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1. Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Author

Jannik Boos, Caspar I. van der Made, Gayatri Ramakrishnan, Eamon Coughlan, Rosanna Asselta, Britt-Sabina Löscher, Luca V.C. Valenti, Rafael de Cid, Luis Bujanda, Antonio Julià, Erola Pairo-Castineira, J. Kenneth Baillie, Sandra May, Berina Zametica, Julia Heggemann, Agustín Albillos, Jesus M. Banales, Jordi Barretina, Natalia Blay, Paolo Bonfanti, Maria Buti, Javier Fernandez, Sara Marsal, Daniele Prati, Luisa Ronzoni, Nicoletta Sacchi, Joachim L. Schultze, Olaf Riess, Andre Franke, Konrad Rawlik, David Ellinghaus, Alexander Hoischen, Axel Schmidt, Kerstin U. Ludwig, Valeria Rimoldi, Elvezia M. Paraboschi, Alessandra Bandera, Flora Peyvandi, Giacomo Grasselli, Francesco Blasi, Francesco Malvestiti, Serena Pelusi, Cristiana Bianco, Lorenzo Miano, Angela Lombardi, Pietro Invernizzi, Alessio Gerussi, Giuseppe Citerio, Andrea Biondi, Maria Grazia Valsecchi, Marina Elena Cazzaniga, Giuseppe Foti, Ilaria Beretta, Mariella D'Angiò, Laura Rachele Bettini, Xavier Farré, Susana Iraola-Guzmán, Manolis Kogevinas, Gemma Castaño-Vinyals, Koldo Garcia-Etxebarria, Beatriz Nafria, Mauro D'Amato, Adriana Palom, Colin Begg, Sara Clohisey, Charles Hinds, Peter Horby, Julian Knight, Lowell Ling, David Maslove, Danny McAuley, Johnny Millar, Hugh Montgomery, Alistair Nichol, Peter J.M. Openshaw, Alexandre C. Pereira, Chris P. Ponting, Kathy Rowan, Malcolm G. Semple, Manu Shankar-Hari, Charlotte Summers, Timothy Walsh, Latha Aravindan, Ruth Armstrong, Heather Biggs, Ceilia Boz, Adam Brown, Richard Clark, Audrey Coutts, Judy Coyle, Louise Cullum, Sukamal Das, Nicky Day, Lorna Donnelly, Esther Duncan, Angie Fawkes, Paul Fineran, Max Head Fourman, Anita Furlong, James Furniss, Bernadette Gallagher, Tammy Gilchrist, Ailsa Golightly, Fiona Griffiths, Katarzyna Hafezi, Debbie Hamilton, Ross Hendry, Andy Law, Dawn Law, Rachel Law, Sarah Law, Rebecca Lidstone-Scott, Louise Macgillivray, Alan Maclean, Hanning Mal, Sarah McCafferty, Ellie Mcmaster, Jen Meikle, Shona C. Moore, Kirstie Morrice, Lee Murphy, Sheena Murphy, Mybaya Hellen, Wilna Oosthuyzen, Chenqing Zheng, Jiantao Chen, Nick Parkinson, Trevor Paterson, Katherine Schon, Andrew Stenhouse, Mihaela Das, Maaike Swets, Helen Szoor-McElhinney, Filip Taneski, Lance Turtle, Tony Wackett, Mairi Ward, Jane Weaver, Nicola Wrobel, Marie Zechner, Gill Arbane, Aneta Bociek, Sara Campos, Neus Grau, Tim Owen Jones, Rosario Lim, Martina Marotti, Marlies Ostermann, Christopher Whitton, Zoe Alldis, Raine Astin-Chamberlain, Fatima Bibi, Jack Biddle, Sarah Blow, Matthew Bolton, Catherine Borra, Ruth Bowles, Maudrian Burton, Yasmin Choudhury, David Collier, Amber Cox, Amy Easthope, Patrizia Ebano, Stavros Fotiadis, Jana Gurasashvili, Rosslyn Halls, Pippa Hartridge, Delordson Kallon, Jamila Kassam, Ivone Lancoma-Malcolm, Maninderpal Matharu, Peter May, Oliver Mitchelmore, Tabitha Newman, Mital Patel, Jane Pheby, Irene Pinzuti, Zoe Prime, Oleksandra Prysyazhna, Julian Shiel, Melanie Taylor, Carey Tierney, Suzanne Wood, Anne Zak, Olivier Zongo, Stephen Bonner, Keith Hugill, Jessica Jones, Steven Liggett, Evie Headlam, Nageswar Bandla, Minnie Gellamucho, Michelle Davies, Christopher Thompson, Marwa Abdelrazik, Dhanalakshmi Bakthavatsalam, Munzir Elhassan, Arunkumar Ganesan, Anne Haldeos, Jeronimo Moreno-Cuesta, Dharam Purohit, Rachel Vincent, Kugan Xavier, Kumar Rohit, Frater Alasdair, Malik Saleem, Carter David, Jenkins Samuel, Zoe Lamond, Wall Alanna, Jaime Fernandez-Roman, David O. Hamilton, Emily Johnson, Brian Johnston, Maria Lopez Martinez, Suleman Mulla, David Shaw, Alicia A.C. Waite, Victoria Waugh, Ingeborg D. Welters, Karen Williams, Anna Cavazza, Maeve Cockrell, Eleanor Corcoran, Maria Depante, Clare Finney, Ellen Jerome, Mark McPhail, Monalisa Nayak, Harriet Noble, Kevin O'Reilly, Evita Pappa, Rohit Saha, Sian Saha, John Smith, Abigail Knighton, David Antcliffe, Dorota Banach, Stephen Brett, Phoebe Coghlan, Ziortza Fernandez, Anthony Gordon, Roceld Rojo, Sonia Sousa Arias, Maie Templeton, Megan Meredith, Lucy Morris, Lucy Ryan, Amy Clark, Julia Sampson, Cecilia Peters, Martin Dent, Margaret Langley, Saima Ashraf, Shuying Wei, Angela Andrew, Archana Bashyal, Neil Davidson, Paula Hutton, Stuart McKechnie, Jean Wilson, David Baptista, Rebecca Crowe, Rita Fernandes, Rosaleen Herdman-Grant, Anna Joseph, Denise O'Connor, Meryem Allen, Adam Loveridge, India McKenley, Eriko Morino, Andres Naranjo, Richard Simms, Kathryn Sollesta, Andrew Swain, Harish Venkatesh, Jacyntha Khera, Jonathan Fox, Gillian Andrew, Lucy Barclay, Marie Callaghan, Rachael Campbell, Sarah Clark, Dave Hope, Lucy Marshall, Corrienne McCulloch, Kate Briton, Jo Singleton, Sohphie Birch, Lutece Brimfield, Zoe Daly, David Pogson, Steve Rose, Ceri Battle, Elaine Brinkworth, Rachel Harford, Carl Murphy, Luke Newey, Tabitha Rees, Marie Williams, Sophie Arnold, Petra Polgarova, Katerina Stroud, Eoghan Meaney, Megan Jones, Anthony Ng, Shruti Agrawal, Nazima Pathan, Deborah White, Esther Daubney, Kay Elston, Lina Grauslyte, Musarat Hussain, Mandeep Phull, Tatiana Pogreban, Lace Rosaroso, Erika Salciute, George Franke, Joanna Wong, Aparna George, Laura Ortiz-Ruiz de Gordoa, Emily Peasgood, Claire Phillips, Michelle Bates, Jo Dasgin, Jaspret Gill, Annette Nilsson, James Scriven, Carlos Castro Delgado, Deborah Dawson, Lijun Ding, Georgia Durrant, Obiageri Ezeobu, Sarah Farnell-Ward, Abiola Harrison, Rebecca Kanu, Susannah Leaver, Elena Maccacari, Soumendu Manna, Romina Pepermans Saluzzio, Joana Queiroz, Tinashe Samakomva, Christine Sicat, Joana Texeira, Edna Fernandes Da Gloria, Ana Lisboa, John Rawlins, Jisha Mathew, Ashley Kinch, William James Hurt, Nirav Shah, Victoria Clark, Maria Thanasi, Nikki Yun, Kamal Patel, Sara Bennett, Emma Goodwin, Matthew Jackson, Alissa Kent, Clare Tibke, Wiesia Woodyatt, Ahmed Zaki, Azmerelda Abraheem, Peter Bamford, Kathryn Cawley, Charlie Dunmore, Maria Faulkner, Rumanah Girach, Helen Jeffrey, Rhianna Jones, Emily London, Imrun Nagra, Farah Nasir, Hannah Sainsbury, Clare Smedley, Tahera Patel, Matthew Smith, Srikanth Chukkambotla, Aayesha Kazi, Janice Hartley, Joseph Dykes, Muhammad Hijazi, Sarah Keith, Meherunnisa Khan, Janet Ryan-Smith, Philippa Springle, Jacqueline Thomas, Nick Truman, Samuel Saad, Dabheoc Coleman, Christopher Fine, Roseanna Matt, Bethan Gay, Jack Dalziel, Syamlan Ali, Drew Goodchild, Rhiannan Harling, Ravi Bhatterjee, Wendy Goddard, Chloe Davison, Stephen Duberly, Jeanette Hargreaves, Rachel Bolton, Miriam Davey, David Golden, Rebecca Seaman, Shiney Cherian, Sean Cutler, Anne Emma Heron, Anna Roynon-Reed, Tamas Szakmany, Gemma Williams, Owen Richards, Yusuf Cheema, Hollie Brooke, Sarah Buckley, Jose Cebrian Suarez, Ruth Charlesworth, Karen Hansson, John Norris, Alice Poole, Alastair Rose, Rajdeep Sandhu, Brendan Sloan, Elizabeth Smithson, Muthu Thirumaran, Veronica Wagstaff, Alexandra Metcalfe, Mark Brunton, Jess Caterson, Holly Coles, Matthew Frise, Sabi Gurung Rai, Nicola Jacques, Liza Keating, Emma Tilney, Shauna Bartley, Parminder Bhuie, Sian Gibson, Amanda Lyle, Fiona McNeela, Jayachandran Radhakrishnan, Alistair Hughes, Bryan Yates, Jessica Reynolds, Helen Campbell, Maria Thompsom, Steve Dodds, Stacey Duffy, Sandra Greer, Karen Shuker, Ascanio Tridente, Reena Khade, Ashok Sundar, George Tsinaslanidis, Isobel Birkinshaw, Joseph Carter, Kate Howard, Joanne Ingham, Rosie Joy, Harriet Pearson, Samantha Roche, Zoe Scott, Hollie Bancroft, Mary Bellamy, Margaret Carmody, Jacqueline Daglish, Faye Moore, Joanne Rhodes, Mirriam Sangombe, Salma Kadiri, Maria Croft, Ian White, Victoria Frost, Maia Aquino, Rajeev Jha, Vinodh Krishnamurthy, Lai Lim, Li Lim, Edward Combes, Teishel Joefield, Sonja Monnery, Valerie Beech, Sallyanne Trotman, Christine Almaden-Boyle, Pauline Austin, Louise Cabrelli, Stephen Cole, Matt Casey, Susan Chapman, Clare Whyte, Yolanda Baird, Aaron Butler, Indra Chadbourn, Linda Folkes, Heather Fox, Amy Gardner, Raquel Gomez, Gillian Hobden, Luke Hodgson, Kirsten King, Michael Margarson, Tim Martindale, Emma Meadows, Dana Raynard, Yvette Thirlwall, David Helm, Jordi Margalef, Kristine Criste, Rebecca Cusack, Kim Golder, Hannah Golding, Oliver Jones, Samantha Leggett, Michelle Male, Martyna Marani, Kirsty Prager, Toran Williams, Belinda Roberts, Karen Salmon, Peter Anderson, Katie Archer, Karen Austin, Caroline Davis, Alison Durie, Olivia Kelsall, Jessica Thrush, Charlie Vigurs, Laura Wild, Hannah-Louise Wood, Helen Tranter, Alison Harrison, Nicholas Cowley, Michael McAlindon, Andrew Burtenshaw, Stephen Digby, Emma Low, Aled Morgan, Naiara Cother, Tobias Rankin, Sarah Clayton, Alex McCurdy, Cecilia Ahmed, Balvinder Baines, Sarah Clamp, Julie Colley, Risna Haq, Anne Hayes, Jonathan Hulme, Samia Hussain, Sibet Joseph, Rita Kumar, Zahira Maqsood, Manjit Purewal, Leonie Benham, Zena Bradshaw, Joanna Brown, Melanie Caswell, Jason Cupitt, Sarah Melling, Stephen Preston, Nicola Slawson, Emma Stoddard, Scott Warden, Bethan Deacon, Ceri Lynch, Carla Pothecary, Lisa Roche, Gwenllian Sera Howe, Jayaprakash Singh, Keri Turner, Hannah Ellis, Natalie Stroud, Jodie Hunt, Joy Dearden, Emma Dobson, Andy Drummond, Michelle Mulcahy, Sheila Munt, Grainne O'Connor, Jennifer Philbin, Chloe Rishton, Redmond Tully, Sarah Winnard, Susanne Cathcart, Katharine Duffy, Alex Puxty, Kathryn Puxty, Lynne Turner, Jane Ireland, Gary Semple, Kate Long, Simon Whiteley, Elizabeth Wilby, Bethan Ogg, Amanda Cowton, Andrea Kay, Melanie Kent, Kathryn Potts, Ami Wilkinson, Suzanne Campbell, Ellen Brown, Julie Melville, Jay Naisbitt, Rosane Joseph, Maria Lazo, Olivia Walton, Alan Neal, Peter Alexander, Schvearn Allen, Joanne Bradley-Potts, Craig Brantwood, Jasmine Egan, Timothy Felton, Grace Padden, Luke Ward, Stuart Moss, Susannah Glasgow, Lynn Abel, Michael Brett, Brian Digby, Lisa Gemmell, James Hornsby, Patrick MacGoey, Pauline O'Neil, Richard Price, Natalie Rodden, Kevin Rooney, Radha Sundaram, Nicola Thomson, Bridget Hopkins, Laura Thrasyvoulou, Heather Willis, Martyn Clark, Martina Coulding, Edward Jude, Jacqueline McCormick, Oliver Mercer, Darsh Potla, Hafiz Rehman, Heather Savill, Victoria Turner, Charlotte Downes, Kathleen Holding, Katie Riches, Mary Hilton, Mel Hayman, Deepak Subramanian, Priya Daniel, Oluronke Adanini, Nikhil Bhatia, Maines Msiska, Rebecca Collins, Ian Clement, Bijal Patel, A. Gulati, Carole Hays, K. Webster, Anne Hudson, Andrea Webster, Elaine Stephenson, Louise McCormack, Victoria Slater, Rachel Nixon, Helen Hanson, Maggie Fearby, Sinead Kelly, Victoria Bridgett, Philip Robinson, Julie Camsooksai, Charlotte Humphrey, Sarah Jenkins, Henrik Reschreiter, Beverley Wadams, Yasmin Death, Victoria Bastion, Daphene Clarke, Beena David, Harriet Kent, Rachel Lorusso, Gamu Lubimbi, Sophie Murdoch, Melchizedek Penacerrada, Alastair Thomas, Jennifer Valentine, Ana Vochin, Retno Wulandari, Brice Djeugam, Gillian Bell, Katy English, Amro Katary, Louise Wilcox, Michelle Bruce, Karen Connolly, Tracy Duncan, Helen T-Michael, Gabriella Lindergard, Samuel Hey, Claire Fox, Jordan Alfonso, Laura Jayne Durrans, Jacinta Guerin, Bethan Blackledge, Jade Harris, Martin Hruska, Ayaa Eltayeb, Thomas Lamb, Tracey Hodgkiss, Lisa Cooper, Joanne Rothwell, Angela Allan, Felicity Anderson, Callum Kaye, Jade Liew, Jasmine Medhora, Teresa Scott, Erin Trumper, Adriana Botello, Liana Lankester, Nikitas Nikitas, Colin Wells, Bethan Stowe, Kayleigh Spencer, Craig Brandwood, Lara Smith, Katie Birchall, Laurel Kolakaluri, Deborah Baines, Anila Sukumaran, Elena Apetri, Cathrine Basikolo, Laura Catlow, Bethan Charles, Paul Dark, Reece Doonan, Alice Harvey, Daniel Horner, Karen Knowles, Stephanie Lee, Diane Lomas, Chloe Lyons, Tracy Marsden, Danielle McLaughlan, Liam McMorrow, Jessica Pendlebury, Jane Perez, Maria Poulaka, Nicola Proudfoot, Melanie Slaughter, Kathryn Slevin, Vicky Thomas, Danielle Walker, Angiy Michael, Matthew Collis, Tracey Cosier, Gemma Millen, Neil Richardson, Natasha Schumacher, Heather Weston, James Rand, Nicola Baxter, Steven Henderson, Sophie Kennedy-Hay, Christopher McParland, Laura Rooney, Malcolm Sim, Gordan McCreath, Louise Akeroyd, Shereen Bano, Matt Bromley, Lucy Gurr, Tom Lawton, James Morgan, Kirsten Sellick, Deborah Warren, Brian Wilkinson, Janet McGowan, Camilla Ledgard, Amelia Stacey, Kate Pye, Ruth Bellwood, Michael Bentley, Jeremy Bewley, Zoe Garland, Lisa Grimmer, Bethany Gumbrill, Rebekah