15 results on '"Hattersley, Andrew T."'
Search Results
2. Phenotype-based targeted treatment of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes
- Author
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Cardoso, Pedro, Young, Katie G., Nair, Anand T. N., Hopkins, Rhian, McGovern, Andrew P., Haider, Eram, Karunaratne, Piyumanga, Donnelly, Louise, Mateen, Bilal A., Sattar, Naveed, Holman, Rury R., Bowden, Jack, Hattersley, Andrew T., Pearson, Ewan R., Jones, Angus G., Shields, Beverley M., McKinley, Trevelyan J., and Dennis, John M.
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- 2024
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3. Genetic drivers of heterogeneity in type 2 diabetes pathophysiology
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Suzuki, Ken, Hatzikotoulas, Konstantinos, Southam, Lorraine, Taylor, Henry J., Yin, Xianyong, Lorenz, Kim M., Mandla, Ravi, Huerta-Chagoya, Alicia, Melloni, Giorgio E. M., Kanoni, Stavroula, Rayner, Nigel W., Bocher, Ozvan, Arruda, Ana Luiza, Sonehara, Kyuto, Namba, Shinichi, Lee, Simon S. K., Preuss, Michael H., Petty, Lauren E., Schroeder, Philip, Vanderwerff, Brett, Kals, Mart, Bragg, Fiona, Lin, Kuang, Guo, Xiuqing, Zhang, Weihua, Yao, Jie, Kim, Young Jin, Graff, Mariaelisa, Takeuchi, Fumihiko, Nano, Jana, Lamri, Amel, Nakatochi, Masahiro, Moon, Sanghoon, Scott, Robert A., Cook, James P., Lee, Jung-Jin, Pan, Ian, Taliun, Daniel, Parra, Esteban J., Chai, Jin-Fang, Bielak, Lawrence F., Tabara, Yasuharu, Hai, Yang, Thorleifsson, Gudmar, Grarup, Niels, Sofer, Tamar, Wuttke, Matthias, Sarnowski, Chloé, Gieger, Christian, Nousome, Darryl, Trompet, Stella, Kwak, Soo-Heon, Long, Jirong, Sun, Meng, Tong, Lin, Chen, Wei-Min, Nongmaithem, Suraj S., Noordam, Raymond, Lim, Victor J. Y., Tam, Claudia H. T., Joo, Yoonjung Yoonie, Chen, Chien-Hsiun, Raffield, Laura M., Prins, Bram Peter, Nicolas, Aude, Yanek, Lisa R., Chen, Guanjie, Brody, Jennifer A., Kabagambe, Edmond, An, Ping, Xiang, Anny H., Choi, Hyeok Sun, Cade, Brian E., Tan, Jingyi, Broadaway, K. Alaine, Williamson, Alice, Kamali, Zoha, Cui, Jinrui, Thangam, Manonanthini, Adair, Linda S., Adeyemo, Adebowale, Aguilar-Salinas, Carlos A., Ahluwalia, Tarunveer S., Anand, Sonia S., Bertoni, Alain, Bork-Jensen, Jette, Brandslund, Ivan, Buchanan, Thomas A., Burant, Charles F., Butterworth, Adam S., Canouil, Mickaël, Chan, Juliana C. N., Chang, Li-Ching, Chee, Miao-Li, Chen, Ji, Chen, Shyh-Huei, Chen, Yuan-Tsong, Chen, Zhengming, Chuang, Lee-Ming, Cushman, Mary, Danesh, John, Das, Swapan K., de Silva, H. Janaka, Dedoussis, George, Dimitrov, Latchezar, Doumatey, Ayo P., Du, Shufa, Duan, Qing, Eckardt, Kai-Uwe, Emery, Leslie S., Evans, Daniel S., Evans, Michele K., Fischer, Krista, Floyd, James S., Ford, Ian, Franco, Oscar H., Frayling, Timothy M., Freedman, Barry I., Genter, Pauline, Gerstein, Hertzel C., Giedraitis, Vilmantas, González-Villalpando, Clicerio, González-Villalpando, Maria Elena, Gordon-Larsen, Penny, Gross, Myron, Guare, Lindsay A., Hackinger, Sophie, Hakaste, Liisa, Han, Sohee, Hattersley, Andrew T., Herder, Christian, Horikoshi, Momoko, Howard, Annie-Green, Hsueh, Willa, Huang, Mengna, Huang, Wei, Hung, Yi-Jen, Hwang, Mi Yeong, Hwu, Chii-Min, Ichihara, Sahoko, Ikram, Mohammad Arfan, Ingelsson, Martin, Islam, Md. Tariqul, Isono, Masato, Jang, Hye-Mi, Jasmine, Farzana, Jiang, Guozhi, Jonas, Jost B., Jørgensen, Torben, Kamanu, Frederick K., Kandeel, Fouad