المؤلفون: Devineni, Divya, Akbarpour, Meleeka, Gong, Yufan, Wong, Nathan

المصدر: Cardiovascular Drugs and Therapy. 38(2)

مصطلحات موضوعية: Cardiovascular risk, Diabetes, GLP-1 receptor agonists, SGLT2-inhibitors, Adult, Male, Humans, Glycemic Control, Precision Medicine, Cardiovascular Diseases, Sodium-Glucose Transporter 2, Risk Factors, Population Health, Diabetes Mellitus, Heart Disease Risk Factors, Atherosclerosis, Glucagon-Like Peptide 1, Glucose, Diabetes Mellitus, Type 2, Glucagon-Like Peptide-1 Receptor, Hypoglycemic Agents

الوصف: PURPOSE: Data are limited on sodium glucose co-transport 2 inhibitors (SGLT2-is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) among real-world cohorts of underrepresented patients. We examined these therapies and glycemic control in US adults with diabetes mellitus (DM) by atherosclerotic cardiovascular disease (ASCVD) risk and sociodemographic factors. METHODS: In the NIH Precision Medicine Initiative All of Us Research Program, we categorized DM as (1) moderate risk, (2) high risk, and (3) with ASCVD. We examined proportions on DM therapies, including SGLT2-i or GLP-1 RA, and at glycemic control by sociodemographic factors and CVD risk groups. RESULTS: Our 81,332 adults aged ≥ 18 years with DM across 340 US sites included 22.3% non-Hispanic Black, 17.2% Hispanic, and 1.8% Asian participants; 31.1%, 30.3%, and 38.6% were at moderate risk, high risk, or with ASCVD, respectively. Those with DM and ASCVD were most likely on SGLT2-i (8.6%) or GLP-1 RA (11.9%). SGLT2-i use was

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الوصول الحر: https://escholarship.org/uc/item/4qr8161gTest

المؤلفون: Polak, Joseph F, Backlund, Jye‐Yu C, Budoff, Matt, Raskin, Philip, Bebu, Ionut, Lachin, John M, Group, DCCT EDIC Research

المصدر: Journal of the American Heart Association. 10(24)

مصطلحات موضوعية: Heart Disease, Diabetes, Prevention, Cardiovascular, Nutrition, Heart Disease - Coronary Heart Disease, Clinical Research, Atherosclerosis, Metabolic and endocrine, Adult, Carotid Artery, Common, Carotid Intima-Media Thickness, Cohort Studies, Coronary Artery Disease, Diabetes Mellitus, Type 1, Female, Humans, Male, Risk Factors, Ultrasonography, carotid intima-media thickness, coronary artery disease, type 1 diabetes, DCCT/EDIC Research Group, carotid intima‐media thickness, Cardiorespiratory Medicine and Haematology

الوصف: Background Carotid artery intima-media thickness (IMT) is associated with the risk of subsequent cardiovascular events in the general population. This association has not been established in type 1 diabetes. Methods and Results We studied if carotid IMT is associated with the risk of a first coronary artery disease event in participants with type 1 diabetes in the EDIC (Epidemiology of Diabetes Interventions and Complications) study, the long-term observational follow-up of the DCCT (Diabetes Control and Complications Trial). Between 1994 and 1996, common carotid artery and internal carotid artery IMT were measured with high-resolution ultrasound in 1309 study participants with a mean age of 35 years and diabetes duration of 13.8 years; 52% were men. Cox proportional hazards models evaluated the association of standardized common carotid artery IMT and internal carotid artery IMT with subsequent cardiovascular events over the next 17 years. Models were adjusted for age, sex, mean hemoglobin A1c levels, and traditional cardiovascular risk factors. Associations of common carotid artery IMT with subsequent CAD were significant after adjustment for imaging device, sex, and age (hazard ratio [HR], 1.23 per 0.09 mm [95% CI, [1.04-1.45]; P=0.0141), but did not remain significant after further adjustment for traditional risk factors and hemoglobin A1c (HR, 1.14 per 0.09 mm [95% CI, 0.97-1.33]; P=0.1206). No significant associations with subsequent coronary artery disease events were seen for internal carotid artery IMT. Conclusions In the DCCT/EDIC cohort with type 1 diabetes, common carotid artery IMT, but not internal carotid artery IMT, is weakly associated with subsequent coronary artery events, an association eliminated after adjusting for coexistent traditional cardiovascular risk factors. Registration URL: https://www.clinicaltrials.govTest; Unique identifiers: NCT00360815 and NCT00360893.