Johnson, Katie Sweet, Denise Webster, Georgia Efford, Karen Convery, Deirdre Fottrell-Gould, Lisa Hudig, Jocelyn Keshet-Price, Georgina Randell, Katie Stammers, Maria Bokhari, Vanessa Linnett, Rachael Lucas, Wendy McCormick, Jenny Ritzema, Amanda Sanderson, Helen Wild, Anthony Rostron, Alistair Roy, Lindsey Woods, Sarah Cornell, Fiona Wakinshaw, Kimberley Rogerson, Jordan Jarmain, Robert Parker, Amie Reddy, Ian Turner-Bone, Laura Wilding, Peter Harding, Caroline Abernathy, Louise Foster, Andrew Gratrix, Vicky Martinson, Priyai Parkinson, Elizabeth Stones, Llucia Carbral-Ortega, Georgia Bercades, David Brealey, Ingrid Hass, Niall MacCallum, Gladys Martir, Eamon Raith, Anna Reyes, Deborah Smyth, Letizia Zitter, Sarah Benyon, Suzie Marriott, Linda Park, Samantha Keenan, Elizabeth Gordon, Helen Quinn, Kizzy Baines, Lenka Cagova, Adama Fofano, Lucie Garner, Helen Holcombe, Sue Mepham, Alice Michael Mitchell, Lucy Mwaura, Krithivasan Praman, Alain Vuylsteke, Julie Zamikula, Bally Purewal, Vanessa Rivers, Stephanie Bell, Hayley Blakemore, Borislava Borislavova, Beverley Faulkner, Emma Gendall, Elizabeth Goff, Kati Hayes, Matt Thomas, Ruth Worner, Kerry Smith, Deanna Stephens, Louise Mew, Esther Mwaura, Richard Stewart, Felicity Williams, Lynn Wren, Sara-Beth Sutherland, Emily Bevan, Jane Martin, Dawn Trodd, Geoff Watson, Caroline Wrey Brown, Amy Collins, Waqas Khaliq, Estefania Treus Gude, Olugbenga Akinkugbe, Alasdair Bamford, Emily Beech, Holly Belfield, Michael Bell, Charlene Davies, Gareth A.L. Jones, Tara McHugh, Hamza Meghari, Lauran O'Neill, Mark J. Peters, Samiran Ray, Ana Luisa Tomas, Iona Burn, Geraldine Hambrook, Katarina Manso, Ruth Penn, Pradeep Shanmugasundaram, Julie Tebbutt, Danielle Thornton, Jade Cole, Rhys Davies, Donna Duffin, Helen Hill, Ben Player, Emma Thomas, Angharad Williams, Denise Griffin, Nycola Muchenje, Mcdonald Mupudzi, Richard Partridge, Jo-Anna Conyngham, Rachel Thomas, Mary Wright, Maria Alvarez Corral, Reni Jacob, Cathy Jones, Craig Denmade, Sarah Beavis, Katie Dale, Rachel Gascoyne, Joanne Hawes, Kelly Pritchard, Lesley Stevenson, Amanda Whileman, Patricia Doble, Joanne Hutter, Corinne Pawley, Charmaine Shovelton, Marius Vaida, Deborah Butcher, Susie O'Sullivan, Nicola Butterworth-Cowin, Norfaizan Ahmad, Joann Barker, Kris Bauchmuller, Sarah Bird, Kay Cawthron, Kate Harrington, Yvonne Jackson, Faith Kibutu, Becky Lenagh, Shamiso Masuko, Gary H. Mills, Ajay Raithatha, Matthew Wiles, Jayne Willson, Helen Newell, Alison Lye, Lorenza Nwafor, Claire Jarman, Sarah Rowland-Jones, David Foote, Joby Cole, Roger Thompson, James Watson, Lisa Hesseldon, Irene Macharia, Luke Chetam, Jacqui Smith, Amber Ford, Samantha Anderson, Kathryn Birchall, Kay Housley, Sara Walker, Leanne Milner, Helena Hanratty, Helen Trower, Patrick Phillips, Simon Oxspring, Ben Donne, Catherine Jardine, Dewi Williams, Alasdair Hay, Rebecca Flanagan, Gareth Hughes, Scott Latham, Emma McKenna, Jennifer Anderson, Robert Hull, Kat Rhead, Carina Cruz, Natalie Pattison, Rob Charnock, Denise McFarland, Denise Cosgrove, Ashar Ahmed, Anna Morris, Srinivas Jakkula, Asifa Ali, Megan Brady, Sam Dale, Annalisa Dance, Lisa Gledhill, Jill Greig, Kathryn Hanson, Kelly Holdroyd, Marie Home, Diane Kelly, Ross Kitson, Lear Matapure, Deborah Melia, Samantha Mellor, Tonicha Nortcliffe, Jez Pinnell, Matthew Robinson, Lisa Shaw, Ryan Shaw, Lesley Thomis, Alison Wilson, Tracy Wood, Lee-Ann Bayo, Ekta Merwaha, Tahira Ishaq, Sarah Hanley, Meg Hibbert, Dariusz Tetla, Chrsitopher Woodford, Latha Durga, Gareth Kennard-Holden, Debbie Branney, Jordan Frankham, Sally Pitts, Nigel White, Shondipon Laha, Mark Verlander, Alexandra Williams, Abdelhakim Altabaibeh, Ana Alvaro, Kayleigh Gilbert, Louise Ma, Loreta Mostoles, Chetan Parmar, Kathryn Simpson, Champa Jetha, Lauren Booker, Anezka Pratley, Colene Adams, Anita Agasou, Tracie Arden, Amy Bowes, Pauline Boyle, Mandy Beekes, Heather Button, Nigel Capps, Mandy Carnahan, Anne Carter, Danielle Childs, Denise Donaldson, Kelly Hard, Fran Hurford, Yasmin Hussain, Ayesha Javaid, James Jones, Sanal Jose, Michael Leigh, Terry Martin, Helen Millward, Nichola Motherwell, Rachel Rikunenko, Jo Stickley, Julie Summers, Louise Ting, Helen Tivenan, Louise Tonks, Rebecca Wilcox, Maureen Holland, Natalie Keenan, Marc Lyons, Helen Wassall, Chris Marsh, Mervin Mahenthran, Emma Carter, Thomas Kong, Helen Blackman, Ben Creagh-Brown, Sinead Donlon, Natalia Michalak-Glinska, Sheila Mtuwa, Veronika Pristopan, Armorel Salberg, Eleanor Smith, Sarah Stone, Charles Piercy, Jerik Verula, Dorota Burda, Rugia Montaser, Lesley Harden, Irving Mayangao, Cheryl Marriott, Paul Bradley, Celia Harris, Susan Anderson, Eleanor Andrews, Janine Birch, Emma Collins, Kate Hammerton, Ryan O'Leary, Michele Clark, Sarah Purvis, Russell Barber, Claire Hewitt, Annette Hilldrith, Karen Jackson-Lawrence, Sarah Shepardson, Maryanne Wills, Susan Butler, Silvia Tavares, Amy Cunningham, Julia Hindale, Sarwat Arif, Sarah Bean, Karen Burt, Michael Spivey, Carrie Demetriou, Charlotte Eckbad, Sarah Hierons, Lucy Howie, Sarah Mitchard, Lidia Ramos, Alfredo Serrano-Ruiz, Katie White, Fiona Kelly, Daniele Cristiano, Natalie Dormand, Zohreh Farzad, Mahitha Gummadi, Kamal Liyanage, Brijesh Patel, Sara Salmi, Geraldine Sloane, Vicky Thwaites, Mathew Varghese, Anelise C. Zborowski, John Allan, Tim Geary, Gordon Houston, Alistair Meikle, Peter O'Brien, Miranda Forsey, Agilan Kaliappan, Anne Nicholson, Joanne Riches, Mark Vertue, Elizabeth Allan, Kate Darlington, Ffyon Davies, Jack Easton, Sumit Kumar, Richard Lean, Daniel Menzies, Richard Pugh, Xinyi Qiu, Llinos Davies, Hannah Williams, Jeremy Scanlon, Gwyneth Davies, Callum Mackay, Joannne Lewis, Stephanie Rees, Metod Oblak, Monica Popescu, Mini Thankachen, Andrew Higham, Kerry Simpson, Jayne Craig, Rosie Baruah, Sheila Morris, Susie Ferguson, Amy Shepherd, Luke Stephen Prockter Moore, Marcela Paola Vizcaychipi, Laura Gomes de Almeida Martins, Jaime Carungcong, Inthakab Ali Mohamed Ali, Karen Beaumont, Mark Blunt, Zoe Coton, Hollie Curgenven, Mohamed Elsaadany, Kay Fernandes, Sameena Mohamed Ally, Harini Rangarajan, Varun Sarathy, Sivarupan Selvanayagam, Dave Vedage, Matthew White, Mandy Gill, Paul Paul, Valli Ratnam, Sarah Shelton, Inez Wynter, Siobhain Carmody, Valerie Joan Page, Claire Marie Beith, Karen Black, Suzanne Clements, Alan Morrison, Dominic Strachan, Margaret Taylor, Michelle Clarkson, Stuart D'Sylva, Kathryn Norman, Fiona Auld, Joanne Donnachie, Ian Edmond, Lynn Prentice, Nikole Runciman, Dario Salutous, Lesley Symon, Anne Todd, Patricia Turner, Abigail Short, Laura Sweeney, Euan Murdoch, Dhaneesha Senaratne, Michaela Hill, Thogulava Kannan, Wild Laura, Rikki Crawley, Abigail Crew, Mishell Cunningham, Allison Daniels, Laura Harrison, Susan Hope, Ken Inweregbu, Sian Jones, Nicola Lancaster, Jamie Matthews, Alice Nicholson, Gemma Wray, Helen Langton, Rachel Prout, Malcolm Watters, Catherine Novis, Anthony Barron, Ciara Collins, Sundeep Kaul, Heather Passmore, Claire Prendergast, Anna Reed, Paula Rogers, Rajvinder Shokkar, Meriel Woodruff, Hayley Middleton, Oliver Polgar, Claire Nolan, Kanta Mahay, Dawn Collier, Anil Hormis, Victoria Maynard, Cheryl Graham, Rachel Walker, Ellen Knights, Alicia Price, Alice Thomas, Chris Thorpe, Teresa Behan, Caroline Burnett, Jonathan Hatton, Elaine Heeney, Atideb Mitra, Maria Newton, Rachel Pollard, Rachael Stead, Vishal Amin, Elena Anastasescu, Vikram Anumakonda, Komala Karthik, Rizwana Kausar, Karen Reid, Jacqueline Smith, Janet Imeson-Wood, Denise Skinner, Jane Gaylard, Dee Mullan, Julie Newman, Alison Brown, Vikki Crickmore, Gabor Debreceni, Joy Wilkins, Liz Nicol, Rosie Reece-Anthony, Mark Birt, Alison Ghosh, Emma Williams, Louise Allen, Eva Beranova, Nikki Crisp, Joanne Deery, Tracy Hazelton, Alicia Knight, Carly Price, Sorrell Tilbey, Salah Turki, Sharon Turney, Joshua Cooper, Cheryl Finch, Sarah Liderth, Alison Quinn, Natalia Waddington, Tina Coventry, Susan Fowler, Michael MacMahon, Amanda McGregor, Anne Cowley, Judith Highgate, Jane Gregory, Susan O'Connell, Tim Smith, Luigi Barberis, Shameer Gopal, Nichola Harris, Victoria Lake, Stella Metherell, Elizabeth Radford, Amelia Daniel, Joanne Finn, Rajnish Saha, Nikki White, Phil Donnison, Fiona Trim, Beena Eapen, Jenny Birch, Laura Bough, Josie Goodsell, Rebecca Tutton, Patricia Williams, Sarah Williams, Barbara Winter-Goodwin, Ailstair Nichol, Kathy Brickell, Michelle Smyth, Lorna Murphy, Samantha Coetzee, Alistair Gales, Igor Otahal, Meena Raj, Craig Sell, Paula Hilltout, Jayne Evitts, Amanda Tyler, Joanne Waldron, Kate Beesley, Sarah Board, Agnieszka Kubisz-Pudelko, Alison Lewis, Jess Perry, Lucy Pippard, Di Wood, Clare Buckley, Peter Barry, Neil Flint, Patel Rekha, Dawn Hales, Lara Bunni, Claire Jennings, Monica Latif, Rebecca Marshall, Gayathri Subramanian, Peter J. McGuigan, Christopher Wasson, Stephanie Finn, Jackie Green, Erin Collins, Bernadette King, Andy Campbell, Sara Smuts, Joseph Duffield, Oliver Smith, Lewis Mallon, Watkins Claire, Liam Botfield, Joanna Butler, Catherine Dexter, Jo Fletcher, Atul Garg, Aditya Kuravi, Poonam Ranga, Emma Virgilio, Zakaula Belagodu, Bridget Fuller, Anca Gherman, Olumide Olufuwa, Remi Paramsothy, Carmel Stuart, Naomi Oakley, Charlotte Kamundi, David Tyl, Katy Collins, Pedro Silva, June Taylor, Laura King, Charlotte Coates, Maria Crowley, Phillipa Wakefield, Jane Beadle, Laura Johnson, Janet Sargeant, Madeleine Anderson, Ailbhe Brady, Rebekah Chan, Jeff Little, Shane McIvor, Helena Prady, Helen Whittle, Bijoy Mathew, Ben Attwood, Penny Parsons, Geraldine Ward, Pamela Bremmer, West Joe, Baird Tracy, Ruddy Jim, Ellie Davies, Sonia Sathe, Catherine Dennis, Alastair McGregor, Victoria Parris, Sinduya Srikaran, Anisha Sukha, Noreen Clarke, Jonathan Whiteside, Mairi Mascarenhas, Avril Donaldson, Joanna Matheson, Fiona Barrett, Marianne O'Hara, Laura Okeefe, Clare Bradley, Christine Eastgate-Jackson, Helder Filipe, Daniel Martin, Amitaa Maharajh, Sara Mingo Garcia, Glykeria Pakou, Mark De Neef, Kathy Dent, Elizabeth Horsley, Muhmmad Nauman Akhtar, Sandra Pearson, Dorota Potoczna, Sue Spencer, Melanie Clapham, Rosemary Harper, Una Poultney, Polly Rice, Rachel Mutch, Lisa Armstrong, Hayley Bates, Emma Dooks, Fiona Farquhar, Brigid Hairsine, Chantal McParland, Sophie Packham, Rehana Bi, Barney Scholefield, Lydia Ashton, Linsha George, Sophie Twiss, David Wright, Manish Chablani, Amy Kirkby, Kimberley Netherton, Kim Davies, Linda O'Brien, Zohra Omar, Emma Perkins, Tracy Lewis, Isobel Sutherland, Karen Burns, Dr Ben Chandler, Kerry Elliott, Janine Mallinson, Alison Turnbull, Prisca Gondo, Bernard Hadebe, Abdul Kayani, Bridgett Masunda, Taya Anderson, Dan Hawcutt, Laura O'Malley, Laura Rad, Naomi Rogers, Paula Saunderson, Kathryn Sian Allison, Deborah Afolabi, Jennifer Whitbread, Dawn Jones, Rachael Dore, Matthew Halkes, Pauline Mercer, Lorraine Thornton, Joy Dawson, Sweyn Garrioch, Melanie Tolson, Jonathan Aldridge, Ritoo Kapoor, David Loader, Karen Castle, Sally Humphreys, Ruth Tampsett, Katherine Mackintosh, Amanda Ayers, Wendy Harrison, Julie North, Suzanne Allibone, Roman Genetu, Vidya Kasipandian, Amit Patel, Ainhi Mac, Anthony Murphy, Parisa Mahjoob, Roonak Nazari, Lucy Worsley, Andrew Fagan, Thomas Bemand, Ethel Black, Arnold Dela Rosa, Ryan Howle, Shaman Jhanji, Ravishankar Rao Baikady, Kate Colette Tatham, Benjamin Thomas, Dina Bell, Rosalind Boyle, Katie Douglas, Lynn Glass, Emma Lee, Liz Lennon, Austin Rattray, Abigail Taylor, Rachel Anne Hughes, Helen Thomas, Alun Rees, Michaela Duskova, Janet Phipps, Suzanne Brooks, Michelle Edwards, Sheena Quaid, Ekaterina Watson, Adam Brayne, Emma Fisher, Jane Hunt, Peter Jackson, Duncan Kaye, Nicholas Love, Juliet Parkin, Victoria Tuckey, Lynne Van Koutrik, Sasha Carter, Benedict Andrew, Louise Findlay, Katie Adams, Jen Service, Alison Williams, Claire Cheyne, Anne Saunderson, Sam Moultrie, Miranda Odam, Kathryn Hall, Isheunesu Mapfunde, Charlotte Willis, Alex Lyon, Chunda Sri-Chandana, Joslan Scherewode, Lorraine Stephenson, Sarah Marsh, John Hardy, Henry Houlden, Eleanor Moncur, Ambreen Tariq, Arianna Tucci, Maria Hobrok, Ronda Loosley, Heather McGuinness, Helen Tench, Rebecca Wolf-Roberts, Val Irvine, Benjamin Shelley, Claire Gorman, Abhinav Gupta, Elizabeth Timlick, Rebecca Brady, Barry Milligan, Arianna Bellini, Jade Bryant, Anton Mayer, Amy Pickard, Nicholas Roe, Jason Sowter, Alex Howlett, Katy Fidler, Emma Tagliavini, and Kevin Donnelly