R., Kasturiratne, Anuradhani, Katsuya, Tomohiro, Kaur, Varinderpal, Kawaguchi, Takahisa, Keaton, Jacob M., Kho, Abel N., Khor, Chiea-Chuen, Kibriya, Muhammad G., Kim, Duk-Hwan, Kronenberg, Florian, Kuusisto, Johanna, Läll, Kristi, Lange, Leslie A., Lee, Kyung Min, Lee, Myung-Shik, Lee, Nanette R., Leong, Aaron, Li, Liming, Li, Yun, Li-Gao, Ruifang, Ligthart, Symen, Lindgren, Cecilia M., Linneberg, Allan, Liu, Ching-Ti, Liu, Jianjun, Locke, Adam E., Louie, Tin, Luan, Jian’an, Luk, Andrea O., Luo, Xi, Lv, Jun, Lynch, Julie A., Lyssenko, Valeriya, Maeda, Shiro, Mamakou, Vasiliki, Mansuri, Sohail Rafik, Matsuda, Koichi, Meitinger, Thomas, Melander, Olle, Metspalu, Andres, Mo, Huan, Morris, Andrew D., Moura, Filipe A., Nadler, Jerry L., Nalls, Michael A., Nayak, Uma, Ntalla, Ioanna, Okada, Yukinori, Orozco, Lorena, Patel, Sanjay R., Patil, Snehal, Pei, Pei, Pereira, Mark A., Peters, Annette, Pirie, Fraser J., Polikowsky, Hannah G., Porneala, Bianca, Prasad, Gauri, Rasmussen-Torvik, Laura J., Reiner, Alexander P., Roden, Michael, Rohde, Rebecca, Roll, Katheryn, Sabanayagam, Charumathi, Sandow, Kevin, Sankareswaran, Alagu, Sattar, Naveed, Schönherr, Sebastian, Shahriar, Mohammad, Shen, Botong, Shi, Jinxiu, Shin, Dong Mun, Shojima, Nobuhiro, Smith, Jennifer A., So, Wing Yee, Stančáková, Alena, Steinthorsdottir, Valgerdur, Stilp, Adrienne M., Strauch, Konstantin, Taylor, Kent D., Thorand, Barbara, Thorsteinsdottir, Unnur, Tomlinson, Brian, Tran, Tam C., Tsai, Fuu-Jen, Tuomilehto, Jaakko, Tusie-Luna, Teresa, Udler, Miriam S., Valladares-Salgado, Adan, van Dam, Rob M., van Klinken, Jan B., Varma, Rohit, Wacher-Rodarte, Niels, Wheeler, Eleanor, Wickremasinghe, Ananda R., van Dijk, Ko Willems, Witte, Daniel R., Yajnik, Chittaranjan S., Yamamoto, Ken, Yamamoto, Kenichi, Yoon, Kyungheon, Yu, Canqing, Yuan, Jian-Min, Yusuf, Salim, Zawistowski, Matthew, Zhang, Liang, Zheng, Wei, Raffel, Leslie J., Igase, Michiya, Ipp, Eli, Redline, Susan, Cho, Yoon Shin, Lind, Lars, Province, Michael A., Fornage, Myriam, Hanis, Craig L., Ingelsson, Erik, Zonderman, Alan B., Psaty, Bruce M., Wang, Ya-Xing, Rotimi, Charles N., Becker, Diane M., Matsuda, Fumihiko, Liu, Yongmei, Yokota, Mitsuhiro, Kardia, Sharon L. R., Peyser, Patricia A., Pankow, James S., Engert, James C., Bonnefond, Amélie, Froguel, Philippe, Wilson, James G., Sheu, Wayne H. H., Wu, Jer-Yuarn, Hayes, M. Geoffrey, Ma, Ronald C. W., Wong, Tien-Yin, Mook-Kanamori, Dennis O., Tuomi, Tiinamaija, Chandak, Giriraj R., Collins, Francis S., Bharadwaj, Dwaipayan, Paré, Guillaume, Sale, Michèle M., Ahsan, Habibul, Motala, Ayesha A., Shu, Xiao-Ou, Park, Kyong-Soo, Jukema, J. Wouter, Cruz, Miguel, Chen, Yii-Der Ida, Rich, Stephen S., McKean-Cowdin, Roberta, Grallert, Harald, Cheng, Ching-Yu, Ghanbari, Mohsen, Tai, E-Shyong, Dupuis, Josee, Kato, Norihiro, Laakso, Markku, Köttgen, Anna, Koh, Woon-Puay, Bowden, Donald W., Palmer, Colin N. A., Kooner, Jaspal S., Kooperberg, Charles, Liu, Simin, North, Kari E., Saleheen, Danish, Hansen, Torben, Pedersen, Oluf, Wareham, Nicholas J., Lee, Juyoung, Kim, Bong-Jo, Millwood, Iona Y., Walters, Robin G., Stefansson, Kari, Ahlqvist, Emma, Goodarzi, Mark O., Mohlke, Karen L., Langenberg, Claudia, Haiman, Christopher A., Loos, Ruth J. F., Florez, Jose C., Rader, Daniel J., Ritchie, Marylyn D., Zöllner, Sebastian, Mägi, Reedik, Marston, Nicholas A., Ruff, Christian T., van Heel, David A., Finer, Sarah, Denny, Joshua C., Yamauchi, Toshimasa, Kadowaki, Takashi, Chambers, John C., Ng, Maggie C. Y., Sim, Xueling, Below, Jennifer E., Tsao, Philip S., Chang, Kyong-Mi, McCarthy, Mark I., Meigs, James B., Mahajan, Anubha, Spracklen, Cassandra N., Mercader, Josep M., Boehnke, Michael, Rotter, Jerome I., Vujkovic, Marijana, Voight, Benjamin F., Morris, Andrew P., and Zeggini, Eleftheria
