Browsing by Author "Lin, Yuan"
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Item Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma(Wiley, 2017-09-01) Lin, Yuan; Chahal, Harvind S.; Wu, Wenting; Cho, Hyunje G.; Ransohoff, Katherine J.; Song, Fengju; Tang, Jean Y.; Sarin, Kavita Y.; Han, Jiali; Epidemiology, School of Public HealthDNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA: OR = 0.93, P = 1.35 × 10-6 ; rs659857 in exon of MUS81: OR = 1.06, P = 3.09 × 10-6 and rs57343616 in 3' UTR of NABP2: OR = 1.11, P = 6.47 × 10-6 ) as significantly associated with BCC risk in meta-analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes-XPA, MUS81 and NABP2-may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome-wide association meta-analysis.Item The Continuing Evolution of Precision Health in Type 2 Diabetes: Achievements and Challenges(Springer, 2019) Lin, Yuan; Wessel, Jennifer; Epidemiology, School of Public HealthPurpose of Review The purpose of this review was to summarize recent advances in the genomics of type 2 diabetes (T2D) and to highlight current initiatives to advance precision health. Recent Findings Generation of multi-omic data to measure each of the “biologic layers,” developments in describing genomic function and annotation in T2D relevant tissue, along with the increasing recognition that T2D is a heterogeneous disease, and large-scale collaborations have all contributed to advancing our understanding of the molecular basis of T2D. Summary Substantial advances have been made in understanding the molecular basis of T2D pathogenesis, such that precision health diabetes is increasingly becoming a reality. For precision diabetes to become a routine in clinical and public health, additional large-scale multi-omic initiatives are needed along with better assessment of our environment to delineate an individual’s diabetes subtype for improved detection and management.Item Distinct transcriptomic landscapes of cutaneous basal cell carcinomas and squamous cell carcinomas(Elsevier, 2019) Wan, Jun; Dai, Hongji; Zhang, Xiaoli; Liu, Sheng; Lin, Yuan; Somani, Ally-Khan; Xie, Jingwu; Han, Jiali; Medical and Molecular Genetics, School of MedicineThe majority of non-melanoma skin cancer (NMSC) is cutaneous basal cell carcinoma (BCC) or squamous cell carcinoma (SCC), which are also called keratinocyte carcinomas, as both of them originate from keratinocytes. The incidence of keratinocyte carcinomas is over 5 million per year in the US, three-fold higher than the total incidence of all other types of cancer combined. While there are several reports on gene expression profiling of BCC and SCC, there are significant variations in the reported gene expression changes in different studies. One reason is that tumor-adjacent normal skin specimens were not included in many studies as matched controls. Furthermore, while numerous studies of skin stem cells in mouse models have been reported, their relevance to human skin cancer remains unknown. In this report, we analyzed gene expression profiles of paired specimens of keratinocyte carcinomas with their matched normal skin tissues as the control. Among several novel findings, we discovered a significant number of zinc finger encoding genes up-regulated in human BCC. In BCC, a novel link was found between hedgehog signaling, Wnt signaling, and the cilium. While the SCC cancer-stem-cell gene signature is shared between human and mouse SCCs, the hair follicle stem-cell signature of mice was not highly represented in human SCC. Differential gene expression (DEG) in human BCC shares gene signature with both bulge and epidermal stem cells. We have also determined that human BCCs and SCCs have distinct gene expression patterns, and some of them are not fully reflected in current mouse models.Item Genome-wide association study identifies 14 novel risk alleles associated with basal cell carcinoma(SpringerNature, 2016-08-19) Chahal, Harvind S.; Wu, Wenting; Ransohoff, Katherine J.; Yang, Lingyao; Hedlin, Haley; Desai, Manisha; Lin, Yuan; Dai, Hong-Ji; Qureshi, Abrar A.; Li, Wen-Qing; Kraft, Peter; Hinds, David A.; Tang, Jean Y.; Han, Jiali; Sarin, Kavita Y.; Department of Epidemiology, Richard M. Fairbanks School of Public HealthBasal cell