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الوصول الحر: https://escholarship.org/uc/item/9f03q3wzTest

المؤلفون: Muiru, Anthony N, Scherzer, Rebecca, Ascher, Simon B, Jotwani, Vasantha, Grunfeld, Carl, Shigenaga, Judy, Spaulding, Kimberly A, Ng, Derek K, Gustafson, Deborah, Spence, Amanda B, Sharma, Anjali, Cohen, Mardge H, Parikh, Chirag R, Ix, Joachim H, Estrella, Michelle M, Shlipak, Michael G

المصدر: BMC Nephrology. 22(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Public Health, Health Sciences, Clinical Research, Infectious Diseases, Kidney Disease, Prevention, HIV/AIDS, Renal and urogenital, Good Health and Well Being, Adult, Anti-Retroviral Agents, Biomarkers, Female, Glycated Hemoglobin, HIV Infections, Hepatitis A Virus Cellular Receptor 1, Humans, Kidney Tubules, Middle Aged, Renal Insufficiency, Chronic, Risk Factors, Urine biomarkers HIV CKD, Clinical Sciences, Urology & Nephrology, Clinical sciences, Health services and systems, Nursing

الوصف: BackgroundNovel urine biomarkers have enabled the characterization of kidney tubular dysfunction and injury among persons living with HIV, a population at an increased risk of kidney disease. Even though several urine biomarkers predict progressive kidney function decline, antiretroviral toxicity, and mortality in the setting of HIV infection, the relationships among the risk factors for chronic kidney disease (CKD) and urine biomarkers are unclear.MethodsWe assessed traditional and infection-related CKD risk factors and measured 14 urine biomarkers at baseline and at follow-up among women living with HIV in the Women's Interagency Health Study (WIHS). We then used simultaneously adjusted multivariable linear regression models to evaluate the associations of CKD risk factors with longitudinal changes in biomarker levels.ResultsOf the 647 women living with HIV in this analysis, the majority (67%) were Black, the median age was 45 years and median follow-up time was 2.5 years. Each traditional and infection-related CKD risk factor was associated with a unique set of changes in urine biomarkers. For example, baseline hemoglobin a1c was associated with worse tubular injury (higher interleukin [IL]-18), proximal tubular reabsorptive dysfunction (higher α1-microglobulin), tubular reserve (lower uromodulin) and immune response to injury (higher chitinase-3-like protein-1 [YKL-40]). Furthermore, increasing hemoglobin a1c at follow-up was associated with further worsening of tubular injury (higher kidney injury molecule-1 [KIM-1] and IL-18), as well as higher YKL-40. HCV co-infection was associated with worsening proximal tubular reabsorptive dysfunction (higher β2-microglobulin [β2m]), and higher YKL-40, whereas HIV viremia was associated with worsening markers of tubular and glomerular injury (higher KIM-1 and albuminuria, respectively).ConclusionsCKD risk factors are associated with unique patterns of biomarker changes among women living with HIV, suggesting that serial measurements of multiple biomarkers may help in detecting and monitoring kidney disease in this setting.

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الوصول الحر: https://escholarship.org/uc/item/8gv8h3s6Test

المؤلفون: Yuan, Tze-An, Yourk, Vandy, Farhat, Ali, Guo, Katherine L, Garcia, Angela, Meyskens, Frank L, Liu-Smith, Feng

المصدر: International journal of molecular sciences. 21(5)

مصطلحات موضوعية: Humans, Melanoma, Receptor, IGF Type 1, Insulin-Like Growth Factor I, Estrogen Receptor alpha, Estrogen Receptor beta, Prognosis, Risk Factors, Case-Control Studies, Follow-Up Studies, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Adolescent, Adult, Aged, Middle Aged, Child, Child, Preschool, Infant, Infant, Newborn, Female, Male, Young Adult, Biomarkers, Tumor, cutaneous melanoma, estrogen receptors, gender disparities, genetic variants, insulin-like growth factor 1, insulin-like growth factor 1 receptor, Estrogen, Clinical Research, Cancer, Genetics, 2.1 Biological and endogenous factors, Chemical Physics, Other Chemical Sciences, Other Biological Sciences