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- 2024
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4. Comparison of Bayesian approaches for developing prediction models in rare disease: application to the identification of patients with Maturity-Onset Diabetes of the Young
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Cardoso, Pedro, primary, McDonald, Timothy J., additional, Patel, Kashyap A., additional, Pearson, Ewan R., additional, Hattersley, Andrew T., additional, Shields, Beverley M., additional, and McKinley, Trevelyan J., additional
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- 2024
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5. Phenotypic characterization of nonautoimmune diabetes in adult Ugandans with low body mass index
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Kibirige, Davis, primary, Sekitoleko, Isaac, additional, Lumu, William, additional, Thomas, Nihal, additional, Hawkins, Meredith, additional, Jones, Angus G., additional, Hattersley, Andrew T., additional, Smeeth, Liam, additional, and Nyirenda, Moffat J., additional
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- 2024
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6. Developmentally dynamic changes in DNA methylation in the human pancreas.
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MacCalman, Ailsa, De Franco, Elisa, Franklin, Alice, Flaxman, Christine S., Richardson, Sarah J., Murrall, Kathryn, Burrage, Joe, Walker, Emma M., Morgan, Noel G., Hattersley, Andrew T., Dempster, Emma L., Hannon, Eilis, Jeffries, Aaron R., Owens, Nick D. L., and Mill, Jonathan
- Abstract
Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across pancreas development, with > 21% of sites characterized as developmental differentially methylated positions (dDMPs) including many annotated to genes associated with monogenic diabetes. An analysis of DNA methylation in postnatal pancreas tissue showed that the dramatic temporal changes in DNA methylation occurring in the developing pancreas are largely limited to the prenatal period. Significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small proportion of sites showing sex-specific DNA methylation trajectories across pancreas development. Pancreas dDMPs were not distributed equally across the genome and were depleted in regulatory domains characterized by open chromatin and the binding of known pancreatic development transcription factors. Finally, we compared our pancreas dDMPs to previous findings from the human brain, identifying evidence for tissue-specific developmental changes in DNA methylation. This study represents the first systematic exploration of DNA methylation patterns during human fetal pancreas development and confirms the prenatal period as a time of major epigenomic plasticity. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Association of Gestational Free and Total Triiodothyronine With Gestational Hypertension, Preeclampsia, Preterm Birth, and Birth Weight: An Individual Participant Data Meta-analysis.