Subjects
SARS-CoV-2, host genetics, toll-like receptor 7, targeted sequencing, rare variants, variant collapsing analysis, Genetics, QH426-470
Abstract

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Published
2024
Full Text
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2. Link between persistent, unexplained gamma-glutamyltransferase elevation and porto-sinusoidal vascular disorder

Author

Nicola Pugliese, Francesca Romana Ponziani, Federica Cerini, Luca di Tommaso, Federica Turati, Marco Maggioni, Matteo Angelo Manini, Francesco Santopaolo, Cristiana Bianco, Chiara Masetti, Maria Cristina Giustiniani, Carlo La Vecchia, Luca Valenti, Luigi Terracciano, Mauro Viganò, and Alessio Aghemo

Subjects
PSVD, vascular liver disorder, GGT, non-cirrhotic portal hypertension, nodular regenerative hyperplasia, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Porto-sinusoidal vascular disorder (PSVD) is a group of vascular disorders characterized by lesions involving portal venules and sinusoids, irrespective of the presence of portal hypertension. Liver biopsy is essential for diagnosis. In a single-center study, we demonstrated high rates of PSVD in patients with persistently elevated gamma-glutamyltransferase (GGT). This multicenter study aims to establish PSVD prevalence in a larger dataset of individuals with persistent and unexplained GGT elevation, and to identify associated risk factors. Methods: The study included all patients who underwent liver biopsy for persistent and unexplained GGT elevation in five Italian hepatology units between March 2015 and December 2021. Results: A total of 144 patients met the inclusion criteria. The majority were males (76/144, 52.8%) and mean age was 51.9 years (range 19-74). Only 12 (8.3%) had liver stiffness measurements (LSM) >10 kPa, while 7 (4.8%) had ultrasound evidence of portal hypertension. Histological findings were consistent with PSVD in 96 patients (67%). Alternative diagnoses were steatohepatitis in 13 (9%), sarcoidosis in 3 (2%) and congenital hepatic fibrosis in 3 (2%) patients. Histological findings were non-specific in 29 (20%) patients. PSVD was associated with male sex (odds ratio [OR] 2.60, 95% CI 1.13-5.99), LSM

Published
2024
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3. Rationale and design of the CV-PREVITAL study: an Italian multiple cohort randomised controlled trial investigating innovative digital strategies in primary cardiovascular prevention

Author

Roberta Pastorino, Eloisa Arbustini, Andrea Faini, Gianfranco Parati, Grzegorz Bilo, Davide Soranna, Antonella Zambon, Sergio Leonardi, Alessandro Gialluisi, Lorenzo Giovanni Mantovani, Walter Ricciardi, Fabio Blandini, Giovanni Scambia, Catherine Klersy, Marialaura Bonaccio, Augusto Di Castelnuovo, Simona Costanzo, Amalia De Curtis, Mariarosaria Persichillo, Chiara Cerletti, Maria Benedetta Donati, Licia Iacoviello, Giuseppe Remuzzi, Camilla Torlasco, Giuseppe Ambrosio, Gabriele Zoppoli, Maria Chiara Grimaldi, Daniela Pedicino, Giovanna Liuzzo, Serena Pelusi, Daniele Prati, Luca Valenti, Francesca Gorini, Maurizio Sanguinetti, Giuseppe Ferrante, Gianluigi Condorelli, Giulio Pompilio, Stefania Boccia, Luigi Badano, Victor Savevski, Tiziana Bachetti, Gian Franco Gensini, Silvano Bosari, Alice Bonanni, Elena Tremoli, Angelo Santoliquido, Stefano Genovese, Sara Boveri, Gianfranco Gensini, Francesco Gianfagna, Italo Porto, Fabio Tuzzolino, Carolina Lombardi, Egidio Traversi, Fabrizio Veglia, Andrea Urbani, Domenico D’Amario, Gaetano Antonio Lanza, Antonio Uccelli, José Pablo Werba, Livio Luzi, Pietro Ameri, Davide Gentilini, Luisa Gilardini, Cecilia Invitti, Maurizio Volterrani, Maria Teresa La Rovere, Giovanni Gentile, Francesco Clemenza, Mario Urtis, Francesca Ieva, Maria Carla Roncaglioni, Valentina Milani, Paola Baiardi, Debora Rosa, Fabiana Madotto, Emilia Ruggiero, Teresa Panzera, Simona Esposito, Sara Magnacca, Fabrizia Noro, Roberta Parisi, Francesca Bracone, Irene Baroni, Damiano Baldassarre, Roberta Baetta, Luigi Frati, Pier Giulio Conaldi, Massimo Fini, Antonio Di Malta, Mauro Amato, Alice Bonomi, Francesca Colazzo, Martino Pengo, Luciana Auteri, Marta Baviera, Alberico Catapano, Alexis Elias Malavazos, Serenella Castelvecchio, Massimiliano Marco Corsi-Romanelli, Rosanna Cardani, Valentina Agnese, Bianca Pane, Laura Spinardi, Marco Visconti, Anna Di Blasio, Luisa Ojeda-Fernández, Andreana Foresta, Simonetta Scalvini, Antonia Pierobon, Alessandra Gorini, Annarosa Racca, Manuela Bandi, Lorenzo Menicanti, Gualtiero Colombo, Chiara Vavassori, Maria Luisa Biondi, Beatrice Frigerio, Alessio Ravani, Daniela Sansaro, Daniela Coggi, Alessandra Romandini, Monica Giroli, Mattia Giuliani, Maurizio Rondinelli, Catia Trudu, Carmen Cinieri, Massimo Monturano, Elisa Perger, Lucia Zanotti, Lidia Cova, Luca Grappiolo, Laura Papa, Ignazio Romano, Luisa Ojeda, Fiorenza Clerici, Angela Palumbo, Roberto Mattioli, Ermanno Longhi, Anwal Ghulam, Sabatino Orlandi, Sabrina Franciosa, Martina Morelli, Fiorella De Rita, Giovanni de Gaetano, Massimiliano MarcoCorsi Romanelli, Ambra Cerri, Carola Dubini, Manuel Bruno Trevisan, Laura Valentina Renna, Paola Giubbilini, Lucia Ramputi, Giada DeAngeli, Francesca Olmetti, Maurizio Bussotti, Carlo Gaetano, Martina Balbi, Laura Comini, Monica Lorenzoni, Adriana Olivares, Camilla Garrè, Riccardo Sideri, Giuseppe Caruana, Nicola Cuscino, Gabriele Di Gesaro, Alessio Greco, Italia Loddo, Domenico Palombo, Giovanni Spinella, Gaddiel Mozzetta, Alice Finotello, Giovanni Pratesi, Margherita Clerici, Cristiana Bianco, Rossana Carpani, Giulia Periti, Sara Margarita, Anna Severino, Alessia D’Aiello, Ramona Vinci, Mattia Brecciaroli, Simone Filomia, Luca Proto, Dalila Tarquini, Arianna Elia, Alessia Currao, Alessandro Di Toro, Lorenzo Giuliani, Giuseppe Caminiti, Federica Marcolongo, Barbara Sposato, Fiorella Guadagni, Valentina Morsella, Angelica Marziale, and Giulia Protti

Subjects
Medicine
Abstract

Introduction Prevention of cardiovascular disease (CVD) is of key importance in reducing morbidity, disability and mortality worldwide. Observational studies suggest that digital health interventions can be an effective strategy to reduce cardiovascular (CV) risk. However, evidence from large randomised clinical trials is lacking.Methods and analysis The CV-PREVITAL study is a multicentre, prospective, randomised, controlled, open-label interventional trial designed to compare the effectiveness of an educational and motivational mobile health (mHealth) intervention versus usual care in reducing CV risk. The intervention aims at improving diet, physical activity, sleep quality, psycho-behavioural aspects, as well as promoting smoking cessation and adherence to pharmacological treatment for CV risk factors. The trial aims to enrol approximately 80 000 subjects without overt CVDs referring to general practitioners’ offices, community pharmacies or clinics of Scientific Institute for Research, Hospitalization and Health Care (Italian acronym IRCCS) affiliated with the Italian Cardiology Network. All participants are evaluated at baseline and after 12 months to assess the effectiveness of the intervention on short-term endpoints, namely improvement in CV risk score and reduction of major CV risk factors. Beyond the funded life of the study, a long-term (7 years) follow-up is also planned to assess the effectiveness of the intervention on the incidence of major adverse CV events. A series of ancillary studies designed to evaluate the effect of the mHealth intervention on additional risk biomarkers are also performed.Ethics and dissemination This study received ethics approval from the ethics committee of the coordinating centre (Monzino Cardiology Center; R1256/20-CCM 1319) and from all other relevant IRBs and ethics committees. Findings are disseminated through scientific meetings and peer-reviewed journals and via social media. Partners are informed about the study’s course and findings through regular meetings.Trial registration number NCT05339841.

Published
2023
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4. Validation of a targeted gene panel sequencing for the diagnosis of hereditary chronic liver diseases

Author

Luisa Ronzoni, Ilaria Marini, Giulia Passignani, Francesco Malvestiti, Daniele Marchelli, Cristiana Bianco, Serena Pelusi, Daniele Prati, and Luca Valenti

Subjects
hereditary chronic liver diseases, targeted sequencing, gene panel design, whole exome sequencing (WES), next-generation sequencing, NGS, Genetics, QH426-470
Abstract

Background: The cause of chronic liver diseases (CLD) remains undiagnosed in up to 30% of adult patients. Whole-Exome Sequencing (WES) can improve the diagnostic rate of genetic conditions, but it is not yet widely available, due to the costs and the difficulties in results interpretation. Targeted panel sequencing (TS) represents an alternative more focused diagnostic approach.Aims: To validate a customized TS for hereditary CLD diagnosis.Methods: We designed a customized panel including 82 CLD-associated genes (iron overload, lipid metabolism, cholestatic diseases, storage diseases, specific hereditary CLD and susceptibility to liver diseases). DNA samples from 19 unrelated adult patients with undiagnosed CLD were analyzed by both TS (HaloPlex) and WES (SureSelect Human All Exon kit v5) and the diagnostic performances were compared.Results: The mean depth of coverage of TS-targeted regions was higher with TS than WES (300x vs. 102x; p < 0.0001). Moreover, TS yielded a higher average coverage per gene and lower fraction of exons with low coverage (p < 0.0001). Overall, 374 unique variants were identified across all samples, 98 of which were classified as “Pathogenic” or “Likely Pathogenic” with a high functional impact (HFI). The majority of HFI variants (91%) were detected by both methods; 6 were uniquely identified by TS and 3 by WES. Discrepancies in variant calling were mainly due to variability in read depth and insufficient coverage in the corresponding target regions. All variants were confirmed by Sanger sequencing except two uniquely detected by TS. Detection rate and specificity for variants in TS-targeted regions of TS were 96.9% and 97.9% respectively, whereas those of WES were 95.8% and 100%, respectively.Conclusion: TS was confirmed to be a valid first-tier genetic test, with an average mean depth per gene higher than WES and a comparable detection rate and specificity.

Published
2023
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5. Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real‐Life Cohort Study

Author

Luca Valenti, Serena Pelusi, Alessio Aghemo, Sara Gritti, Luisa Pasulo, Cristiana Bianco, Claudia Iegri, Giuliana Cologni, Elisabetta Degasperi, Roberta D’Ambrosio, Paolo delPoggio, Alessandro Soria, Massimo Puoti, Isabella Carderi, Marie Graciella Pigozzi, Canio Carriero, Angiola Spinetti, Valentina Zuccaro, Massimo Memoli, Alessia Giorgini, Mauro Viganò, Maria Grazia Rumi, Tiziana Re, Ombretta Spinelli, Maria Chiara Colombo, Tiziana Quirino, Barbara Menzaghi, Gianpaolo Lorini, Angelo Pan, Antonella D’Arminio Monforte, Elisabetta Buscarini, Aldo Autolitano, Paolo Bonfanti, Natalia Terreni, Gianpiero Aimo, Monia Mendeni, Daniele Prati, Pietro Lampertico, Massimo Colombo, Stefano Fagiuoli, and for the NAVIGATORE‐Lombardia Network

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real‐life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE‐Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow‐up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2, 1.03‐1.09) and diabetes (OR 2.01 [1.65‐2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35‐0.60]; P

Published
2022
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6. Clinical and genetic determinants of the fatty liver–coagulation balance interplay in individuals with metabolic dysfunction

Author

Luca Valenti, Armando Tripodi, Vincenzo La Mura, Serena Pelusi, Cristiana Bianco, Erica Scalambrino, Sara Margarita, Francesco Malvestiti, Luisa Ronzoni, Marigrazia Clerici, Roberta D’Ambrosio, Mirella Fraquelli, Rossana Carpani, Daniele Prati, and Flora Peyvandi

Subjects
NAFLD, PNPLA3, ABO blood group, von Willebrand factor, Liver fibrosis, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: The aim of this study was to examine the determinants of the interplay between liver damage and the coagulation balance in individuals at risk of non-alcoholic fatty liver disease (NAFLD). Methods: We considered 581 healthy participants with ≥3 metabolic alterations undergoing clinical and genomic evaluation, measurement of liver stiffness (LSM) and controlled attenuation parameter (CAP) by Fibroscan, Pro-C3, coagulation balance (von Willebrand factor [vWF], factor VIII/protein C ratio [F8/PC] as the main outcome, D-dimer as marker of coagulation/fibrinolysis activation). Results: Liver fibrosis indices (both Fibrosis-4 [FIB-4] and liver stiffness measurement [LSM]), but not liver fat (CAP), were independently associated with higher F8/PC ratio (p

Published
2022
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7. Definition of Healthy Ranges for Alanine Aminotransferase Levels: A 2021 Update

Author

Luca Valenti, Serena Pelusi, Cristiana Bianco, Ferruccio Ceriotti, Alessandra Berzuini, Laura Iogna Prat, Roberta Trotti, Francesco Malvestiti, Roberta D’Ambrosio, Pietro Lampertico, Agostino Colli, Massimo Colombo, Emmanuel A. Tsochatzis, Mirella Fraquelli, and Daniele Prati

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

The changing epidemiology of liver disease, and modifications in the recommended analytical methodology call for a re‐evaluation of the upper reference limits (URLs) of alanine aminotransferase (ALT) levels. Using the same approach consolidated 20 years ago to define the healthy population, we defined the URL for the newly recommended International Federation of Clinical Chemistry (IFCC) standardized test. In a cross‐sectional study, we examined 21,296 apparently healthy blood donors (age 18‐65 years) and calculated the sex‐specific URL by the 95th percentile in individuals without risk factors for liver disease. These were tested for the ability to predict liver damage in a subset of 745 participants with dysmetabolism, in an independent cohort of 977 unselected donors, and in 899 patients with chronic liver disease. ALT levels were measured by the IFCC test. Male sex, body mass index, glucose, lipids, ferritin, hypertension, and younger age were independent ALT predictors (P

Published
2021
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8. Impact of SARS-CoV-2 infection on the recovery of peripheral blood mononuclear cells by density gradient

Author

Maria D. I. Manunta, Giuseppe Lamorte, Francesca Ferrari, Elena Trombetta, Mario Tirone, Cristiana Bianco, Alessandra Cattaneo, Luigi Santoro, Guido Baselli, Manuela Brasca, Mahnoosh Ostadreza, Elisa Erba, Andrea Gori, Alessandra Bandera, Laura Porretti, Luca V. C. Valenti, and Daniele Prati

