was significantly associated with increased melanoma risk, an association primarily driven by orange and orange juice consumption. Skin color was found to be a significant effect modifier for the association between total citrus consumption and melanoma risk, but only before adjusting for multiple comparisons. No significant associations were observed for high total citrus consumption or consumption of any individual citrus products and NMSC risk. Significant associations for half a serving of citrus consumption and NMSC risk were likely due to chance or confounding. Index SNPs on chromosomes 3, 9, and 16 were significant according to the joint 2-df test, and 7 SNPs on chromosome 16 displayed evidence of a citrus-gene interaction. Conclusion. My analyses provide evidence in support of high citrus consumption significantly increasing risk of melanoma, but not NMSC. I also identified SNPs on AFG3L1P that may modify this association. Future research should further explore these associations, particularly for NMSC and to confirm my genetic findings.Item Citrus Consumption and Risk of Non-Melanoma Skin Cancer in the UK Biobank(Taylor & Francis, 2022) Marley, Andrew R.; Li, Ming; Champion, Victoria L.; Song, Yiqing; Han, Jiali; Li, Xin; Epidemiology, School of Public HealthBackground: Non-melanoma skin cancer (NMSC) incidence has been dramatically increasing worldwide. Psoralen, a known photocarcinogen, is naturally abundant in citrus products, leading to the hypothesis that high citrus consumption may increase NMSC risk. Methods: We fitted age- and multivariable-adjusted logistic regression models to evaluate the association between citrus consumption and NMSC risk among 197,372 UKBB participants. A total of 9,613 NMSC cases were identified using International Classification of Disease 10 codes. Citrus consumption data were collected via five rounds of 24-hour recall questionnaires. Results: We found no association between high total citrus consumption and NMSC risk, although a slightly elevated NMSC risk was observed among participants who consumed >0 to half a serving of total citrus per day (OR [95% CI] = 1.08 [1.01-1.16]). There was no association between individual citrus products and NMSC risk. Conclusion: High citrus consumption was not associated with an increased risk of NMSC in our UKBB sample. Further studies are needed to clarify these associations. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1952439 .Item Citrus-Gene Interaction and Melanoma Risk in the UK Biobank(Wiley, 2022) Marley, Andrew R.; Li, Ming; Champion, Victoria L.; Song, Yiqing; Han, Jiali; Li, Xin; Epidemiology, School of Public HealthHigh citrus consumption may increase melanoma risk; however, little is known about the biological mechanisms of this association, or whether it is modified by genetic variants. We conducted a genome-wide analysis of gene-citrus consumption interactions on melanoma risk among 1563 melanoma cases and 193 296 controls from the UK Biobank. Both the 2-degrees-of-freedom (df) joint test of genetic main effect and gene-environment (G-E) interaction and the standard 1-df G-E interaction test were performed. Three index SNPs (lowest P-value SNP among highly correlated variants [r2 > .6]) were identified from among the 365 genome-wide significant 2-df test results (rs183783391 on chromosome 3 [MITF], rs869329 on chromosome 9 [MTAP] and rs11446223 on chromosome 16 [DEF8]). Although all three were statistically significant for the 2-df test (4.25e-08, 1.98e-10 and 4.93e-13, respectively), none showed evidence of interaction according to the 1-df test (P = .73, .24 and .12, respectively). Eight nonindex, 2-df test significant SNPs on chromosome 16 were significant (P < .05) according to the 1-df test, providing evidence of citrus-gene interaction. Seven of these SNPs were mapped to AFG3L1P (rs199600347, rs111822773, rs113178244, rs3803683, rs73283867, rs78800020, rs73283871), and one SNP was mapped to GAS8 (rs74583214). We identified several genetic loci that may elucidate the association between citrus consumption and melanoma risk. Further studies are needed to confirm these findings.Item Early innate and adaptive immune perturbations determine long-term severity of chronic virus and Mycobacterium tuberculosis coinfection(Elsevier, 2021) Xu, Wenxi; Snell, Laura M.; Guo, Mengdi; Boukhaled, Giselle; Macleod, Bethany L.; Li, Ming; Tullius, Michael V.; Guidos, Cynthia J.; Tsao, Ming-Sound; Divangahi, Maziar; Horwitz, Marcus A.; Liu, Jun; Brooks, David G.; Microbiology and Immunology, School of MedicineChronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection. Here, we