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Derakhshan, Arash, Männistö, Tuija, Liangmiao Chen, Osinga, Joris A. J., Ashoor, Ghalia, Xuemian Lu, Bliddal, Sofie, Fang-Biao Tao, Brown, Suzanne J., Vaidya, Bijay, Hattersley, Andrew T., Itoh, Sachiko, Popova, Polina V., Aminorroaya, Ashraf, Reiko Kishi, Kianpour, Maryam, Vasukova, Elena A., López-Bermejo, Abel, Oken, Emily, and Chatzi, Leda
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TRIIODOTHYRONINE ,HYPERTENSION in pregnancy - Published
- 2024
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8. Penetrance and expressivity of mitochondrial variants in a large clinically unselected population.
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Cannon, Stuart J, Hall, Timothy, Hawkes, Gareth, Colclough, Kevin, Boggan, Roisin M, Wright, Caroline F, Pickett, Sarah J, Hattersley, Andrew T, Weedon, Michael N, and Patel, Kashyap A
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- 2024
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9. Hyperglycaemia is a causal risk factor for upper limb pathologies.
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Green, Harry D, Burden, Ella, Chen, Ji, Evans, Jonathan, Patel, Kashyap, Wood, Andrew R, Beaumont, Robin N, Tyrrell, Jessica, Frayling, Timothy M, Hattersley, Andrew T, Oram, Richard A, Bowden, Jack, Barroso, Inês, Smith, Christopher, and Weedon, Michael N
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CARPAL tunnel syndrome ,HYPERGLYCEMIA ,MUSCULOSKELETAL system diseases ,FAT ,DIABETES complications ,GENETIC techniques - Abstract
Background Diabetes (regardless of type) and obesity are associated with a range of musculoskeletal disorders. The causal mechanisms driving these associations are unknown for many upper limb pathologies. We used genetic techniques to test the causal link between glycemia, obesity and musculoskeletal conditions. Methods In the UK Biobank's unrelated European cohort (N = 379 708) we performed mendelian randomisation (MR) analyses to test for a causal effect of long-term high glycaemia and adiposity on four musculoskeletal pathologies: frozen shoulder, Dupuytren's disease, carpal tunnel syndrome and trigger finger. We also performed single-gene MR using rare variants in the GCK gene. Results Using MR, we found evidence that long-term high glycaemia has a causal role in the aetiology of upper limb conditions. A 10-mmol/mol increase in genetically predicted haemoglobin A1C (HbA1c) was associated with frozen shoulder: odds ratio (OR) = 1.50 [95% confidence interval (CI), 1.20–1.88], Dupuytren's disease: OR = 1.17 (95% CI, 1.01–1.35), trigger finger: OR = 1.30 (95% CI, 1.09–1.55) and carpal tunnel syndrome: OR = 1.20 (95% CI, 1.09–1.33). Carriers of GCK mutations have increased odds of frozen shoulder: OR = 7.16 (95% CI, 2.93–17.51) and carpal tunnel syndrome: OR = 2.86 (95% CI, 1.50–5.44) but not Dupuytren's disease or trigger finger. We found evidence that an increase in genetically predicted body mass index (BMI) of 5 kg/m
2 was associated with carpal tunnel syndrome: OR = 1.13 (95% CI, 1.10–1.16) and associated negatively with Dupuytren's disease: OR = 0.94 (95% CI, 0.90–0.98), but no evidence of association with frozen shoulder or trigger finger. Trigger finger (OR 1.96 (95% CI, 1.42–2.69) P = 3.6e-05) and carpal tunnel syndrome [OR 1.63 (95% CI, 1.36–1.95) P = 8.5e-08] are associated with genetically predicted unfavourable adiposity increase of one standard deviation of body fat. Conclusions Our study consistently demonstrates a causal role of long-term high glycaemia in the aetiology of upper limb musculoskeletal conditions. Clinicians treating diabetes patients should be aware of these complications in clinic, specifically those managing the care of GCK mutation carriers. Upper limb musculoskeletal conditions should be considered diabetes complications. [ABSTRACT FROM AUTHOR]- Published
- 2024
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10. Integrating multiple lines of evidence to assess the effects of maternal BMI on pregnancy and perinatal outcomes.