الوصف: The mechanism of gender disparity in cutaneous melanoma incidence remains unclear. Steroid hormones including estrogens have long been implicated in the course of melanoma, but the conclusion is controversial. Estrogen receptors (ERs) and insulin-like growth factor 1 receptor (IGF1R) show extensive crosstalk in cancer development, but how the ER/IGF1R network impacts melanoma is currently unclear. Here we studied the melanoma associations of selected SNPs from the ER/IGF1R network. Part of the International Genes, Environment, and Melanoma (GEM) cohort was used as a discovery set, and the Gene Environment Association Studies Initiative (GENEVA) dataset served as a validation set. Based on the associations with other malignant disease conditions, thirteen single nucleotide polymorphism (SNP) variants in ESR1, ESR2, IGF1, and IGF1R were selected for candidate gene association analyses. The rs1520220 in IGF1 and rs2229765 in IGF1R variants were significantly associated with melanoma risk in the GEM dataset after Benjamini-Hochberg multiple comparison correction, although they were not validated in the GENEVA set. The discrepancy may be caused by the multiple melanoma characteristics in the GEM patients. Further analysis of gender disparity was carried out for IGF1 and IGF1R SNPs in the GEM dataset. The GG phenotype in IGF1 rs1520220 (recessive model) presented an increased risk of melanoma (OR = 8.11, 95% CI: 2.20, 52.5, p = 0.006) in men but a significant opposite effect in women (OR = 0.15, 95% CI: 0.018, 0.86, p = 0.045). The AA genotype in IGF1R rs2229765 (recessive model) showed a significant protective effect in men (OR = 0.24, 95% CI: 0.07, 0.64, p = 0.008) and no effect in women. Results from the current study are warranted for further validation.

الوصول الحر: https://escholarship.org/uc/item/8xw1f78mTest

المؤلفون: Budoff, Matthew, Backlund, Jye-Yu C, Bluemke, David A, Polak, Joseph, Bebu, Ionut, Schade, David, Strowig, Suzanne, Raskin, Philip, Lachin, John M, Group, DCCT EDIC Research

المصدر: JACC Cardiovascular Imaging. 12(7)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Cardiovascular, Heart Disease - Coronary Heart Disease, Diabetes, Prevention, Autoimmune Disease, Aging, Patient Safety, Heart Disease, Good Health and Well Being, Adolescent, Adult, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, Diabetes Mellitus, Type 1, Disease Progression, Female, Humans, Incidence, Male, Middle Aged, Multidetector Computed Tomography, Predictive Value of Tests, Prognosis, Risk Factors, Time Factors, Vascular Calcification, Young Adult, cardiovascular disease, coronary artery calcification, major adverse cardiovascular event, type 1 diabetes, DCCT/EDIC Research Group, Cardiorespiratory Medicine and Haematology, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Clinical sciences

الوصف: OBJECTIVES:This study sought to determine the relationship between coronary artery calcium (CAC) scores and subsequent cardiovascular disease (CVD) events in DCCT (Diabetes Control and Complications Trial)/EDIC (Epidemiology of Diabetes Interventions and Complications) participants. BACKGROUND:The CAC score has been validated for improved risk stratification in general populations; however, this association has not been well studied in type 1 diabetes (T1DM). METHODS:Computed tomography (CT) to measure CAC was performed in 1,205 DCCT/EDIC participants at a mean of 42.8 years of age during EDIC years 7 to 9, after the end of DCCT. This study analyzed the association between CAC and time to the first subsequent CVD event or to the first major adverse cardiac event (MACE), a follow-up of 10 to 13 years. CAC was categorized as: 0, >0 to 100, >100 to 300, or >300 Agatston units. RESULTS:Of 1,156 participants at risk for subsequent CVD, 105 had an initial CVD event (8.5 per 1,000 patient-years); and of 1,187 participants at risk for MACE, 51 had an initial MACE event (3.9 per 1,000 patient-years). Event rates among those with scores of zero (n = 817 [70.7%]) were very low for CVD (5.6 per 1,000 patient years). CAC scores >100 to 300 (hazard ratio [HR]: 4.17, 5.40) and >300 (HR: 6.06, 6.91) were associated with higher risks of CVD and MACE, respectively, compared to CAC of 0 (p < 0.0001). CAC scores >0 to 100 were nominally associated with CVD (HR: 1.71; p = 0.0415) but not with MACE (HR: 1.11; p = 0.8134). Similar results were observed when also adjusted for mean HbA1c and conventional CVD risk factors. The increment in the AUC due to CAC was modest. CONCLUSIONS:CAC scores >100 Agatston units were significantly associated with an increased risk of the subsequent occurrence of CVD and MACE in DCCT/EDIC cohort. (Diabetes Control and Complications Trial [DCCT]; NCT00360815; Epidemiology of Diabetes Interventions and Complications [EDIC]; NCT00360893).