Subjects
Medicine, Science
Abstract

Abstract SARS-CoV-2 virus infection is responsible for coronavirus disease (COVID-19), which is characterised by a hyperinflammatory response that plays a major role in determining the respiratory and immune-mediated complications of this condition. While isolating peripheral blood mononuclear cells (PBMCs) from whole blood of COVID-19 patients by density gradient centrifugation, we noticed some changes in the floating properties and in the sedimentation of the cells on density medium. Investigating this further, we found that in early phase COVID-19 patients, characterised by reduced circulating lymphocytes and monocytes, the PBMC fraction contained surprisingly high levels of neutrophils. Furthermore, the neutrophil population exhibited alterations in the cell size and in the internal complexity, consistent with the presence of low density neutrophils (LDNs) and immature forms, which may explain the shift seen in the floating abilities and that may be predictive of the severity of the disease. The percentage of this subset of neutrophils found in the PBMC band was rather spread (35.4 ± 27.2%, with a median 28.8% and IQR 11.6–56.1, Welch’s t-test early phase COVID-19 versus blood donor healthy controls P

Published
2021
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9. The Long Non-Coding BC200 Is a Novel Circulating Biomarker of Parathyroid Carcinoma

Author

Annamaria Morotti, Filomena Cetani, Giulia Passoni, Simona Borsari, Elena Pardi, Vito Guarnieri, Chiara Verdelli, Giulia Stefania Tavanti, Luca Valenti, Cristiana Bianco, Stefano Ferrero, Sabrina Corbetta, and Valentina Vaira

Subjects
parathyroid, epigenetics, long non-coding RNAs, brain cytoplasmic RNA 1, biomarker, parathyroid carcinoma, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Long non-coding RNAs (lncRNAs) are an important class of epigenetic regulators involved in both physiological processes and cancer development. Preliminary evidence suggested that lncRNAs could act as accurate prognostic and diagnostic biomarkers. Parathyroid cancer is a rare endocrine neoplasia, whose management represents a clinical challenge due to the lack of accurate molecular biomarkers. Our previous findings showed that human parathyroid tumors are characterized by a different lncRNAs signature, suggesting heterogeneity through the different histotypes. Particularly, we found that the lncRNA BC200/BCYRN1 could represent a candidate biomarker for parathyroid carcinomas (PCas). Here we aimed to extend our preliminary data evaluating whether BC200 could be an accurate non-invasive biomarker of PCas to support the clinical management of patients affected by parathyroid tumors at diagnosis, prognosis and follow-up. To provide a non-invasive point-of-care for parathyroid carcinoma diagnosis and follow-up, we analyzed BC200 expression in patients’ serum through digital PCR. Our results show that BC200 counts are higher in serum from patients harboring PCa (n=4) compared to patients with parathyroid adenoma (PAd; n=27). Further, in PAd patients circulating BC200 levels are positively correlated with serum total calcium. Then, we found that BC200 is overexpressed in metastatic PCas (n=4) compared to non-metastatic ones (n=9). Finally, the lncRNA expression in PCa patients’ serum drops are reduced after parathyroidectomy, suggesting its possible use in the post-operative setting for patients follow-up. Overall, these findings extend the knowledge on BC200 in parathyroid tumors, supporting its role as a useful biomarker for management of PCa.

Published
2022
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10. Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targetsKey points

Author

Cristiana Bianco, Elia Casirati, Francesco Malvestiti, and Luca Valenti

Subjects
alcoholic liver disease, cirrhosis, fatty liver disease, genetics, IL32, interleukin-32, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Summary: Fatty liver disease can be triggered by a combination of excess alcohol, dysmetabolism and other environmental cues, which can lead to steatohepatitis and can evolve to acute/chronic liver failure and hepatocellular carcinoma, especially in the presence of shared inherited determinants. The recent identification of the genetic causes of steatohepatitis is revealing new avenues for more effective risk stratification. Discovery of the mechanisms underpinning the detrimental effect of causal mutations has led to some breakthroughs in the comprehension of the pathophysiology of steatohepatitis. Thanks to this approach, hepatocellular fat accumulation, altered lipid droplet remodelling and lipotoxicity have now taken centre stage, while the role of adiposity and gut-liver axis alterations have been independently validated. This process could ignite a virtuous research cycle that, starting from human genomics, through omics approaches, molecular genetics and disease models, may lead to the development of new therapeutics targeted to patients at higher risk. Herein, we also review how this knowledge has been applied to: a) the study of the main PNPLA3 I148M risk variant, up to the stage of the first in-human therapeutic trials; b) highlight a role of MBOAT7 downregulation and lysophosphatidyl-inositol in steatohepatitis; c) identify IL-32 as a candidate mediator linking lipotoxicity to inflammation and liver disease. Although this precision medicine drug discovery pipeline is mainly being applied to non-alcoholic steatohepatitis, there is hope that successful products could be repurposed to treat alcohol-related liver disease as well.

Published
2021
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11. A multi-society Delphi consensus statement on new fatty liver disease nomenclature

Author

Mary E, R, Jeffrey V, L, Vlad, R, Sven M, F, Arun J, S, Fasiha, K, Diana, R, Manal F, A, Quentin M, A, Juan Pablo, A, Marco, A, Ramon, B, Ulrich, B, Jerome, B, Elisabetta, B, Christopher, B, Graciela E, C, Abhijit, C, Helena, C, Donna, C, Kenneth, C, Mohamed, E, Samuel, K, Wayne, E, Jiangao, F, Samer, G, Cynthia D, G, Stephen A, H, Seung Up, K, Bart, K, Marko, K, Kris, K, Florence, L, Rohit, L, Robert, M, Timothy R, M, Elisabeth, P, Michael, R, Manuel, R, Marcelo, S, Shivaram Prasad, S, Silvia C, S, C Wendy, S, Dina, T, Luca, V, Miriam B, V, Vincent, W, Stavra, X, Yusuf, Y, Zobair, Y, Ansley, H, Marcela, V, Newsome, NVeeral Ajmeral, P, Alazawi, W, Alkhatry, M, Alkhouri, N, Allen, A, Allison, M, Alswat, K, R Alvares-da-Silva, M, Alves-Bezerra, M, J Armstrong, M, Arufe, D, Aschner, P, Baffy, G, Bansal, M, Bedossa, P, Belfort, R, Berg, T, Berzigotti, A, Betel, M, Bianco, C, Brass, C, L Brosgart, C, Matthews Brunt, E, Buti, M, Caldwell, S, Carr, R, Casanovas, T, Castera, L, Caussy, C, Cerda, E, Chalasani, N, Kheong Chan, W, Charatcharoenwitthaya, P, Charlton, M, Cheung, A, Chiodi, D, Chung, R, Cohen, D, Corey, K, P Cotrim, H, Crespo, J, Dassanayake, A, Davidson, N, De Knegt, R, De Ledinghen, V, Demir, M, Diaz, S, Mae Diehl, A, Dimmig, B, Dirchwolf, M, Duseja, A, Dvorak, K, Ekstedt, M, El Wakil, R, Lucía Ferraz, M, Friedman, S, Fuchs, M, Gastaldelli, A, Geerts, A, Geier, A, Girala, M, Goh, G, Goossens, N, Graupera, I, Hagström, H, Henry, Z, Hunyady, B, Hutchison, A, Isaacs, S, Jornayvaz, F, Kemp, C, Kile, D, Kim, W, Kleiner, D, Kohli, R, Kugelmas, M, Lavine, J, Lazo, M, Leite, N, Lozano, A, Luukkonen, P, Macedo, P, Mansour, D, Mantzoros, C, Marchesini, G, Marciano, S, Martinez, K, Vladimirova Mateva, L, M Mato, J, Mccary, A, Miele, L, Mikolasevic, I, Miller, V, Moreno, R, Moylan, C, Nakajima, A, Charles Nault, J, Norris, S, Noureddin, M, P Oliveira, C, Ong, A, Padilla, M, Pais, R, Panduro, A, K Panigrahi, M, Papatheodoridis, G, Pelusi, S, Pérez, M, Perez Escobar, J, Perseghin, G, Pessoa, M, Petta, S, Pinzani, M, Platon Lupsor, M, Rabiee, A, Romeo, S, Rotman, Y, Rowe, I, Salupere, R, Satapathy, S, M Schattenberg, J, Schaufert, W, Schnabl, B, Seim, L, Serfaty, L, Shapiro, D, K Singal, A, Skladany, L, Stefan, N, Stine, J, Sundaram, S, Svegliati-Baroni, G, Szabo, G, Tacke, F, Tanwandee, T, Targher, G, Terrault, N, Tetri, B, Thiele, M, Tisthammer, B, Torre Delgadillo, A, Trauner, M, Tsochatzis, E, Van Kleef, L, Van Mil, S, Vanwagner, L, Antonio Velarde Ruiz Velasco, J, Vesterhus, M, Vilar-Gomez, E, Watt, K, Wattacheril, J, Wilkins, F, Willemse, J, Zekry, A, Zelber-Sagi, S, Rinella, Mary E, Lazarus, Jeffrey V, Ratziu, Vlad, Francque, Sven M, Sanyal, Arun J, Kanwal, Fasiha, Romero, Diana, Abdelmalek, Manal F, Anstee, Quentin M, Arab, Juan Pablo, Arrese, Marco, Bataller, Ramon, Beuers, Ulrich, Boursier, Jerome, Bugianesi, Elisabetta, Byrne, Christopher, Castro Narro, Graciela E, Chowdhury, Abhijit, Cortez-Pinto, Helena, Cryer, Donna, Cusi, Kenneth, El-Kassas, Mohamed, Klein, Samuel, Eskridge, Wayne, Fan, Jiangao, Gawrieh, Samer, Guy, Cynthia D, Harrison, Stephen A, Kim, Seung Up, Koot, Bart, Korenjak, Marko, Kowdley, Kris, Lacaille, Florence, Loomba, Rohit, Mitchell-Thain, Robert, Morgan, Timothy R, Powell, Elisabeth, Roden, Michael, Romero-Gómez, Manuel, Silva, Marcelo, Singh, Shivaram Prasad, Sookoian, Silvia C, Spearman, C Wendy, Tiniakos, Dina, Valenti, Luca, Vos, Miriam B, Wai-Sun Wong, Vincent, Xanthakos, Stavra, Yilmaz, Yusuf, Younossi, Zobair, Hobbs, Ansley, Villota-Rivas, Marcela, Philip NVeeral Ajmeral, William Alazawi, Maryam Alkhatry, Naim Alkhouri, Alina Allen, Michael Allison, Khalid Alswat, Mario R Alvares-da-Silva, Michele Alves-Bezerra, Matthew J Armstrong, Diego Arufe, Pablo Aschner, Gyorgy Baffy, Meena Bansal, Pierre Bedossa, Renata Belfort, Thomas Berg, Annalisa Berzigotti, Michael Betel, Cristiana Bianco, Clifford Brass, Carol L Brosgart, Elizabeth Matthews Brunt, Maria Buti, Steve Caldwell, Rotonya Carr, Teresa Casanovas, Laurent Castera, Cyrielle Caussy, Eira Cerda, Naga Chalasani, Wah Kheong Chan, Phunchai Charatcharoenwitthaya, Michael Charlton, Amanda Cheung, Daniela Chiodi, Ray Chung, David Cohen, Kathleen Corey, Helma P Cotrim, Javier Crespo, Anuradha Dassanayake, Nicholas Davidson, Robert De Knegt, Victor De Ledinghen, Münevver Demir, Sebastian Diaz, Anna Mae Diehl, Bruce Dimmig, Melisa Dirchwolf, Ajay Duseja, Karel Dvorak, Mattias Ekstedt, Reda El Wakil, María Lucía Ferraz, Scott Friedman, Michael Fuchs, Amalia Gastaldelli, Anja Geerts, Andreas Geier, Marcos Girala, George Goh, Nicolas Goossens, Isabel Graupera, Hannes Hagström, Zachary Henry, Bela Hunyady, Alan Hutchison, Scott Isaacs, François Jornayvaz, Cynthia Kemp, Denise Kile, Won Kim, David Kleiner, Rohit Kohli, Marcelo Kugelmas, Joel Lavine, Mariana Lazo, Nathalie Leite, Adelina Lozano, Panu Luukkonen, Paula Macedo, Dina Mansour, Christos Mantzoros, Giulio Marchesini, Sebastián Marciano, Kim Martinez, Lyudmila Vladimirova Mateva, Jose M Mato, Alexis McCary, Luca Miele, Ivana Mikolasevic, Veronica Miller, Rosalba Moreno, Cynthia Moylan, Atsushi Nakajima, Jean Charles Nault, Suzanne Norris, Mazen Noureddin, C P Oliveira, Arlin Ong, Martín Padilla, Raluca Pais, Arturo Panduro, Manas K Panigrahi, George Papatheodoridis, Serena Pelusi, Marlene Pérez, Juanita Perez Escobar, Gianluca Perseghin, Mario Pessoa, Salvatore Petta, Massimo Pinzani, Monica Platon Lupsor, Atoosa Rabiee, Stefano Romeo, Yaron Rotman, Ian Rowe, Riina Salupere, Sanjaya Satapathy, Jörn M Schattenberg, Wendy Schaufert, Bernd Schnabl, Lynn Seim, Lawrence Serfaty, David Shapiro, Ashwani K Singal, Lubomir Skladany, Norbert Stefan, Jonathan Stine, Shikha Sundaram, Gianluca Svegliati-Baroni, Gyonzgi Szabo, Frank Tacke, Tawesak Tanwandee, Giovanni Targher, Norah Terrault, Brent Tetri, Maja Thiele, Baron Tisthammer, Aldo Torre Delgadillo, Michael Trauner, Emmanuel Tsochatzis, Laurens Van Kleef, Saskia Van Mil, Lisa VanWagner, Jose Antonio Velarde Ruiz Velasco, Mette Vesterhus, Eduardo Vilar-Gomez, Kymberly Watt, Julia Wattacheril, Fonda Wilkins, José Willemse, Amany Zekry, Shira Zelber-Sagi, Mary E, R, Jeffrey V, L, Vlad, R, Sven M, F, Arun J, S, Fasiha, K, Diana, R, Manal F, A, Quentin M, A, Juan Pablo, A, Marco, A, Ramon, B, Ulrich, B, Jerome, B, Elisabetta, B, Christopher, B, Graciela E, C, Abhijit, C, Helena, C, Donna, C, Kenneth, C, Mohamed, E, Samuel, K, Wayne, E, Jiangao, F, Samer, G, Cynthia D, G, Stephen A, H, Seung Up, K, Bart, K, Marko, K, Kris, K, Florence, L, Rohit, L, Robert, M, Timothy R, M, Elisabeth, P, Michael, R, Manuel, R, Marcelo, S, Shivaram Prasad, S, Silvia C, S, C Wendy, S, Dina, T, Luca, V, Miriam B, V, Vincent, W, Stavra, X, Yusuf, Y, Zobair, Y, Ansley, H, Marcela, V, Newsome, NVeeral Ajmeral, P, Alazawi, W, Alkhatry, M, Alkhouri, N, Allen, A, Allison, M, Alswat, K, R Alvares-da-Silva, M, Alves-Bezerra, M, J Armstrong, M, Arufe, D, Aschner, P, Baffy, G, Bansal, M, Bedossa, P, Belfort, R, Berg, T, Berzigotti, A, Betel, M, Bianco, C, Brass, C, L Brosgart, C, Matthews Brunt, E, Buti, M, Caldwell, S, Carr, R, Casanovas, T, Castera, L, Caussy, C, Cerda, E, Chalasani, N, Kheong Chan, W, Charatcharoenwitthaya, P, Charlton, M, Cheung, A, Chiodi, D, Chung, R, Cohen, D, Corey, K, P Cotrim, H, Crespo, J, Dassanayake, A, Davidson, N, De Knegt, R, De Ledinghen, V, Demir, M, Diaz, S, Mae Diehl, A, Dimmig, B, Dirchwolf, M, Duseja, A, Dvorak, K, Ekstedt, M, El Wakil, R, Lucía Ferraz, M, Friedman, S, Fuchs, M, Gastaldelli, A, Geerts, A, Geier, A, Girala, M, Goh, G, Goossens, N, Graupera, I, Hagström, H, Henry, Z, Hunyady, B, Hutchison, A, Isaacs, S, Jornayvaz, F, Kemp, C, Kile, D, Kim, W, Kleiner, D, Kohli, R, Kugelmas, M, Lavine, J, Lazo, M, Leite, N, Lozano, A, Luukkonen, P, Macedo, P, Mansour, D, Mantzoros, C, Marchesini, G, Marciano, S, Martinez, K, Vladimirova Mateva, L, M Mato, J, Mccary, A, Miele, L, Mikolasevic, I, Miller, V, Moreno, R, Moylan, C, Nakajima, A, Charles Nault, J, Norris, S, Noureddin, M, P Oliveira, C, Ong, A, Padilla, M, Pais, R, Panduro, A, K Panigrahi, M, Papatheodoridis, G, Pelusi, S, Pérez, M, Perez Escobar, J, Perseghin, G, Pessoa, M, Petta, S, Pinzani, M, Platon Lupsor, M, Rabiee, A, Romeo, S, Rotman, Y, Rowe, I, Salupere, R, Satapathy, S, M Schattenberg, J, Schaufert, W, Schnabl, B, Seim, L, Serfaty, L, Shapiro, D, K Singal, A, Skladany, L, Stefan, N, Stine, J, Sundaram, S, Svegliati-Baroni, G, Szabo, G, Tacke, F, Tanwandee, T, Targher, G, Terrault, N, Tetri, B, Thiele, M, Tisthammer, B, Torre Delgadillo, A, Trauner, M, Tsochatzis, E, Van Kleef, L, Van Mil, S, Vanwagner, L, Antonio Velarde Ruiz Velasco, J, Vesterhus, M, Vilar-Gomez, E, Watt, K, Wattacheril, J, Wilkins, F, Willemse, J, Zekry, A, Zelber-Sagi, S, Rinella, Mary E, Lazarus, Jeffrey V, Ratziu, Vlad, Francque, Sven M, Sanyal, Arun J, Kanwal, Fasiha, Romero, Diana, Abdelmalek, Manal F, Anstee, Quentin M, Arab, Juan Pablo, Arrese, Marco, Bataller, Ramon, Beuers, Ulrich, Boursier, Jerome, Bugianesi, Elisabetta, Byrne, Christopher, Castro Narro, Graciela E, Chowdhury, Abhijit, Cortez-Pinto, Helena, Cryer, Donna, Cusi, Kenneth, El-Kassas, Mohamed, Klein, Samuel, Eskridge, Wayne, Fan, Jiangao, Gawrieh, Samer, Guy, Cynthia D, Harrison, Stephen A, Kim, Seung Up, Koot, Bart, Korenjak, Marko, Kowdley, Kris, Lacaille, Florence, Loomba, Rohit, Mitchell-Thain, Robert, Morgan, Timothy R, Powell, Elisabeth, Roden, Michael, Romero-Gómez, Manuel, Silva, Marcelo, Singh, Shivaram Prasad, Sookoian, Silvia C, Spearman, C Wendy, Tiniakos, Dina, Valenti, Luca, Vos, Miriam B, Wai-Sun Wong, Vincent, Xanthakos, Stavra, Yilmaz, Yusuf, Younossi, Zobair, Hobbs, Ansley, Villota-Rivas, Marcela, Philip NVeeral Ajmeral, William Alazawi, Maryam Alkhatry, Naim Alkhouri, Alina Allen, Michael Allison, Khalid Alswat, Mario R Alvares-da-Silva, Michele Alves-Bezerra, Matthew J Armstrong, Diego Arufe, Pablo Aschner, Gyorgy Baffy, Meena Bansal, Pierre Bedossa, Renata Belfort, Thomas Berg, Annalisa Berzigotti, Michael Betel, Cristiana Bianco, Clifford Brass, Carol L Brosgart, Elizabeth Matthews Brunt, Maria Buti, Steve Caldwell, Rotonya Carr, Teresa Casanovas, Laurent Castera, Cyrielle Caussy, Eira Cerda, Naga Chalasani, Wah Kheong Chan, Phunchai Charatcharoenwitthaya, Michael Charlton, Amanda Cheung, Daniela Chiodi, Ray Chung, David Cohen, Kathleen Corey, Helma P Cotrim, Javier Crespo, Anuradha Dassanayake, Nicholas Davidson, Robert De Knegt, Victor De Ledinghen, Münevver Demir, Sebastian Diaz, Anna Mae Diehl, Bruce Dimmig, Melisa Dirchwolf, Ajay Duseja, Karel Dvorak, Mattias Ekstedt, Reda El Wakil, María Lucía Ferraz, Scott Friedman, Michael Fuchs, Amalia Gastaldelli, Anja Geerts, Andreas Geier, Marcos Girala, George Goh, Nicolas Goossens, Isabel Graupera, Hannes Hagström, Zachary Henry, Bela Hunyady, Alan Hutchison, Scott Isaacs, François Jornayvaz, Cynthia Kemp, Denise Kile, Won Kim, David Kleiner, Rohit Kohli, Marcelo Kugelmas, Joel Lavine, Mariana Lazo, Nathalie Leite, Adelina Lozano, Panu Luukkonen, Paula Macedo, Dina Mansour, Christos Mantzoros, Giulio Marchesini, Sebastián Marciano, Kim Martinez, Lyudmila Vladimirova Mateva, Jose M Mato, Alexis McCary, Luca Miele, Ivana Mikolasevic, Veronica Miller, Rosalba Moreno, Cynthia Moylan, Atsushi Nakajima, Jean Charles Nault, Suzanne Norris, Mazen Noureddin, C P Oliveira, Arlin Ong, Martín Padilla, Raluca Pais, Arturo Panduro, Manas K Panigrahi, George Papatheodoridis, Serena Pelusi, Marlene Pérez, Juanita Perez Escobar, Gianluca Perseghin, Mario Pessoa, Salvatore Petta, Massimo Pinzani, Monica Platon Lupsor, Atoosa Rabiee, Stefano Romeo, Yaron Rotman, Ian Rowe, Riina Salupere, Sanjaya Satapathy, Jörn M Schattenberg, Wendy Schaufert, Bernd Schnabl, Lynn Seim, Lawrence Serfaty, David Shapiro, Ashwani K Singal, Lubomir Skladany, Norbert Stefan, Jonathan Stine, Shikha Sundaram, Gianluca Svegliati-Baroni, Gyonzgi Szabo, Frank Tacke, Tawesak Tanwandee, Giovanni Targher, Norah Terrault, Brent Tetri, Maja Thiele, Baron Tisthammer, Aldo Torre Delgadillo, Michael Trauner, Emmanuel Tsochatzis, Laurens Van Kleef, Saskia Van Mil, Lisa VanWagner, Jose Antonio Velarde Ruiz Velasco, Mette Vesterhus, Eduardo Vilar-Gomez, Kymberly Watt, Julia Wattacheril, Fonda Wilkins, José Willemse, Amany Zekry, and Shira Zelber-Sagi