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Borges, Maria Carolina, Clayton, Gemma L., Freathy, Rachel M., Felix, Janine F., Fernández-Sanlés, Alba, Soares, Ana Gonçalves, Kilpi, Fanny, Yang, Qian, McEachan, Rosemary R. C., Richmond, Rebecca C., Liu, Xueping, Skotte, Line, Irizar, Amaia, Hattersley, Andrew T., Bodinier, Barbara, Scholtens, Denise M., Nohr, Ellen A., Bond, Tom A., Hayes, M. Geoffrey, and West, Jane
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PREGNANCY outcomes ,NEONATAL intensive care units ,BODY mass index ,INDUCED labor (Obstetrics) ,GESTATIONAL diabetes - Abstract
Background: Higher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, whether these associations are causal remains unclear. Methods: We explored the relation of maternal pre-/early-pregnancy BMI with 20 pregnancy and perinatal outcomes by integrating evidence from three different approaches (i.e. multivariable regression, Mendelian randomisation, and paternal negative control analyses), including data from over 400,000 women. Results: All three analytical approaches supported associations of higher maternal BMI with lower odds of maternal anaemia, delivering a small-for-gestational-age baby and initiating breastfeeding, but higher odds of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, caesarean section, large-for-gestational age, high birthweight, low Apgar score at 1 min, and neonatal intensive care unit admission. For example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR = 1.67; 95% CI = 1.63, 1.70 per standard unit in BMI) and Mendelian randomisation (OR = 1.59; 95% CI = 1.38, 1.83), which was not seen for paternal BMI (OR = 1.01; 95% CI = 0.98, 1.04). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomisation. Conclusions: Our findings support a causal role for maternal pre-/early-pregnancy BMI on 14 out of 20 adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. Funding: Medical Research Council, British Heart Foundation, European Research Council, National Institutes of Health, National Institute for Health Research, Research Council of Norway, Wellcome Trust. [ABSTRACT FROM AUTHOR]
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- 2024
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11. Comment on Garvey et al. Association of Baseline Factors With Glycemic Outcomes in GRADE: A Comparative Effectiveness Randomized Clinical Trial. Diabetes Care 2024;47:562–570.
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Cardoso, Pedro, Young, Katie G., Hattersley, Andrew T., Shields, Beverley M., Jones, Angus G., and Dennis, John M.
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GLUCAGON-like peptide 1 ,TREATMENT effect heterogeneity ,SODIUM-glucose cotransporter 2 inhibitors ,TYPE 2 diabetes ,CD26 antigen - Abstract
The article discusses a recent analysis of the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) randomized controlled trial. The study compares the glycemic outcomes of four commonly used drug classes for type 2 diabetes: sulfonylureas, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon-like peptide 1 receptor agonists (GLP-1RA), and insulin. The findings indicate that there is differential glycemic response among these drug classes, with sex and age being identified as important factors in treatment effectiveness. The article also addresses some points of clarification regarding the study's findings. Overall, the study contributes to the growing evidence of treatment effect heterogeneity in noninsulin type 2 diabetes therapies. [Extracted from the article]
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- 2024
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12. Human inherited PD-L1 deficiency is clinically and immunologically less severe than PD-1 deficiency
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Johnson, Matthew B., Ogishi, Masato, Domingo-Vila, Clara, De Franco, Elisa, Wakeling, Matthew N., Imane, Zineb, Resnick, Brittany, Williams, Evangelia, Galão, Rui Pedro, Caswell, Richard, Russ-Silsby, James, Seeleuthner, Yoann, Rinchai, Darawan, Fagniez, Iris, Benson, Basilin, Dufort, Matthew J., Speake, Cate, Smithmyer, Megan E., Hudson, Michelle, Dobbs, Rebecca, Quandt, Zoe, Hattersley, Andrew T., Zhang, Peng, Boisson-Dupuis, Stephanie, Anderson, Mark S., Casanova, Jean-Laurent, Tree, Timothy I., and Oram, Richard A.