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الوصول الحر: https://escholarship.org/uc/item/2dq119c8Test

المؤلفون: Triolo, Taylor M, Fouts, Alexandra, Pyle, Laura, Yu, Liping, Gottlieb, Peter A, Steck, Andrea K, Group, the Type 1 Diabetes TrialNet Study

المصدر: Diabetes Care. 42(2)

مصطلحات موضوعية: Prevention, Genetics, Diabetes, Pediatric, Autoimmune Disease, Metabolic and endocrine, Adolescent, Adult, Autoantibodies, Autoimmunity, Child, Child, Preschool, Diabetes Mellitus, Type 1, Disease Progression, Diseases in Twins, Environment, Female, Genetic Predisposition to Disease, Glutamate Decarboxylase, Humans, Insulin, Islets of Langerhans, Male, Mass Screening, Risk Factors, Seroepidemiologic Studies, Siblings, Twins, Twins, Dizygotic, Twins, Monozygotic, Young Adult, Type 1 Diabetes TrialNet Study Group

الوصف: ObjectiveThere are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings.Research design and methodsSubjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years.ResultsAt screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody-positive, 13% for single autoantibody-positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody-positive, 12% for single autoantibody-positive, and 0.5% for initially autoantibody-negative subjects.ConclusionsRisk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody-positive identical twins and multiple autoantibody-positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.

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الوصول الحر: https://escholarship.org/uc/item/8vw9x078Test

المؤلفون: Redondo, Maria J, Steck, Andrea K, Sosenko, Jay, Anderson, Mark, Antinozzi, Peter, Michels, Aaron, Wentworth, John M, Atkinson, Mark A, Pugliese, Alberto, Geyer, Susan, Group, the Type 1 Diabetes TrialNet Study

المصدر: Diabetes Care. 41(12)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Health Sciences, Prevention, Genetics, Autoimmune Disease, Nutrition, Diabetes, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Adolescent, Adult, Antibody Specificity, Autoantibodies, Autoimmunity, Child, Child, Preschool, Cohort Studies, Diabetes Mellitus, Type 1, Disease Progression, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Infant, Male, Middle Aged, Obesity, Overweight, Polymorphism, Single Nucleotide, Risk Factors, Transcription Factor 7-Like 2 Protein, Young Adult, Type 1 Diabetes TrialNet Study Group, Medical and Health Sciences, Endocrinology & Metabolism, Biomedical and clinical sciences, Health sciences

الوصف: ObjectiveThe type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes.Research design and methodsWe evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried ≥1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used.ResultsDuring follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibody-positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying ≥1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age.ConclusionsThe type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.

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الوصول الحر: https://escholarship.org/uc/item/8qs5877sTest

المؤلفون: Campbell, Patrick T, VanWagner, Lisa B, Colangelo, Laura A, Lewis, Cora E, Henkel, Anne, Ajmera, Veeral H, Lloyd‐Jones, Donald M, Vaughan, Douglas E, Khan, Sadiya S

المصدر: Liver International. 40(5)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Digestive Diseases, Clinical Research, Prevention, Chronic Liver Disease and Cirrhosis, Liver Disease, Adult, Cross-Sectional Studies, Female, Humans, Male, Non-alcoholic Fatty Liver Disease, Obesity, Plasminogen Activator Inhibitor 1, Risk Factors, Young Adult, computed tomography, hepatic, metabolic syndrome, obesity, steatosis, Gastroenterology & Hepatology, Clinical sciences

الوصف: BackgroundPrior studies have demonstrated a cross-sectional association between elevated plasminogen activator inhibitor-1 (PAI-1) levels and nonalcoholic fatty liver disease (NAFLD). However, there are no prospective longitudinal assessments of the association between PAI-1 and NAFLD. We aimed to describe the association between PAI-1 levels in early adulthood with NAFLD in midlife.MethodsAmong the 5115 participants in the coronary artery risk development in young adults (CARDIA) study, participants were randomly selected from a subset that was free of obesity, diabetes and hypertension at the 1992-1993 exam and attended the 2005-2006 exam (n = 996). A subset of participants (n = 896) also had CT liver fat measured (2010-2011). Participants with secondary causes of steatosis were excluded (n = 87). NAFLD was defined as liver attenuation ≤51 Hounsfield units. Logistic regression models assessed the association between PAI-1 and NAFLD.ResultsOf 809 participants, 53% were female, 37% black with a mean age of 32 years. Median PAI-1 level at 1st assessment (1992-1993) was 23.4 ng/mL among participants with NAFLD vs 11.9 ng/mL among those without NAFLD (P

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الوصول الحر: https://escholarship.org/uc/item/3v16n0p8Test