carcinoma (BCC) is the most common cancer worldwide with an annual incidence of 2.8 million cases in the United States alone. Previous studies have demonstrated an association between 21 distinct genetic loci and BCC risk. Here, we report the results of a two-stage genome-wide association study of BCC, totalling 17,187 cases and 287,054 controls. We confirm 17 previously reported loci and identify 14 new susceptibility loci reaching genome-wide significance (P<5 × 10(-8), logistic regression). These newly associated SNPs lie within predicted keratinocyte regulatory elements and in expression quantitative trait loci; furthermore, we identify candidate genes and non-coding RNAs involved in telomere maintenance, immune regulation and tumour progression, providing deeper insight into the pathogenesis of BCC.Item Genome-wide association study identifies novel susceptibility loci for cutaneous squamous cell carcinoma(SpringerNature, 2016-07-18) Chahal, Harvind S.; Lin, Yuan; Ransohoff, Katherine J.; Hinds, David A.; Wu, Wenting; Dai, Hong-Ji; Qureshi, Abrar A.; Li, Wen-Qing; Kraft, Peter; Tang, Jean Y.; Han, Jiali; Sarin, Kavita Y.; Department of Epidemiology, Richard M. Fairbanks School of Public HealthCutaneous squamous cell carcinoma represents the second most common cutaneous malignancy, affecting 7-11% of Caucasians in the United States. The genetic determinants of susceptibility to cutaneous squamous cell carcinoma remain largely unknown. Here we report the results of a two-stage genome-wide association study of cutaneous squamous cell carcinoma, totalling 7,404 cases and 292,076 controls. Eleven loci reached genome-wide significance (P<5 × 10(-8)) including seven previously confirmed pigmentation-related loci: MC1R, ASIP, TYR, SLC45A2, OCA2, IRF4 and BNC2. We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation. These susceptibility loci provide deeper insight into the pathogenesis of squamous cell carcinoma.Item Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma(Nature Research, 2020-02-10) Sarin, Kavita Y.; Lin, Yuan; Daneshjou, Roxana; Ziyatdinov, Andrey; Thorleifsson, Gudmar; Rubin, Adam; Pardo, Luba M.; Wu, Wenting; Khavari, Paul A.; Uitterlinden, Andre; Nijsten, Tamar; Toland, Amanda E.; Olafsson, Jon H.; Sigurgeirsson, Bardur; Thorisdottir, Kristin; Jorgensen, Eric; Whittemore, Alice S.; Kraft, Peter; Stacey, Simon N.; Stefansson, Kari; Asgari, Maryam M.; Han, Jiali; Epidemiology, School of Public HealthCutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility.Item Lactation Duration and Long-Term Thyroid Function: A Study among Women with Gestational Diabetes(MDPI, 2018-07-21) Panuganti, Pranati L.; Hinkle, Stefanie N.; Rawal, Shristi; Grunnet, Louise G.; Lin, Yuan; Liu, Aiyi; Thuesen, Anne C.B.; Ley, Sylvia H.; Olesen, Sjurdur F.; Zhang, Cuilin; Epidemiology, School of Public HealthLactation is associated with reduced postpartum weight retention and a lower risk of several cardiometabolic disorders in population-based studies. We examined the association between lactation and long-term thyroid function among women with history of gestational diabetes mellitus (GDM), a high-risk population for subsequent metabolic complications. The study included 550 women who developed GDM in the Danish National Birth Cohort (1996⁻2002) and followed-up in the Diabetes & Women's Health Study (2012⁻2014). We assessed adjusted associations between cumulative lactation duration and concentrations of thyroid stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) measured at follow-up. Women with longer cumulative lactation duration tended to have higher fT3 levels (adjusted β and 95% confidence interval (CI) for ≥12 months vs. none: 0.19 (0.03⁻0.36); p-trend = 0.05). When restricted to women with a single lifetime pregnancy to control for parity (n = 70), women who lactated for >6 months (vs. none) had higher fT3 levels (0.46 pmol/L (0.12⁻0.80); p-trend = 0.02) and a higher fT3:fT4 ratio (0.61 (0.17⁻1.05); p-trend = 0.007). Our findings suggested that a longer duration of lactation may be related to greater serum fT3 levels and fT3:fT4 ratio 9⁻16 years postpartum among Danish women with a history of GDM. The association was particularly pronounced among women who only had one lifetime pregnancy.