- Abstract
We previously reported two siblings with inherited PD-1 deficiency who died from autoimmune pneumonitis at 3 and 11 years of age after developing other autoimmune manifestations, including type 1 diabetes (T1D). We report here two siblings, aged 10 and 11 years, with neonatal-onset T1D (diagnosed at the ages of 1 day and 7 wk), who are homozygous for a splice-site variant of CD274 (encoding PD-L1). This variant results in the exclusive expression of an alternative, loss-of-function PD-L1 protein isoform in overexpression experiments and in the patients’ primary leukocytes. Surprisingly, cytometric immunophenotyping and single-cell RNA sequencing analysis on blood leukocytes showed largely normal development and transcriptional profiles across lymphoid and myeloid subsets in the PD-L1-deficient siblings, contrasting with the extensive dysregulation of both lymphoid and myeloid leukocyte compartments in PD-1 deficiency. Our findings suggest that PD-1 and PD-L1 are essential for preventing early-onset T1D but that, unlike PD-1 deficiency, PD-L1 deficiency does not lead to fatal autoimmunity with extensive leukocytic dysregulation.
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- 2024
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13. Ethnic differences in the manifestation of early-onset type 2 diabetes.
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Kibirige D, Katte JC, Hill AV, Sekitoleko I, Lumu W, Knupp J, Squires S, Hattersley AT, Smeeth L, Jones AG, and Nyirenda MJ
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- Humans, Female, Male, Adult, Middle Aged, Black People statistics & numerical data, Uganda epidemiology, Body Mass Index, Cohort Studies, Follow-Up Studies, Prognosis, Ethnicity statistics & numerical data, Risk Factors, Biomarkers analysis, Waist Circumference, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 ethnology, Diabetes Mellitus, Type 2 pathology, Age of Onset, White People statistics & numerical data
- Abstract
Introduction: We undertook phenotypic characterization of early-onset and late-onset type 2 diabetes (T2D) in adult black African and white European populations with recently diagnosed T2D to explore ethnic differences in the manifestation of early-onset T2D., Research Design and Methods: Using the Uganda Diabetes Phenotype study cohort of 500 adult Ugandans and the UK StartRight study cohort of 714 white Europeans with recently diagnosed islet autoantibody-negative T2D, we compared the phenotypic characteristics of participants with early-onset T2D (diagnosed at <40 years) and late-onset T2D (diagnosed at ≥40 years)., Results: One hundred and thirty-four adult Ugandans and 113 white Europeans had early-onset T2D. Compared with late-onset T2D, early-onset T2D in white Europeans was significantly associated with a female predominance (52.2% vs 39.1%, p=0.01), increased body mass index (mean (95% CI) 36.7 (35.2-38.1) kg/m
2 vs 33.0 (32.4-33.6) kg/m2 , p<0.001), waist circumference (112.4 (109.1-115.6) cm vs 108.8 (107.6-110.1) cm, p=0.06), and a higher frequency of obesity (82.3% vs 63.4%, p<0.001). No difference was seen with the post-meal C-peptide levels as a marker of beta-cell function (mean (95% CI) 2130.94 (1905.12-2356.76) pmol/L vs 2039.72 (1956.52-2122.92), p=0.62).In contrast, early-onset T2D in Ugandans was associated with less adiposity (mean (95% CI) waist circumference 93.1 (89.9-96.3) cm vs 97.4 (95.9-98.8) cm, p=0.006) and a greater degree of beta-cell dysfunction (120 min post-glucose load C-peptide mean (95% CI) level 896.08 (780.91-1011.24) pmol/L vs 1310.10 (1179.24-1440.95) pmol/L, p<0.001), without female predominance (53.0% vs 57.9%, p=0.32) and differences in the body mass index (mean (95% CI) 27.3 (26.2-28.4) kg/m2 vs 27.9 (27.3-28.5) kg/m2 , p=0.29)., Conclusions: These differences in the manifestation of early-onset T2D underscore the need for ethnic-specific and population-specific therapeutic and preventive approaches for the condition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2024
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14. Precision treatment of beta-cell monogenic diabetes: a systematic review.