Abstract

The principal limitations of the terms NAFLD and NASH are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. A modified Delphi process was led by three large pan-national liver associations. The consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. A total of 236 panellists from 56 countries participated in 4 online surveys and 2 hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83%, and 78%, respectively. Seventy-four percent of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms “nonalcoholic” and “fatty” were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction–associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least 1 of 5 cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic steatotic liver disease. A new category, outside pure metabolic dysfunction–associated steatotic liver disease, termed metabolic and alcohol related/associated liver disease (MetALD), was selected to describe those with metabolic dysfunction–associated steatotic liver disease, who consume greater amounts of alcohol per week (140–350 g/wk and 210–420 g/wk for females and males, respectively). The new nomenclature and diagnostic criteria are widely supported and non-stigmati

Published
2023

12. Adverse effect of PNPLA3 p.I148M genetic variant on kidney function in middle-aged individuals with metabolic dysfunction

Author

Alessandro Mantovani, Serena Pelusi, Sara Margarita, Francesco Malvestiti, Michela Dell'Alma, Cristiana Bianco, Luisa Ronzoni, Daniele Prati, Giovanni Targher, and Luca Valenti

Subjects
nonalcoholic fatty liver disease, glomerular filtration rate, Hepatology, precision medicine, polygenic risk score, Gastroenterology, Pharmacology (medical), genetics, nonalcoholic steatohepatitis
Published
2023

13. A multi-society Delphi consensus statement on new fatty liver disease nomenclature

Author

Rinella, Mary E, Lazarus, Jeffrey V, Ratziu, Vlad, Francque, Sven M, Sanyal, Arun J, Kanwal, Fasiha, Romero, Diana, Abdelmalek, Manal F, Anstee, Quentin M, Arab, Juan Pablo, Arrese, Marco, Bataller, Ramon, Beuers, Ulrich, Boursier, Jerome, Bugianesi, Elisabetta, Byrne, Christopher, Castro Narro, Graciela E, Chowdhury, Abhijit, Cortez-Pinto, Helena, Cryer, Donna, Cusi, Kenneth, El-Kassas, Mohamed, Klein, Samuel, Eskridge, Wayne, Fan, Jiangao, Gawrieh, Samer, Guy, Cynthia D, Harrison, Stephen A, Kim, Seung Up, Koot, Bart, Korenjak, Marko, Kowdley, Kris, Lacaille, Florence, Loomba, Rohit, Mitchell-Thain, Robert, Morgan, Timothy R, Powell, Elisabeth, Roden, Michael, Romero-Gómez, Manuel, Silva, Marcelo, Singh, Shivaram Prasad, Sookoian, Silvia C, Spearman, C Wendy, Tiniakos, Dina, Valenti, Luca, Vos, Miriam B, Wong, Vincent Wai-Sun, Xanthakos, Stavra, Yilmaz, Yusuf, Younossi, Zobair, Hobbs, Ansley, Villota-Rivas, Marcela, Newsome, Philip NVeeral Ajmeral, William Alazawi, Maryam Alkhatry, Naim Alkhouri, Alina Allen, Michael Allison, Khalid Alswat, Mario R Alvares-da-Silva, Michele Alves-Bezerra, Matthew J Armstrong, Diego Arufe, Pablo Aschner, Gyorgy Baffy, Meena Bansal, Pierre Bedossa, Renata Belfort, Thomas Berg, Annalisa Berzigotti, Michael Betel, Cristiana Bianco, Clifford Brass, Carol L Brosgart, Elizabeth Matthews Brunt, Maria Buti, Steve Caldwell, Rotonya Carr, Teresa Casanovas, Laurent Castera, Cyrielle Caussy, Eira Cerda, Naga Chalasani, Wah Kheong Chan, Phunchai Charatcharoenwitthaya, Michael Charlton, Amanda Cheung, Daniela Chiodi, Ray Chung, David Cohen, Kathleen Corey, Helma P Cotrim, Javier Crespo, Anuradha Dassanayake, Nicholas Davidson, Robert De Knegt, Victor De Ledinghen, Münevver Demir, Sebastian Diaz, Anna Mae Diehl, Bruce Dimmig, Melisa Dirchwolf, Ajay Duseja, Karel Dvorak, Mattias Ekstedt, Reda El Wakil, María Lucía Ferraz, Scott Friedman, Michael Fuchs, Amalia Gastaldelli, Anja Geerts, Andreas Geier, Marcos Girala, George Goh, Nicolas Goossens, Isabel Graupera, Hannes Hagström, Zachary Henry, Bela Hunyady, Alan Hutchison, Scott Isaacs, François Jornayvaz, Cynthia Kemp, Denise Kile, Won Kim, David Kleiner, Rohit Kohli, Marcelo Kugelmas, Joel Lavine, Mariana Lazo, Nathalie Leite, Adelina Lozano, Panu Luukkonen, Paula Macedo, Dina Mansour, Christos Mantzoros, Giulio Marchesini, Sebastián Marciano, Kim Martinez, Lyudmila Vladimirova Mateva, Jose M Mato, Alexis McCary, Luca Miele, Ivana Mikolasevic, Veronica Miller, Rosalba Moreno, Cynthia Moylan, Atsushi Nakajima, Jean Charles Nault, Suzanne Norris, Mazen Noureddin, C P Oliveira, Arlin Ong, Martín Padilla, Raluca Pais, Arturo Panduro, Manas K Panigrahi, George Papatheodoridis, Serena Pelusi, Marlene Pérez, Juanita Perez Escobar, Gianluca Perseghin, Mario Pessoa, Salvatore Petta, Massimo Pinzani, Monica Platon Lupsor, Atoosa Rabiee, Stefano Romeo, Yaron Rotman, Ian Rowe, Riina Salupere, Sanjaya Satapathy, Jörn M Schattenberg, Wendy Schaufert, Bernd Schnabl, Lynn Seim, Lawrence Serfaty, David Shapiro, Ashwani K Singal, Lubomir Skladany, Norbert Stefan, Jonathan Stine, Shikha Sundaram, Gianluca Svegliati-Baroni, Gyonzgi Szabo, Frank Tacke, Tawesak Tanwandee, Giovanni Targher, Norah Terrault, Brent Tetri, Maja Thiele, Baron Tisthammer, Aldo Torre Delgadillo, Michael Trauner, Emmanuel Tsochatzis, Laurens Van Kleef, Saskia Van Mil, Lisa VanWagner, Jose Antonio Velarde Ruiz Velasco, Mette Vesterhus, Eduardo Vilar-Gomez, Kymberly Watt, Julia Wattacheril, Fonda Wilkins, José Willemse, Amany Zekry, Shira Zelber-Sagi, Mary E, R, Jeffrey V, L, Vlad, R, Sven M, F, Arun J, S, Fasiha, K, Diana, R, Manal F, A, Quentin M, A, Juan Pablo, A, Marco, A, Ramon, B, Ulrich, B, Jerome, B, Elisabetta, B, Christopher, B, Graciela E, C, Abhijit, C, Helena, C, Donna, C, Kenneth, C, Mohamed, E, Samuel, K, Wayne, E, Jiangao, F, Samer, G, Cynthia D, G, Stephen A, H, Seung Up, K, Bart, K, Marko, K, Kris, K, Florence, L, Rohit, L, Robert, M, Timothy R, M, Elisabeth, P, Michael, R, Manuel, R, Marcelo, S, Shivaram Prasad, S, Silvia C, S, C Wendy, S, Dina, T, Luca, V, Miriam B, V, Vincent, W, Stavra, X, Yusuf, Y, Zobair, Y, Ansley, H, Marcela, V, Newsome, NVeeral Ajmeral, P, Alazawi, W, Alkhatry, M, Alkhouri, N, Allen, A, Allison, M, Alswat, K, R Alvares-da-Silva, M, Alves-Bezerra, M, J Armstrong, M, Arufe, D, Aschner, P, Baffy, G, Bansal, M, Bedossa, P, Belfort, R, Berg, T, Berzigotti, A, Betel, M, Bianco, C, Brass, C, L Brosgart, C, Matthews Brunt, E, Buti, M, Caldwell, S, Carr, R, Casanovas, T, Castera, L, Caussy, C, Cerda, E, Chalasani, N, Kheong Chan, W, Charatcharoenwitthaya, P, Charlton, M, Cheung, A, Chiodi, D, Chung, R, Cohen, D, Corey, K, P Cotrim, H, Crespo, J, Dassanayake, A, Davidson, N, De Knegt, R, De Ledinghen, V, Demir, M, Diaz, S, Mae Diehl, A, Dimmig, B, Dirchwolf, M, Duseja, A, Dvorak, K, Ekstedt, M, El Wakil, R, Lucía Ferraz, M, Friedman, S, Fuchs, M, Gastaldelli, A, Geerts, A, Geier, A, Girala, M, Goh, G, Goossens, N, Graupera, I, Hagström, H, Henry, Z, Hunyady, B, Hutchison, A, Isaacs, S, Jornayvaz, F, Kemp, C, Kile, D, Kim, W, Kleiner, D, Kohli, R, Kugelmas, M, Lavine, J, Lazo, M, Leite, N, Lozano, A, Luukkonen, P, Macedo, P, Mansour, D, Mantzoros, C, Marchesini, G, Marciano, S, Martinez, K, Vladimirova Mateva, L, M Mato, J, Mccary, A, Miele, L, Mikolasevic, I, Miller, V, Moreno, R, Moylan, C, Nakajima, A, Charles Nault, J, Norris, S, Noureddin, M, P Oliveira, C, Ong, A, Padilla, M, Pais, R, Panduro, A, K Panigrahi, M, Papatheodoridis, G, Pelusi, S, Pérez, M, Perez Escobar, J, Perseghin, G, Pessoa, M, Petta, S, Pinzani, M, Platon Lupsor, M, Rabiee, A, Romeo, S, Rotman, Y, Rowe, I, Salupere, R, Satapathy, S, M Schattenberg, J, Schaufert, W, Schnabl, B, Seim, L, Serfaty, L, Shapiro, D, K Singal, A, Skladany, L, Stefan, N, Stine, J, Sundaram, S, Svegliati-Baroni, G, Szabo, G, Tacke, F, Tanwandee, T, Targher, G, Terrault, N, Tetri, B, Thiele, M, Tisthammer, B, Torre Delgadillo, A, Trauner, M, Tsochatzis, E, Van Kleef, L, Van Mil, S, Vanwagner, L, Antonio Velarde Ruiz Velasco, J, Vesterhus, M, Vilar-Gomez, E, Watt, K, Wattacheril, J, Wilkins, F, Willemse, J, Zekry, A, Zelber-Sagi, S, and Vincent Wai-Sun, W

Subjects
steatotic liver disease, MASLD, alcohol, steatohepatiti, MetALD, NASH, nonalcoholic, Delphi, Fatty liver disease, NAFLD, cardiometabolic, nomenclature, mafld, type 2 diabetes, MED/13 - ENDOCRINOLOGIA
Abstract

Unlabelled: The principal limitations of the terms nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the reliance on exclusionary confounder terms and the use of potentially stigmatising language. This study set out to determine if content experts and patient advocates were in favour of a change in nomenclature and/or definition. Methods: A modified Delphi process was led by three large pan-national liver associations. Consensus was defined a priori as a supermajority (67%) vote. An independent committee of experts external to the nomenclature process made the final recommendation on the acronym and its diagnostic criteria. Results: A total of 236 panellists from 56 countries participated in four online surveys and two hybrid meetings. Response rates across the 4 survey rounds were 87%, 83%, 83% and 78%, respectively. 74% of respondents felt that the current nomenclature was sufficiently flawed to consider a name change. The terms 'non-alcoholic' and 'fatty' were felt to be stigmatising by 61% and 66% of respondents, respectively. Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various aetiologies of steatosis. The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors. Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD. A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350g/week and 210 to 420g/week for females and males respectively). Conclusions: The new nomenclature and diagnostic criteria are widely supported, non-stigmatising and can improve awareness and patient identification.