examined how chronic viral infections alter the pulmonary microenvironment to foster coinfection and worsen disease severity. We developed a coordinated system of chronic virus and Mtb infection that induced central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination, and heightened mortality. These disease states were not due to chronic virus-induced immunosuppression or exhaustion; rather, increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lymph node and subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17 differentiation and increasing pulmonary neutrophilia, which diminished long-term survival. Temporally restoring CD4 T cell induction overcame these diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function, and foster long-term coinfection.Item Genetic Testing Guidelines Impact Care in Newborns with Congenital Heart Defects(Elsevier, 2023) Durbin, Matthew D.; Fairman, Korre; Helvaty, Lindsey R.; Huang, Manyan; Li, Ming; Abreu, Daniel; Geddes, Gabrielle C.; Helm, Benjamin M.; Landis, Benjamin J.; McEntire, Alexis; Mitchell, Dana K.; Ware, Stephanie M.; Pediatrics, School of MedicineObjective: To evaluate genetic evaluation practices in newborns with the most common birth defect, congenital heart defects (CHD), we determined the prevalence and the yield of genetic evaluation across time and across patient subtypes, before and after implementation of institutional genetic testing guidelines. Study design: This was a retrospective, cross-sectional study of 664 hospitalized newborns with CHD using multivariate analyses of genetic evaluation practices across time and patient subtypes. Results: Genetic testing guidelines for hospitalized newborns with CHD were implemented in 2014, and subsequently genetic testing increased (40% in 2013 and 75% in 2018, OR 5.02, 95% CI 2.84-8.88, P < .001) as did medical geneticists' involvement (24% in 2013 and 64% in 2018, P < .001). In 2018, there was an increased use of chromosomal microarray (P < .001), gene panels (P = .016), and exome sequencing (P = .001). The testing yield was high (42%) and consistent across years and patient subtypes analyzed. Increased testing prevalence (P < .001) concomitant with consistent testing yield (P = .139) added an estimated 10 additional genetic diagnoses per year, reflecting a 29% increase. Conclusions: In patients with CHD, yield of genetic testing was high. After implementing guidelines, genetic testing increased significantly and shifted to newer sequence-based methods. Increased use of genetic testing identified more patients with clinically important results with potential to impact patient care.Item Identifying Susceptibility Loci for Cutaneous Squamous Cell Carcinoma Using a Fast Sequence Kernel Association Test(Frontiers Media, 2021-05-10) Huang, Manyan; Lyu, Chen; Qureshi, Abrar A.; Han, Jiali; Li, Ming; Epidemiology, Richard M. Fairbanks School of Public HealthCutaneous squamous cell carcinoma (cSCC) accounts for about 20% of all skin cancers, the most common type of malignancy in the United States. Genome-wide association studies (GWAS) have successfully identified multiple genetic variants associated with the risk of cSCC. Most of these studies were single-locus-based, testing genetic variants one-at-a-time. In this article, we performed gene-based association tests to evaluate the joint effect of multiple variants, especially rare variants, on the risk of cSCC by using a fast sequence kernel association test (fastSKAT). The study included 1,710 cSCC cases and 24,304 cancer-free controls from the Nurses’ Health Study, the Nurses’ Health Study II and the Health Professionals Follow-up Study. We used UCSC Genome Browser to define gene units as candidate loci, and further evaluated the association between all variants within each gene unit and disease outcome. Four genes HP1BP3, DAG1, SEPT7P2, and SLFN12 were identified using Bonferroni adjusted significance level. Our study is complementary to the existing GWASs, and our findings may provide additional insights into the etiology of cSCC. Further studies are needed to validate these findings.Item Learning to Crawl: Determining the Role of Genetic Abnormalities on Postoperative Outcomes in Congenital Heart Disease(AHA, 2022-10) Landis, Benjamin J.; Helm, Benjamin M.; Herrmann, Jeremy L.; Hoover, Madeline C.; Durbin, Matthew D.; Elmore, Lindsey R.; Huang, Manyan; Johansen, Michael; Li, Ming; Przybylowski, Leon F.; Geddes, Gabrielle C.; Ware, Stephanie M.; Pediatrics, School of MedicineBackground Our cardiac center established a systematic approach for inpatient cardiovascular genetics evaluations of