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Naylor RN, Patel KA, Kettunen JLT, Männistö JME, Støy J, Beltrand J, Polak M, Vilsbøll T, Greeley SAW, Hattersley AT, and Tuomi T
- Abstract
Background: Beta-cell monogenic forms of diabetes have strong support for precision medicine. We systematically analyzed evidence for precision treatments for GCK-related hyperglycemia, HNF1A-, HNF4A- and HNF1B-diabetes, and mitochondrial diabetes (MD) due to m.3243 A > G variant, 6q24-transient neonatal diabetes mellitus (TND) and SLC19A2-diabetes., Methods: The search of PubMed, MEDLINE, and Embase for individual and group level data for glycemic outcomes using inclusion (English, original articles written after 1992) and exclusion (VUS, multiple diabetes types, absent/aggregated treatment effect measures) criteria. The risk of bias was assessed using NHLBI study-quality assessment tools. Data extracted from Covidence were summarized and presented as descriptive statistics in tables and text., Results: There are 146 studies included, with only six being experimental studies. For GCK-related hyperglycemia, the six studies (35 individuals) assessing therapy discontinuation show no HbA1c deterioration. A randomized trial (18 individuals per group) shows that sulfonylureas (SU) were more effective in HNF1A-diabetes than in type 2 diabetes. Cohort and case studies support SU's effectiveness in lowering HbA1c. Two cross-over trials (each with 15-16 individuals) suggest glinides and GLP-1 receptor agonists might be used in place of SU. Evidence for HNF4A-diabetes is limited. Most reported patients with HNF1B-diabetes (N = 293) and MD (N = 233) are on insulin without treatment studies. Limited data support oral agents after relapse in 6q24-TND and for thiamine improving glycemic control and reducing/eliminating insulin requirement in SLC19A2-diabetes., Conclusion: There is limited evidence, and with moderate or serious risk of bias, to guide monogenic diabetes treatment. Further evidence is needed to examine the optimum treatment in monogenic subtypes., (© 2024. The Author(s).)
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- 2024
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15. Rare variant associations with birth weight identify genes involved in adipose tissue regulation, placental function and insulin-like growth factor signalling.
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Kentistou KA, Lim BEM, Kaisinger LR, Steinthorsdottir V, Sharp LN, Patel KA, Tragante V, Hawkes G, Gardner EJ, Olafsdottir T, Wood AR, Zhao Y, Thorleifsson G, Day FR, Ozanne SE, Hattersley AT, O'Rahilly S, Stefansson K, Ong KK, Beaumont RN, Perry JRB, and Freathy RM
- Abstract
Investigating the genetic factors influencing human birth weight may lead to biological insights into fetal growth and long-term health. Genome-wide association studies of birth weight have highlighted associated variants in more than 200 regions of the genome, but the causal genes are mostly unknown. Rare genetic variants with robust evidence of association are more likely to point to causal genes, but to date, only a few rare variants are known to influence birth weight. We aimed to identify genes that harbour rare variants that impact birth weight when carried by either the fetus or the mother, by analysing whole exome sequence data in UK Biobank participants. We annotated rare (minor allele frequency <0.1%) protein-truncating or high impact missense variants on whole exome sequence data in up to 234,675 participants with data on their own birth weight (fetal variants), and up to 181,883 mothers who reported the birth weight of their first child (maternal variants). Variants within each gene were collapsed to perform gene burden tests and for each associated gene, we compared the observed fetal and maternal effects. We identified 8 genes with evidence of rare fetal variant effects on birth weight, of which 2 also showed maternal effects. One additional gene showed evidence of maternal effects only. We observed 10/11 directionally concordant associations in an independent sample of up to 45,622 individuals (sign test P =0.01). Of the genes identified, IGF1R and PAPPA2 (fetal and maternal-acting) have known roles in insulin-like growth factor bioavailability and signalling. PPARG, INHBE and ACVR1C (all fetal-acting) have known roles in adipose tissue regulation and rare variants in the latter two also showed associations with favourable adiposity patterns in adults. We highlight the dual role of PPARG in both adipocyte differentiation and placental angiogenesis. NOS3, NRK, and ADAMTS8 (fetal and maternal-acting) have been implicated in both placental function and hypertension. Analysis of rare coding variants has identified regulators of fetal adipose tissue and fetoplacental angiogenesis as determinants of birth weight, as well as further evidence for the role of insulin-like growth factors., Competing Interests: Competing interests J.R.B.P. and E.J.G. are employees/shareholders of Insmed. J.R.B.P. also receives research funding from GSK. Y.Z. is a UK University worker at GSK. S.O. has undertaken remunerated consultancy work for Pfizer, Third Rock Ventures, AstraZeneca, NorthSea Therapeutics and Courage Therapeutics. V.S., V.T., T.O., G.T., and K.S. are employees of deCODE genetics, a subsidiary of Amgen.
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- 2024
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