Published
2023

14. Programmed cell death 1 genetic variant and liver damage in nonalcoholic fatty liver disease

Author

Rosaria M. Pipitone, Francesco Malvestiti, Grazia Pennisi, Oveis Jamialahmadi, Paola Dongiovanni, Giorgio Bertolazzi, Jussi Pihlajamäki, Hannele Yki‐Järvinen, Umberto Vespasiani‐Gentilucci, Federica Tavaglione, Samantha Maurotti, Cristiana Bianco, Gabriele Di Maria, Marco Enea, Anna L. Fracanzani, Vesa Kärjä, Giulia Lupo, Ville Männistö, Marica Meroni, Roberto Piciotti, Sami Qadri, Rossella Zito, Antonio Craxì, Vito Di Marco, Calogero Cammà, Claudio Tripodo, Luca Valenti, Stefano Romeo, Salvatore Petta, Stefania Grimaudo, Pipitone, Rosaria M, Malvestiti, Francesco, Pennisi, Grazia, Jamialahmadi, Ovei, Dongiovanni, Paola, Bertolazzi, Giorgio, Pihlajamäki, Jussi, Yki-Järvinen, Hannele, Vespasiani-Gentilucci, Umberto, Tavaglione, Federica, Maurotti, Samantha, Bianco, Cristiana, Di Maria, Gabriele, Enea, Marco, Fracanzani, Anna L, Kärjä, Vesa, Lupo, Giulia, Männistö, Ville, Meroni, Marica, Piciotti, Roberto, Qadri, Sami, Zito, Rossella, Craxì, Antonio, Di Marco, Vito, Cammà, Calogero, Tripodo, Claudio, Valenti, Luca, Romeo, Stefano, Petta, Salvatore, and Grimaudo, Stefania

Subjects
Settore MED/12 - Gastroenterologia, Hepatology, Settore BIO/13 - Biologia Applicata, Gastroenterology, CXCR6, NAFLD, NASH, PDCD1, checkpoint inhibitors
Abstract

Background and aims: Programmed cell death 1/programmed cell death-ligand 1 (PD-1/PDL-1) axis has been reported to modulate liver inflammation and progression to hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease (NAFLD). Here, we examined whether the PDCD1 variation is associated with NAFLD severity in individuals with liver biopsy. Methods: We examined the impact of PDCD1 gene variants on HCC, as robust severe liver disease phenotype in UK Biobank participants. The strongest genetic association with the rs13023138 G>C variation was subsequently tested for association with liver damage in 2889 individuals who underwent liver biopsy for suspected nonalcoholic steatohepatitis (NASH). Hepatic transcriptome was examined by RNA-Seq in a subset of NAFLD individuals (n = 121). Transcriptomic and deconvolution analyses were performed to identify biological pathways modulated by the risk allele. Results: The rs13023138 C>G showed the most robust association with HCC in UK Biobank (p = 5.28E-4, OR = 1.32, 95% CI [1.1, 1.5]). In the liver biopsy cohort, rs13023138 G allele was independently associated with severe steatosis (OR 1.17, 95% CI 1.02-1.34; p = .01), NASH (OR 1.22, 95% CI 1.09-1.37; p C allele was linked to higher hepatic representation of M1 macrophages, paralleled by upregulation of pathways related to inflammation and higher expression of CXCR6. Conclusions: The PDCD1 rs13023138 G allele was associated with HCC development in the general population and with liver disease severity in patients at high risk of NASH.

Published
2023
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15. Trends and risk factors of SARS‐CoV‐2 infection in asymptomatic blood donors

Author

Cristiana Bianco, Daniele Prati, Sara Colonia Uceda Renteria, Leonardo Terranova, Giuseppe Lamorte, Serena Pelusi, Luca Valenti, Elisa Erba, Francesco Malvestiti, Alessandro Cherubini, Massimo Oggioni, Luisa Ronzoni, Ferruccio Ceriotti, Angela Lombardi, Elena Coluccio, and Alessandra Berzuini

Subjects
medicine.medical_specialty, Anemia, Immunology, Population, Blood Donors, 030204 cardiovascular system & hematology, Antibodies, Viral, Asymptomatic, Serology, 03 medical and health sciences, 0302 clinical medicine, COVID‐19, Risk Factors, Seroepidemiologic Studies, ABO blood group system, Internal medicine, medicine, Immunology and Allergy, Seroprevalence, Humans, 030212 general & internal medicine, Prospective Studies, Seroconversion, education, Asymptomatic Infections, education.field_of_study, business.industry, SARS-CoV-2, ferritin, ABO blood group, COVID-19, Hematology, medicine.disease, anemia, 3. Good health, Vaccination, Immunoglobulin M, Donor Infectious Disease Testing, Immunoglobulin G, epidemiology, medicine.symptom, business
Abstract

Background A large proportion of SARS‐CoV‐2‐infected individuals does not develop severe symptoms. Serological tests help in evaluating the spread of infection and disease immunization. The aim of this study was to prospectively examine the trends and risk factors of SARS‐CoV‐2 infection in blood donors. Study design and methods We screened 8798 asymptomatic donors presenting in Milan from July 2020 to February 2021 (10,680 presentations) before the vaccination campaign for anti‐nucleoprotein (NP) antibodies, and for anti‐spike receptor‐binding domain (RBD) antibodies and nasopharyngeal swab PCR in those who tested positive. Results The prevalence of anti‐NP+/RBD+ tests increased progressively with time up to ~15% (p 80 AU/ml). Anti‐RBD titers declined during follow‐up, depending on baseline titers (p

Published
2021

16. Development and Validation of a Score for Fibrotic Nonalcoholic Steatohepatitis

Author

Federica Tavaglione, Oveis Jamialahmadi, Antonio De Vincentis, Sami Qadri, Mohammad Erfan Mowlaei, Rosellina Margherita Mancina, Ester Ciociola, Simone Carotti, Giuseppe Perrone, Vincenzo Bruni, Ida Francesca Gallo, Dario Tuccinardi, Cristiana Bianco, Daniele Prati, Silvia Manfrini, Paolo Pozzilli, Antonio Picardi, Marco Caricato, Hannele Yki-Järvinen, Luca Valenti, Umberto Vespasiani-Gentilucci, and Stefano Romeo

Subjects
Hepatology, Gastroenterology
Abstract

Noninvasive assessment of histological features of nonalcoholic fatty liver disease (NAFLD) has been an intensive research area over the last decade. Herein, we aimed to develop a simple noninvasive score using routine laboratory tests to identify, among individuals at high risk for NAFLD, those with fibrotic nonalcoholic steatohepatitis (NASH) defined as NASH, NAFLD activity score ≥4, and fibrosis stage ≥2.The derivation cohort included 264 morbidly obese individuals undergoing intraoperative liver biopsy in Rome, Italy. The best predictive model was developed and internally validated using a bootstrapping stepwise logistic regression analysis (2000 bootstrap samples). Performance was estimated by the area under the receiver operating characteristic curve (AUROC). External validation was assessed in 3 independent European cohorts (Finland, n = 370; Italy, n = 947; England, n = 5368) of individuals at high risk for NAFLD.The final predictive model, designated as Fibrotic NASH Index (FNI), combined aspartate aminotransferase, high-density lipoprotein cholesterol, and hemoglobin A1c. The performance of FNI for fibrotic NASH was satisfactory in both derivation and external validation cohorts (AUROC = 0.78 and AUROC = 0.80-0.95, respectively). In the derivation cohort, rule-out and rule-in cutoffs were 0.10 for sensitivity ≥0.89 (negative predictive value, 0.93) and 0.33 for specificity ≥0.90 (positive predictive value, 0.57), respectively. In the external validation cohorts, sensitivity ranged from 0.87 to 1 (negative predictive value, 0.99-1) and specificity from 0.73 to 0.94 (positive predictive value, 0.12-0.49) for rule-out and rule-in cutoff, respectively.FNI is an accurate, simple, and affordable noninvasive score which can be used to screen for fibrotic NASH in individuals with dysmetabolism in primary health care.

Published
2023
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17. Metabolic dysfunction outperforms ultrasonographic steatosis to stratify hepatocellular carcinoma risk in patients with advanced hepatitis C cured with direct‐acting antivirals.

Author

Pelusi, Serena, Bianco, Cristiana, Colombo, Massimo, Cologni, Giuliana, del Poggio, Paolo, Pugliese, Nicola, Prati, Daniele, Pigozzi, Marie Graciella, D'Ambrosio, Roberta, Lampertico, Pietro, Fagiuoli, Stefano, Valenti, Luca, Prati, Cristiana Bianco Daniele, De Gasperi, Elisabetta, Aghemo, Alessio, de Nicola, Stella, Masetti, Chiara, Gritti, Sara, Pasulo, Lusia, and Iegri, Claudia

Subjects
METABOLIC disorders, HEPATITIS C, HEPATOCELLULAR carcinoma, ANTIVIRAL agents, FATTY liver
Abstract

Background and Aims: Metabolic dysfunction (MD)‐associated fatty liver disease has been proposed to identify individuals at risk of liver events irrespectively of the contemporary presence of other liver diseases. The aim of this study was to examine the impact of MD in patients cured of chronic hepatis C (CHC). Patients and Methods: We analysed data from a real‐life cohort of 2611 Italian patients cured of CHC with direct antiviral agents and advanced liver fibrosis, without HBV/HIV, transplantation and negative for hepatocellular carcinoma (HCC) history (age 61.4 ± 11.8 years, 63.9% males, median follow‐up 34, 24–40 months). Information about ultrasonographic steatosis (US) after sustained virological response was available in 1978. Results: MD affected 58% of patients, diagnosed due to the presence of diabetes (MD‐diabetes, 19%), overweight without diabetes (MD‐overweight, 37%) or multiple metabolic abnormalities without overweight and diabetes (MD‐metabolic, 2%). MD was more frequent than and not coincident with US (32% MD‐only, 23% MD‐US and 13% US‐only). MD was associated with higher liver stiffness (p < 0.05), particularly in patients with MD‐diabetes and MD‐only subgroups, comprising older individuals with more advanced metabolic and liver disease (p < 0.05). At Cox proportional hazard multivariable analysis, MD was associated with increased risk of HCC (HR 1.97, 95% CI 1.27–3.04; p = 0.0023). Further classification according to diagnostic criteria improved risk stratification (p < 0.0001), with the highest risk observed in patients with MD‐diabetes. Patients with MD‐only appeared at highest risk since the sustained virological response achievement (p = 0.008), with a later catch‐up of those with combined MD‐US, whereas US‐only was not associated with HCC. Conclusions: MD is more prevalent than US in patients cured of CHC with advanced fibrosis and identifies more accurately individuals at risk of developing HCC. [ABSTRACT FROM AUTHOR]

Published
2023
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18. Circulating Interlukin-32 and Altered Blood Pressure Control in Individuals with Metabolic Dysfunction

Author

Melissa Tomasi, Alessandro Cherubini, Serena Pelusi, Sara Margarita, Cristiana Bianco, Francesco Malvestiti, Lorenzo Miano, Stefano Romeo, Daniele Prati, and Luca Valenti

Subjects
Inorganic Chemistry, Organic Chemistry, arterial hypertension, hepatic fat accumulation, IL-32, inflammation, MAFLD, NAFLD, General Medicine, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Catalysis, Computer Science Applications
Abstract

Fatty liver disease is most frequently related to metabolic dysfunction (MAFLD) and associated comorbidities, heightening the risk of cardiovascular disease, and is associated with higher hepatic production of IL32, a cytokine linked with lipotoxicity and endothelial activation. The aim of this study was to examine the relationship between circulating IL32 concentration and blood pressure control in individuals with metabolic dysfunction at high risk of MAFLD. IL32 plasma levels were measured by ELISA in 948 individuals with metabolic dysfunction enrolled in the Liver-Bible-2021 cohort. Higher circulating IL32 levels were independently associated with systolic blood pressure (estimate +0.008 log10 per 1 mmHg increase, 95% c.i. 0.002–0.015; p = 0.016), and inversely correlated with antihypertensive medications (estimate −0.189, 95% c.i. −0.291–−0.088, p = 0.0002). Through multivariable analysis, IL32 levels predicted both systolic blood pressure (estimate 0.746, 95% c.i 0.173–1.318; p = 0.010) and impaired blood pressure control (OR 1.22, 95% c.i. 1.09–1.38; p = 0.0009) independently of demographic and metabolic confounders and of treatment. This study reveals that circulating IL32 levels are associated with impaired blood pressure control in individuals at risk of cardiovascular disease.

Published
2023
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19. Increased burden of inherited IRF3 rare genetic variants in Europeans with severe Non-alcoholic fatty liver diease

Author

Luigi Santoro, Daniele Marchelli, Alessandro Cherubini, Elia Casirati, Francesco Malvestiti, Melissa Tomasi, Paola Dongiovanni, Cristiana Bianco, Marica Meroni, Alessandro Federico, Salvatore Petta, Elisabetta Bugianesi, Giorgio Soardo, Umberto Vespasiani Gentilucci, Luca Miele, Helen Reeves, Daniele Prati, Luisa Ronzoni, Giodo Baselli, and Luca Valenti

Subjects
Hepatology, N/A, Settore MED/12 - GASTROENTEROLOGIA
Published
2022

20. Clinical exome sequencing for diagnosing severe cryptogenic liver disease in adults: A case series

Author

Serena Pelusi, Luisa Ronzoni, Francesco Malvestiti, Cristiana Bianco, Ilaria Marini, Roberta D'Ambrosio, Juri Alessandro Giannotta, Giorgio Soardo, Marco Maggioni, Daniele Prati, and Luca Valenti

Subjects
Adult, Carcinoma, Hepatocellular, polygenic risk scores, Hepatology, cryptogenic liver diseases, whole-exome sequencing, Liver Neoplasms, Mutation, Exome Sequencing, Humans, Exome
Abstract

Liver diseases remain unexplained in up to 30% of adult patients; genetic analysis could help establish the correct diagnosis. In six adult patients with cryptogenic liver disease, we performed whole-exome sequencing (WES) and evaluated the individual predisposition to progressive fatty liver disease by polygenic risk scores (PRS). In one patient, WES was allowed to diagnose the Hermansky-Pudlak syndrome. In the other two patients, genetic variants in LDLRAP1/MSH6 and ALDOB genes were identified, contributing to explaining the clinical presentation and disease pathogenesis (50% diagnostic uptake). In the other three patients, rare variants with a high likelihood of disrupting protein function in APOB, ATP7B, ABCB4 and ATP8B1 were identified. One patient who developed hepatocellular carcinoma during the follow-up had a high PRS value. The study supports the role of WES, combined with risk stratification by PRS and accurate clinical assessment in improving the diagnosis and informed management in patients with cryptogenic liver disease, a positive family history or severe fatty liver not fully accounted for by environmental triggers.