المؤلفون: Wisel, SA, Gardner, JM, Roll, GR, Harbell, J, Freise, CE, Feng, S, Kang, SM, Hirose, R, Kaufman, DB, Posselt, AM, Stock, PG

المصدر: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 17(9)

مصطلحات موضوعية: Humans, Diabetes Mellitus, Type 1, Insulin, Immunosuppressive Agents, Prognosis, Pancreas Transplantation, Islets of Langerhans Transplantation, Risk Factors, Follow-Up Studies, Graft Rejection, Graft Survival, Adult, Middle Aged, Female, Male, Young Adult, clinical research/practice, diabetes: type 1, immunosuppressive regimens, islet transplantation, pancreas/simultaneous pancreas-kidney transplantation, patient characteristics, protocol biopsy, Kidney Disease, Diabetes, Organ Transplantation, Transplantation, Autoimmune Disease, Development of treatments and therapeutic interventions, 5.4 Surgery, Renal and urogenital, Metabolic and endocrine, Medical and Health Sciences, Surgery

الوصف: Islet transplantation offers a minimally invasive approach for β cell replacement in diabetic patients with hypoglycemic unawareness. Attempts at insulin independence may require multiple islet reinfusions from distinct donors, increasing the risk of allogeneic sensitization. Currently, solid organ pancreas transplant is the only remaining surgical option following failed islet transplantation in the United States; however, the immunologic impact of repeated exposure to donor antigens on subsequent pancreas transplantation is unclear. We describe a case series of seven patients undergoing solid organ pancreas transplant following islet graft failure with long-term follow-up of pancreatic graft survival and renal function. Despite highly variable panel reactive antibody levels prior to pancreas transplant (mean 27 ± 35%), all seven patients achieved stable and durable insulin independence with a mean follow-up of 6.7 years. Mean hemoglobin A1c values improved significantly from postislet, prepancreas levels (mean 8.1 ± 1.5%) to postpancreas levels (mean 5.3 ± 0.1%; p = 0.0022). Three patients experienced acute rejection episodes that were successfully managed with thymoglobulin and methylprednisolone, and none of these preuremic type 1 diabetic recipients developed stage 4 or 5 chronic kidney disease postoperatively. These results support pancreas-after-islet transplantation with aggressive immunosuppression and protocol biopsies as a viable strategy to restore insulin independence after islet graft failure.

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الوصول الحر: https://escholarship.org/uc/item/9gt3z474Test

المؤلفون: Chat, Vylyny, Ferguson, Robert, Simpson, Danny, Kazlow, Esther, Lax, Rebecca, Moran, Una, Pavlick, Anna, Frederick, Dennie, Boland, Genevieve, Sullivan, Ryan, Ribas, Antoni, Flaherty, Keith, Osman, Iman, Weber, Jeffrey, Kirchhoff, Tomas

المصدر: Cancer Immunology, Immunotherapy. 68(6)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Clinical Research, Clinical Trials and Supportive Activities, Autoimmune Disease, Genetics, Cancer, Prevention, Human Genome, Aetiology, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Autoimmune Diseases, Biomarkers, Tumor, CTLA-4 Antigen, Female, Genetic Predisposition to Disease, Germ Cells, Humans, Immunotherapy, Interleukin-2, Interleukins, Male, Melanoma, Middle Aged, Polymorphism, Single Nucleotide, Programmed Cell Death 1 Receptor, Risk Factors, Autoimmunity, Germline variants, Immune-checkpoint inhibition, Oncology and carcinogenesis

الوصف: Immune-checkpoint inhibition (ICI) treatments improve outcomes for metastatic melanoma; however, > 60% of treated patients do not respond to ICI. Current biomarkers do not reliably explain ICI resistance. Given the link between ICI and autoimmunity, we investigated if genetic susceptibility to autoimmunity modulates ICI efficacy. In 436 patients with metastatic melanoma receiving single line ICI or combination treatment, we tested 25 SNPs, associated with > 2 autoimmune diseases in recent genome-wide association studies, for modulation of ICI efficacy. We found that rs17388568-a risk variant for allergy, colitis and type 1 diabetes-was associated with increased anti-PD-1 response, with significance surpassing multiple testing adjustments (OR 0.26; 95% CI 0.12-0.53; p = 0.0002). This variant maps to a locus of established immune-related genes: IL2 and IL21. Our study provides first evidence that autoimmune genetic susceptibility may modulate ICI efficacy, suggesting that systematic testing of autoimmune risk loci could reveal personalized biomarkers of ICI response.

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الوصول الحر: https://escholarship.org/uc/item/7nw4z0nmTest