infants with congenital heart disease, including routine chromosomal microarray (CMA) testing. This provides a new opportunity to investigate correlation between genetic abnormalities and postoperative course. Methods and Results Infants who underwent congenital heart disease surgery as neonates (aged ≤28 days) from 2015 to 2020 were identified. Cases with trisomy 21 or 18 were excluded. Diagnostic genetic results or CMA with variant of uncertain significance were considered abnormal. We compared postoperative outcomes following initial congenital heart disease surgery in patients found to have genetic abnormality to those who had negative CMA. Among 355 eligible patients, genetics consultations or CMA were completed in 88%. A genetic abnormality was identified in 73 patients (21%), whereas 221 had negative CMA results. Genetic abnormality was associated with prematurity, extracardiac anomaly, and lower weight at surgery. Operative mortality rate was 9.6% in patients with a genetic abnormality versus 4.1% in patients without an identified genetic abnormality (P=0.080). Mortality was similar when genetic evaluations were diagnostic (9.3%) or identified a variant of uncertain significance on CMA (10.0%). Among 14 patients with 22q11.2 deletion, the 2 mortality cases had additional CMA findings. In patients without extracardiac anomaly, genetic abnormality was independently associated with increased mortality (P=0.019). CMA abnormality was not associated with postoperative length of hospitalization, extracorporeal membrane oxygenation, or >7 days to initial extubation. Conclusions Routine genetic evaluations and CMA may help to stratify mortality risk in severe congenital heart disease with syndromic or nonsyndromic presentations.Item Long non-coding RNAs in renal cell carcinoma: A systematic review and clinical implications(Impact Journals, 2017-04-12) Li, Ming; Wang, Ying; Cheng, Liang; Niu, Wanting; Zhao, Guoan; Raju, Jithin K.; Huo, Jun; Wu, Bin; Yin, Bo; Song, Yongsheng; Bu, Renge; Pathology and Laboratory Medicine, School of MedicineRenal cell carcinoma is one of the most common malignancy in adults, its prognosis is poor in an advanced stage and early detection is difficult due to the lack of molecular biomarkers. The identification of novel biomarkers for RCC is an urgent and meaningful project. Long non-coding RNA (lncRNA) is transcribed from genomic regions with a minimum length of 200 bases and limited protein-coding potential. Recently, lncRNAs have been greatly studied in a variety of cancer types. They participate in a wide variety of biological processes including cancer biology. In this review, we provide a new insight of the profiling of lncRNAs in RCC and their roles in renal carcinogenesis, with an emphasize on their potential in diagnosis, prognosis and potential roles in RCC therapy.Item MondoA deficiency enhances sprint performance in mice(Portland Press, 2014-11-15) Imamura, Minako; Hung-Junn Chang, Benny; Kohjima, Motoyuki; Li, Ming; Hwang, Byounghoon; Taegtmeyer, Heinrich; Harris, Robert A.; Chan, Lawrence; Department of Biochemistry & Molecular Biology, IU School of MedicineMondoA is a basic helix-loop-helix (bHLH)/leucine zipper (ZIP) transcription factor that is expressed predominantly in skeletal muscle. Studies in vitro suggest that the Max-like protein X (MondoA:Mlx) heterodimer senses the intracellular energy status and directly targets the promoter region of thioredoxin interacting protein (Txnip) and possibly glycolytic enzymes. We generated MondoA-inactivated (MondoA-/-) mice by gene targeting. MondoA-/- mice had normal body weight at birth, exhibited normal growth and appeared to be healthy. However, they exhibited unique metabolic characteristics. MondoA-/- mice built up serum lactate and alanine levels and utilized fatty acids for fuel during exercise. Gene expression and promoter analysis suggested that MondoA functionally represses peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α)-mediated activation of pyruvate dehydrogenase kinase 4 (PDK-4) transcription. PDK4 normally down-regulates the activity of pyruvate dehydrogenase, an enzyme complex that catalyses the decarboxylation of pyruvate to acetyl-CoA for entry into the Krebs cycle; in the absence of MondoA, pyruvate is diverted towards lactate and alanine, both products of glycolysis. Dynamic testing revealed that MondoA-/- mice excel in sprinting as their skeletal muscles display an enhanced glycolytic capacity. Our studies uncover a hitherto unappreciated function of MondoA in fuel selection in vivo. Lack of MondoA results in enhanced exercise capacity with sprinting.