Published
2022

21. Rare ATG7 genetic variants predispose patients to severe fatty liver disease

Author

Guido A. Baselli, Oveis Jamialahmadi, Serena Pelusi, Ester Ciociola, Francesco Malvestiti, Marco Saracino, Luigi Santoro, Alessandro Cherubini, Paola Dongiovanni, Marco Maggioni, Cristiana Bianco, Federica Tavaglione, Annalisa Cespiati, Rosellina M. Mancina, Roberta D’Ambrosio, Valentina Vaira, Salvatore Petta, Luca Miele, Umberto Vespasiani-Gentilucci, Alessandro Federico, Jussi Pihlajamaki, Elisabetta Bugianesi, Anna L. Fracanzani, Helen L. Reeves, Giorgio Soardo, Daniele Prati, Stefano Romeo, Luca VC. Valenti, Vittorio Borroni, Antonio Liguori, Luisa Ronzoni, Melissa Tomasi, Angela Lombardi, Mahnoosh Ostadreza, Elia Casirati, Ilaria Marini, Silvia Maier, Chiara Rosso, Gianluca Svegliati Baroni, Carlo Santaniello, Marcello Dallio, Baselli, Guido A, Jamialahmadi, Ovei, Pelusi, Serena, Ciociola, Ester, Malvestiti, Francesco, Saracino, Marco, Santoro, Luigi, Cherubini, Alessandro, Dongiovanni, Paola, Maggioni, Marco, Bianco, Cristiana, Tavaglione, Federica, Cespiati, Annalisa, Mancina, Rosellina M, D'Ambrosio, Roberta, Vaira, Valentina, Petta, Salvatore, Miele, Luca, Vespasiani-Gentilucci, Umberto, Federico, Alessandro, Pihlajamaki, Jussi, Bugianesi, Elisabetta, Fracanzani, Anna L, Reeves, Helen L, Soardo, Giorgio, Prati, Daniele, Romeo, Stefano, and Valenti, Luca Vc

Subjects
Inflammation, Liver Cirrhosis, autophagy, Hepatology, Biopsy, NAFLD, NASH, autophagy, genetics, liver fibrosis, Carcinoma, Liver Neoplasms, NASH, Hepatocellular, Autophagy-Related Protein 7, NAFLD, genetics, liver fibrosis, Humans, Liver, Carcinoma, Hepatocellular, Non-alcoholic Fatty Liver Disease, genetic
Abstract

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants.Methods: We performed whole-exome sequencing in in-dividuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level.Results: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio [OR] 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in the Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p

Published
2022

22. Detailed stratified GWAS analysis for severe COVID-19 in four European populations

Author

Michela Mazzocco, Giuseppe Lamorte, Leonardo Terranova, Cinzia Hu, Xavier Farré, Yascha Khodamoradi, Mauro D'Amato, Christian Herr, David Jiménez, Filippo Martinelli-Boneschi, Anna Latiano, Michael Dreher, Mariella D'Angiò, Rossana Carpani, Francesco Malvestiti, Enrique Navas, Antonio Voza, Anne Ma Dyrhol-Riise, Karina Banasik, Juan Delgado, Florian Kurth, Trinidad Gonzalez Cejudo, Lars Wienbrandt, Carmen de la Horrra, May Sissel Vadla, Aurora Solier, Koldo Garcia-Etxebarria, Karoline I. Gaede, Wolfgang Poller, Eloisa Urrechaga, Paolo Bonfanti, Philipp Schommers, Giuseppe Bellelli, Zehra Karadeniz, Jan Kristian Rybniker, Lisa Knopp, Alfredo Ramirez, Jesus M. Banales, Sibylle Wilfling, Elio Scarpini, Alberto Zanella, Anna Carreras Nolla, Joaquín Dopazo, Sara Pigazzini, Nicole Ludwig, Ingo Kurth, Sandra Ciesek, Dag Arne Lihaug Hoff, Ernesto Contro, Giacomo Grasselli, Maider Intxausti, Kari Risnes, Francisco Mesonero, Thorsten Brenner, Lena J Lippert, Adolfo de Salazar, Maria A. Gutierrez-Stampa, Aaron Blandino Ortiz, María Hernández-Tejero, Rosa Nieto, Jochen Schneider, Anke Hinney, Chiara Scollo, Ariadna Rando-Segura, Victor Moreno, Phillip Suwalski, Valeria Rimoldi, Ricard Ferrer, Jon Lerga-Jaso, Claudio Cappadona, Janine Altmueller, Mahnoosh Ostadreza, Verena Keitel, Lauro Sumoy, Eunate Arana, Annalisa Cavallero, Massimo Castoldi, Stephan Ripke, Antonio Muscatello, Maria J G T Vehreschild, Michael Wittig, Robert Bals, Verena Kopfnagel, David Haschka, Luis Téllez, Heinz Zoller, Isabel Hernández, Carla Bellinghausen, Agustín Ruiz, Manuel Romero-Gómez, Malte C. Ruehlemann, Nikolaus Marx, Luigi Santoro, Silvano Bosari, Carlos Ferrando, M.A. Rodríguez-Gandía, Ronny Myhre, Aleksander Rygh Holten, Marina Elena Cazzaniga, Andreas Lind, Pedro M. Rodrigues, Giacomo Bellani, Alice Braun, Clara Lehmann, Anna Ludovica Fracanzani, Soumya Raychaudhuri, Trine Folseraas, Kerstin U. Ludwig, Lindokuhle Nkambule, Gianni Pezzoli, Julia Kraft, Rocío Gallego-Durán, David Ellinghaus, Rosanna Asselta, Simonas Juzenas, Max Augustin, Mari Niemi, Manolis Kogevinas, Carlo Maj, Serena Pelusi, Stefano Aliberti, Rafael de Cid, Selina Rolker, Victor Andrade, Jonas Bergan, Federico García, Tobias L. Lenz, Andrea Gori, Maria Grazia Valsecchi, Elisa T Helbig, Oliver A. Cornely, Laura Izquierdo-Sanchez, Tom H. Karlsen, Adolfo Garrido Chercoles, Joan Ramon Badia, José Hernández Quero, Benedikt Schaefer, Jatin Arora, Mareike Wendorff, David Pestaña, Thomas Bahmer, Ana Teles, Antonella Ruello, Alessio Gerussi, Francisco J. Medrano, Xiaomin Wang, Joern Walter, Natale Imaz Ayo, Onur oezer, Almut Nebel, Ferruccio Ceriotti, Mercè Boada, Ulf Landmesser, Ana Lleo, Christoph D. Spinner, Sara Bombace, Giuseppe Foti, Antonio Julià, Alessandro Cherubini, Lucia Garbarino, Beatriz Nafria-Jimenez, Hesham ElAbd, Pietro Invernizzi, Paola Faverio, Jordi Barretina, David Toapanta, Iván Galván-Femenía, Sara Marsal, Stefano Duga, Ulrike Protzer, Luisa Roade, Philipp Koehler, Nilda Martinez, Clinton Azuure, Philip Rosenstiel, Daniela Galimberti, Per Hoffmann, Alessandra Bandera, Natalia Blay, Jan Cato Holter, Julia Fazaal, Eike Matthias Wacker, Torsten Feldt, Giovanni Albano, Andre Franke, Mario Cáceres, Roberta Gualtierotti, Sebastian J. Klein, Andreas Glueck, Salvatore Badalamenti, Siegfried Goerg, Isabell Pink, Stefan Schreiber, Leif E. Sander, Javier Fernández, M Seilmaier, Orazio Palmieri, Carsten Skurk, Jan Heyckendorf, Adriana Palom, Stefanie Heilmann-Heimbach, Francesco Blasi, Ilaria My, Mattia Cordioli, Sammra Haider, Giorgio Costantino, Giuseppe Citerio, Nicola Montano, Pedro Castro, Marit Mæhle Grimsrud, Alexander Popov, Ole Bernt Lenning, Holger Neb, Enric Reverter, Erik Solligård, Oliver Witzke, Itziar de Rojas, Flora Peyvandi, Susanne Gjeruldsen Dudman, Daniele Prati, Kristian Tonby, Luca Valenti, Christoph Lange, Alberto Mantovani, Florian Tran, Juan M. Guerrero, Luis Bujanda, Natalia Chueca, Michael Joannidis, Enrique J. Calderon, Elvezia Maria Paraboschi, Vegard Skogen, Bjoern Jensen, Paolo Tentorio, Raúl de Pablo, Cristiana Bianco, Antonio Pesenti, Vicente Friaza, Lars Heggelund, Eva C. Schulte, Markus M. Noethen, Andrea Ganna, Agustín Albillos, Laura Rachele Bettini, Florian Uellendahl-Werth, Covid Aachen Study, Josune Goikoetxea, Jan Kristian Damås, Andrea Biondi, Cristina Sancho, Alessandro Protti, Bettina Heidecker, Ute Hehr, Markus Cornberg, Lise Tuset Gustad, Ana Barreira, Emanuele Pontali, Felix Garcia Sanchez, Johannes R. Hov, Marta Marquié, Maria Buti, Sandra May, Melissa Tomasi, Javier Ampuero, Søren Brunak, Carmen Quereda, Pedro Pablo Espana, Beatriz Mateos, Jan Egil Afset, Mar Riveiro-Barciela, Beatriz Cortés, Thomas Eggermann, Frank Hanses, Julia Schroeder, Karl Erik Mueller, Maria Manunta, Anders Benjamin Kildal, Thomas Illig, Charlotte Thibeault, Maurizio Cecconi, Alena Mayer, Frauke Degenhardt, Douglas Maya-Miles, Alessio Aghemo, Petra Bacher, Marc M. Berger, Francisco Rodriguez-Frias, Fredrik Mueller, Elena Azzolini, Ruben Morilla, Federal Ministry of Education and Research (Germany), German Research Foundation, Novo Nordisk Foundation, Ministero della Salute, European Commission, Fondazione Cariplo, Ministero dell'Istruzione, dell'Università e della Ricerca, Generalitat de Catalunya, Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Fundación 'la Caixa', Eusko Jaurlaritza, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Junta de Andalucía, Centro de Investigación Biomédica en Red Epidemiología y Salud Pública (España), Norwegian Research Council, German Center for Lung Research, Airway Research Center North (Germany), Miltenyi Biotec, University of Cologne, Technical University of Munich, Finnish Institute for Molecular Medicine, University of Helsinki, Saarland University, University Hospital Bonn, Bavarian State Ministry of Education, Science and the Arts, Essen University Hospital, Degenhardt, F, Ellinghaus, D, Juzenas, S, Lerga-Jaso, J, Wendorff, M, Maya-Miles, D, Uellendahl-Werth, F, Elabd, H, Rühlemann, M, Arora, J, Özer, O, Lenning, O, Myhre, R, Vadla, M, Wacker, E, Wienbrandt, L, Ortiz, A, Salazar, A, Chercoles, A, Palom, A, Ruiz, A, Garcia-Fernandez, A, Blanco-Grau, A, Mantovani, A, Zanella, A, Holten, A, Mayer, A, Bandera, A, Cherubini, A, Protti, A, Aghemo, A, Gerussi, A, Ramirez, A, Braun, A, Nebel, A, Barreira, A, Lleo, A, Teles, A, Kildal, A, Biondi, A, Caballero-Garralda, A, Ganna, A, Gori, A, Glück, A, Lind, A, Tanck, A, Hinney, A, Nolla, A, Fracanzani, A, Peschuck, A, Cavallero, A, Dyrhol-Riise, A, Ruello, A, Julià, A, Muscatello, A, Pesenti, A, Voza, A, Rando-Segura, A, Solier, A, Schmidt, A, Cortes, B, Mateos, B, Nafria-Jimenez, B, Schaefer, B, Jensen, B, Bellinghausen, C, Maj, C, Ferrando, C, Horra, C, Quereda, C, Skurk, C, Thibeault, C, Scollo, C, Herr, C, Spinner, C, Gassner, C, Lange, C, Hu, C, Paccapelo, C, Lehmann, C, Angelini, C, Cappadona, C, Azuure, C, Bianco, C, Cea, C, Sancho, C, Hoff, D, Galimberti, D, Prati, D, Haschka, D, Jiménez, D, Pestaña, D, Toapanta, D, Muñiz-Diaz, E, Azzolini, E, Sandoval, E, Binatti, E, Scarpini, E, Helbig, E, Casalone, E, Urrechaga, E, Paraboschi, E, Pontali, E, Reverter, E, Calderón, E, Navas, E, Solligård, E, Contro, E, Arana-Arri, E, Aziz, F, Garcia, F, Sánchez, F, Ceriotti, F, Martinelli-Boneschi, F, Peyvandi, F, Kurth, F, Blasi, F, Malvestiti, F, Medrano, F, Mesonero, F, Rodriguez-Frias, F, Hanses, F, Müller, F, Hemmrich-Stanisak, G, Bellani, G, Grasselli, G, Pezzoli, G, Costantino, G, Albano, G, Cardamone, G, Bellelli, G, Citerio, G, Foti, G, Lamorte, G, Matullo, G, Baselli, G, Kurihara, H, Neb, H, My, I, Kurth, I, Hernández, I, Pink, I, Rojas, I, Galván-Femenia, I, Holter, J, Afset, J, Heyckendorf, J, Kässens, J, Damås, J, Rybniker, J, Altmüller, J, Ampuero, J, Martín, J, Erdmann, J, Banales, J, Badia, J, Dopazo, J, Schneider, J, Bergan, J, Barretina, J, Walter, J, Quero, J, Goikoetxea, J, Delgado, J, Guerrero, J, Fazaal, J, Kraft, J, Schröder, J, Risnes, K, Banasik, K, Müller, K, Gaede, K, Garcia-Etxebarria, K, Tonby, K, Heggelund, L, Izquierdo-Sanchez, L, Bettini, L, Sumoy, L, Sander, L, Lippert, L, Terranova, L, Nkambule, L, Knopp, L, Gustad, L, Garbarino, L, Santoro, L, Téllez, L, Roade, L, Ostadreza, M, Intxausti, M, Kogevinas, M, Riveiro-Barciela, M, Berger, M, Schaefer, M, Niemi, M, Gutiérrez-Stampa, M, Carrabba, M, Figuera Basso, M, Valsecchi, M, Hernandez-Tejero, M, Vehreschild, M, Manunta, M, Acosta-Herrera, M, D'Angiò, M, Baldini, M, Cazzaniga, M, Grimsrud, M, Cornberg, M, Nöthen, M, Marquié, M, Castoldi, M, Cordioli, M, Cecconi, M, D'Amato, M, Augustin, M, Tomasi, M, Boada, M, Dreher, M, Seilmaier, M, Joannidis, M, Wittig, M, Mazzocco, M, Ciccarelli, M, Rodríguez-Gandía, M, Bocciolone, M, Miozzo, M, Ayo, N, Blay, N, Chueca, N, Montano, N, Braun, N, Ludwig, N, Marx, N, Martínez, N, Cornely, O, Witzke, O, Palmieri, O, Faverio, P, Preatoni, P, Bonfanti, P, Omodei, P, Tentorio, P, Castro, P, Rodrigues, P, España, P, Hoffmann, P, Rosenstiel, P, Schommers, P, Suwalski, P, Pablo, R, Ferrer, R, Bals, R, Gualtierotti, R, Gallego-Durán, R, Nieto, R, Carpani, R, Morilla, R, Badalamenti, S, Haider, S, Ciesek, S, May, S, Bombace, S, Marsal, S, Pigazzini, S, Klein, S, Pelusi, S, Wilfling, S, Bosari, S, Volland, S, Brunak, S, Raychaudhuri, S, Schreiber, S, Heilmann-Heimbach, S, Aliberti, S, Ripke, S, Dudman, S, Wesse, T, Zheng, T, Bahmer, T, Eggermann, T, Illig, T, Brenner, T, Pumarola, T, Feldt, T, Folseraas, T, Cejudo, T, Landmesser, U, Protzer, U, Hehr, U, Rimoldi, V, Monzani, V, Skogen, V, Keitel, V, Kopfnagel, V, Friaza, V, Andrade, V, Moreno, V, Albrecht, W, Peter, W, Poller, W, Farre, X, Yi, X, Wang, X, Khodamoradi, Y, Karadeniz, Z, Latiano, A, Goerg, S, Bacher, P, Koehler, P, Tran, F, Zoller, H, Schulte, E, Heidecker, B, Ludwig, K, Fernández, J, Romero-Gómez, M, Albillos, A, Invernizzi, P, Buti, M, Duga, S, Bujanda, L, Hov, J, Lenz, T, Asselta, R, Cid, R, Valenti, L, Karlsen, T, Cáceres, M, Franke, A, Data Science Genetic Epidemiology Lab, and Institute for Molecular Medicine Finland

Subjects
Settore MED/09 - Medicina Interna, Population, Medizin, Genome-wide association study, Human leukocyte antigen, Biology, Genoma humà, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Medisinske Fag: 700 [VDP], ddc:570, Genetics, GWAS, Humans, genetics [COVID-19], education, Molecular Biology, Gene, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Polymorphism, Genetic, Human genome, SARS-CoV-2, GWAS, COVID-19, 1184 Genetics, developmental biology, physiology, Chromosome, COVID-19, genetics [SARS-CoV-2], General Medicine, 3. Good health, GWAS analysis, Respiratory failure, Haplotypes, NAPSA, Technology Platforms, Genètica, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of a well-characterized cohort of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen (HLA) region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a highly pleiotropic ∼0.9-Mb inversion polymorphism and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung., Andre Franke and David Ellinghaus were supported by a grant from the German Federal Ministry of Education and Research (01KI20197), Andre Franke, David Ellinghaus and Frauke Degenhardt were supported by the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). David Ellinghaus was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the Computational Life Sciences funding concept (CompLS grant 031L0165). David Ellinghaus, Karina Banasik and Søren Brunak acknowledge the Novo Nordisk Foundation (grant NNF14CC0001 and NNF17OC0027594). Tobias L. Lenz, Ana Teles and Onur Özer were funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), project numbers 279645989; 433116033; 437857095. Mareike Wendorff and Hesham ElAbd are supported by the German Research Foundation (DFG) through the Research Training Group 1743, "Genes, Environment and Inflammation". This project was supported by a Covid-19 grant from the German Federal Ministry of Education and Research (BMBF; ID: 01KI20197). Luca Valenti received funding from: Ricerca Finalizzata Ministero della Salute RF2016-02364358, Italian Ministry of Health ""CV PREVITAL – strategie di prevenzione primaria cardiovascolare primaria nella popolazione italiana; The European Union (EU) Programme Horizon 2020 (under grant agreement No. 777377) for the project LITMUS- and for the project ""REVEAL""; Fondazione IRCCS Ca' Granda ""Ricerca corrente"", Fondazione Sviluppo Ca' Granda ""Liver-BIBLE"" (PR-0391), Fondazione IRCCS Ca' Granda ""5permille"" ""COVID-19 Biobank"" (RC100017A). Andrea Biondi was supported by the grant from Fondazione Cariplo to Fondazione Tettamanti: "Biobanking of Covid-19 patient samples to support national and international research (Covid-Bank). This research was partly funded by a MIUR grant to the Department of Medical Sciences, under the program "Dipartimenti di Eccellenza 2018–2022". This study makes use of data generated by the GCAT-Genomes for Life. Cohort study of the Genomes of Catalonia, Fundació IGTP. IGTP is part of the CERCA Program / Generalitat de Catalunya. GCAT is supported by Acción de Dinamización del ISCIIIMINECO and the Ministry of Health of the Generalitat of Catalunya (ADE 10/00026); the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) (2017-SGR 529). Marta Marquié received research funding from ant PI19/00335 Acción Estratégica en Salud, integrated in the Spanish National RDI Plan and financed by ISCIIISubdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER-Una manera de hacer Europa")., Beatriz Cortes is supported by national grants PI18/01512. Xavier Farre is supported by VEIS project (001-P-001647) (cofunded by European Regional Development Fund (ERDF), “A way to build Europe”). Additional data included in this study was obtained in part by the COVICAT Study Group (Cohort Covid de Catalunya) supported by IsGlobal and IGTP, EIT COVID-19 Rapid Response activity 73A and SR20-01024 La Caixa Foundation. Antonio Julià and Sara Marsal were supported by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). Antonio Julià was also supported the by national grant PI17/00019 from the Acción Estratégica en Salud (ISCIII) and the FEDER. The Basque Biobank is a hospitalrelated platform that also involves all Osakidetza health centres, the Basque government's Department of Health and Onkologikoa, is operated by the Basque Foundation for Health Innovation and Research-BIOEF. Mario Cáceres received Grants BFU2016-77244-R and PID2019-107836RB-I00 funded by the Agencia Estatal de Investigación (AEI, Spain) and the European Regional Development Fund (FEDER, EU). Manuel Romero Gómez, Javier Ampuero Herrojo, Rocío Gallego Durán and Douglas Maya Miles are supported by the “Spanish Ministry of Economy, Innovation and Competition, the Instituto de Salud Carlos III” (PI19/01404, PI16/01842, PI19/00589, PI17/00535 and GLD19/00100), and by the Andalussian government (Proyectos Estratégicos-Fondos Feder PE-0451-2018, COVID-Premed, COVID GWAs). The position held by Itziar de Rojas Salarich is funded by grant FI20/00215, PFIS Contratos Predoctorales de Formación en Investigación en Salud. Enrique Calderón's team is supported by CIBER of Epidemiology and Public Health (CIBERESP), "Instituto de Salud Carlos III". Jan Cato Holter reports grants from Research Council of Norway grant no 312780 during the conduct of the study. Dr. Solligård: reports grants from Research Council of Norway grant no 312769. The BioMaterialBank Nord is supported by the German Center for Lung Research (DZL), Airway Research Center North (ARCN). The BioMaterialBank Nord is member of popgen 2.0 network (P2N). Philipp Koehler has received non-financial scientific grants from Miltenyi Biotec GmbH, Bergisch Gladbach, Germany, and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. He is supported by the German Federal Ministry of Education and Research (BMBF)., Oliver A. Cornely is supported by the German Federal Ministry of Research and Education and is funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – CECAD, EXC 2030 – 390661388. The COMRI cohort is funded by Technical University of Munich, Munich, Germany. Genotyping was performed by the Genotyping laboratory of Institute for Molecular Medicine Finland FIMM Technology Centre, University of Helsinki. This work was supported by grants of the Rolf M. Schwiete Stiftung, the Saarland University, BMBF and The States of Saarland and Lower Saxony. Kerstin U. Ludwig is supported by the German Research Foundation (DFG, LU-1944/3-1). Genotyping for the BoSCO study is funded by the Institute of Human Genetics, University Hospital Bonn. Frank Hanses was supported by the Bavarian State Ministry for Science and Arts. Part of the genotyping was supported by a grant to Alfredo Ramirez from the German Federal Ministry of Education and Research (BMBF, grant: 01ED1619A, European Alzheimer DNA BioBank, EADB) within the context of the EU Joint Programme – Neurodegenerative Disease Research (JPND). Additional funding was derived from the German Research Foundation (DFG) grant: RA 1971/6-1 to Alfredo Ramirez. Philip Rosenstiel is supported by the DFG (CCGA Sequencing Centre and DFG ExC2167 PMI and by SH state funds for COVID19 research). Florian Tran is supported by the Clinician Scientist Program of the Deutsche Forschungsgemeinschaft Cluster of Excellence “Precision Medicine in Chronic Inflammation” (EXC2167). Christoph Lange and Jan Heyckendorf are supported by the German Center for Infection Research (DZIF). Thorsen Brenner, Marc M Berger, Oliver Witzke und Anke Hinney are supported by the Stiftung Universitätsmedizin Essen. Marialbert Acosta-Herrera was supported by Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. Eva C Schulte is supported by the Deutsche Forschungsgemeinschaft (DFG; SCHU 2419/2-1).

Published
2022
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23. Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real-Life Cohort Study

Author

Gianpaolo Lorini, Roberta D'Ambrosio, Monia Mendeni, Angelo Pan, Valentina Zuccaro, Canio Carriero, Massimo Colombo, Gianpiero Aimo, Natalia Terreni, Barbara Menzaghi, Massimo Memoli, Alessandro Soria, Aldo Autolitano, Elisabetta Degasperi, Serena Pelusi, M. Puoti, Luca Valenti, Cristiana Bianco, Ombretta Spinelli, Elisabetta Buscarini, Antonella d'Arminio Monforte, Sara Gritti, Paolo Del Poggio, Alessia Giorgini, Tiziana Quirino, T. Re, Marie Graciella Pigozzi, Maria Grazia Rumi, Maria Chiara Colombo, Giuliana Cologni, Daniele Prati, Angiola Spinetti, Stefano Fagiuoli, Mauro Viganò, Isabella Carderi, Luisa Pasulo, Pietro Lampertico, Alessio Aghemo, Paolo Bonfanti, C. Iegri, Valenti, L, Pelusi, S, Aghemo, A, Gritti, S, Pasulo, L, Bianco, C, Iegri, C, Cologni, G, Degasperi, E, D'Ambrosio, R, del Poggio, P, Soria, A, Puoti, M, Carderi, I, Pigozzi, M, Carriero, C, Spinetti, A, Zuccaro, V, Memoli, M, Giorgini, A, Vigano, M, Rumi, M, Re, T, Spinelli, O, Colombo, M, Quirino, T, Menzaghi, B, Lorini, G, Pan, A, D'Arminio Monforte, A, Buscarini, E, Autolitano, A, Bonfanti, P, Terreni, N, Aimo, G, Mendeni, M, Prati, D, Lampertico, P, and Fagiuoli, S

Subjects
Liver Cirrhosis, medicine.medical_specialty, Carcinoma, Hepatocellular, Sustained Virologic Response, Chronic liver disease, Gastroenterology, Antiviral Agents, Cohort Studies, 03 medical and health sciences, Liver disease, 0302 clinical medicine, Internal medicine, Diabetes mellitus, Diabetes Mellitus, Medicine, Humans, 2. Zero hunger, Hepatology, business.industry, Hazard ratio, Liver Neoplasms, Odds ratio, Hepatitis C, Chronic, medicine.disease, 3. Good health, Metformin, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, HCV, 030211 gastroenterology & hepatology, business, Body mass index, medicine.drug
Abstract

The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real-life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE-Lombardia registry). In a subset (n=748), liver stiffness measurement (LSM) was available at baseline and follow-up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2, 1.03-1.09) and diabetes (OR 2.01 [1.65-2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35-0.60]; P&nbsp

Published
2021

24. Definition of Healthy Ranges for Alanine Aminotransferase Levels: A 2021 Update

Author

Mirella Fraquelli, Roberta D'Ambrosio, Francesco Malvestiti, Luca Valenti, Serena Pelusi, Daniele Prati, Roberta Trotti, Agostino Colli, Emmanuel Tsochatzis, Pietro Lampertico, Ferruccio Ceriotti, Laura Iogna Prat, Cristiana Bianco, Alessandra Berzuini, and Massimo Colombo

Subjects
Adult, Male, medicine.medical_specialty, Percentile, Adolescent, Blood Donors, RC799-869, Chronic liver disease, Body Mass Index, 03 medical and health sciences, Liver disease, Young Adult, 0302 clinical medicine, Sex Factors, Reference Values, Internal medicine, Epidemiology, medicine, Odds Ratio, Humans, 030304 developmental biology, Aged, 2. Zero hunger, 0303 health sciences, Hepatology, Receiver operating characteristic, Liver Diseases, Age Factors, Alanine Transaminase, Odds ratio, Diseases of the digestive system. Gastroenterology, Middle Aged, medicine.disease, Healthy Volunteers, 3. Good health, Cross-Sectional Studies, Editorial, ROC Curve, Cohort, 030211 gastroenterology & hepatology, Female, Body mass index
Abstract

The changing epidemiology of liver disease, and modifications in the recommended analytical methodology call for a re-evaluation of the upper reference limits (URLs) of alanine aminotransferase (ALT) levels. Using the same ap- proach consolidated 20 years ago to define the healthy population, we defined the URL for the newly recommended International Federation of Clinical Chemistry (IFCC) standardized test. In a cross-sectional study, we examined 21,296 apparently healthy blood donors (age 18-65 years) and calculated the sex-specific URL by the 95th percentile in indi- viduals without risk factors for liver disease. These were tested for the ability to predict liver damage in a subset of 745 participants with dysmetabolism, in an independent cohort of 977 unselected donors, and in 899 patients with chronic liver disease. ALT levels were measured by the IFCC test. Male sex, body mass index, glucose, lipids, ferritin, hyper- tension, and younger age were independent ALT predictors (P < 0.001). Updated URLs were identified at 42/30 U/L in males/females, approximately 30% lower than those currently recommended by the IFCC. Due to improved sensitiv- ity, they conferred the ability to detect steatosis and significant fibrosis in individuals with dysmetabolism (odds ratio [OR] = 2.31, range 1.40-3.80, P = 0.001; and OR = 3.35, range 1.19-9.42, P = 0.021; respectively), although with a limited accuracy, and significant fibrosis in unselected donors (OR = 2.32, 1.02-5.31, P = 0.045). Updated URLs had a moderate to high accuracy to discriminate liver conditions (area under the receiver operating characteristic curve = 0.81, range 0.78-0.91). Conclusion: Updated URLs by the IFCC method were lower than those calculated in initial studies, but higher than those in use with the recommended old, nonstandardized method, and were able to better predict liver disease. The limited awareness that different techniques are still in use should be regarded as a possible source of medical errors.

Published
2021

25. Genetic insight into COVID‐19‐related liver injury

Author

Cristiana Bianco, Luca Valenti, Guido Baselli, Maria Manunta, Luigia Scudeller, Serena Pelusi, Giacomo Grasselli, Francesco Malvestiti, Daniele Prati, Luigi Santoro, and Alessandra Bandera

Subjects
Population, Inflammation, macromolecular substances, Disease, Bioinformatics, Letter to the Editors, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, education, Letter to the Editor, Liver injury, Hepatitis, education.field_of_study, Hepatology, SARS-CoV-2, business.industry, Liver Diseases, fungi, Fatty liver, COVID-19, Alanine Transaminase, medicine.disease, Liver, Infectious disease (medical specialty), 030220 oncology & carcinogenesis, Cohort, 030211 gastroenterology & hepatology, medicine.symptom, business
Abstract

Metabolic dysfunction and fatty liver disease (FLD) are epidemiologically associated with increased risk of severe COVID-19 requiring hospitalization (1, 2). The mechanism may encompass promotion of inflammation by facilitation of liver injury, which is a frequent feature of severe COVID-19 (3). However, metabolic dysfunction rather than FLD itself may induce disease progression (2). Indeed, we previously showed that a genetic FLD-risk score does not predispose to severe COVID-19 in UK Biobank population-based cohort (UKBB) (4).

Published
2020
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26. Red cell–bound antibodies and transfusion requirements in hospitalized patients with COVID-19

Author

Laura Porretti, Luca Valenti, Giuliana Gregato, Giuseppe Lamorte, Alessandra Bandera, Maria Manunta, Giacomo Grasselli, Nicoletta Revelli, Alberto Zanella, Francesco Bertolini, Stefania Villa, Alessandra Cattaneo, Daniele Prati, Cinzia Paccapelo, Francesca Truglio, Cristiana Bianco, Alessandra Berzuini, Elisa Erba, and Andrea Gori

Subjects
Male, Blood transfusion, Erythrocytes, Hospitalized patients, medicine.medical_treatment, 030204 cardiovascular system & hematology, Biochemistry, Immunoglobulin G, 0302 clinical medicine, Coombs test, Medicine, Letter to Blood, Aged, 80 and over, medicine.diagnostic_test, biology, Anemia, Hematology, Middle Aged, Coombs Test, 030220 oncology & carcinogenesis, Female, Antibody, Coronavirus Infections, Erythrocyte Transfusion, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Patients, Immunology, Pneumonia, Viral, Antibodies, 03 medical and health sciences, Betacoronavirus, Internal medicine, mental disorders, Humans, Blood Transfusion, Pandemics, Aged, Autoantibodies, Red Cell, business.industry, SARS-CoV-2, COVID-19, Cell Biology, medicine.disease, biology.protein, business
Abstract

Berzuini et al report the observation that nearly half of patients with COVID-19 tested at their blood center had a positive direct antiglobulin test (DAT). However, eluates did not react with any test cells but did react with red cells from other patients with COVID-19 that were DAT negative. This suggests that COVID-19 may modulate the red cell membrane and present novel antigenic epitopes.

Published
2020

27. Genetic risk scores and personalization of care in fatty liver disease

Author

Stefano Romeo, Cristiana Bianco, Luca Valenti, and Federica Tavaglione

Subjects
Pharmacology, Liver Cirrhosis, Cirrhosis, Carcinoma, Hepatocellular, business.industry, Fatty liver, Liver Neoplasms, Disease, medicine.disease, Bioinformatics, Precision medicine, Chronic liver disease, Non-alcoholic Fatty Liver Disease, Risk Factors, Hepatocellular carcinoma, Drug Discovery, Nonalcoholic fatty liver disease, Genetic predisposition, Disease Progression, Medicine, Humans, business
Abstract

Nonalcoholic fatty liver disease is the leading cause of chronic liver disease. Genetic predisposition, lifestyle, and metabolic comorbidities concur to nonalcoholic fatty liver disease development and progression to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Improvement in risk stratification and development of effective therapies for nonalcoholic steatohepatitis are key unmet clinical needs. Knowledge emerging from genomics could meet this need. A polygenic risk score (PRS) is calculated by summing the number of trait-associated alleles carried by an individual, which can be weighted by their effect size on the trait and captures the individual's genetic risk to develop a disease. In this review, we focalize on the potential use of PRSs for disease detection at an early stage and stratification of the risk of progression to severe forms. PRSs may represent robust instruments to implement targeted prevention programs, hepatocellular carcinoma surveillance in at-risk individuals, and to develop precision medicine therapeutic approaches.

Published
2021

28. Reply to: 'Polygenic risk score: A promising predictor for hepatocellular carcinoma in the population with non-alcoholic fatty liver disease'

Author

Oveis Jamialahmadi, Luca Valenti, Cristiana Bianco, Stefano Romeo, and Serena Pelusi

Subjects
Liver Cirrhosis, medicine.medical_specialty, education.field_of_study, Cirrhosis, Carcinoma, Hepatocellular, Hepatology, business.industry, Fatty liver, Population, Liver Neoplasms, Non alcoholic, Disease, medicine.disease, Gastroenterology, Non-alcoholic Fatty Liver Disease, Risk Factors, Hepatocellular carcinoma, Internal medicine, medicine, Humans, Polygenic risk score, business, education
Published
2021

29. Rare Atg7 Genetic Variants Predispose to Severe Fatty Liver Disease

Author

Daniele Prati, Helen L. Reeves, Paola Dongiovanni, Alessandro Federico, Federica Tavaglione, Jussi Pihlajamäki, Roberta D'Ambrosio, Francesco Malvestiti, Ester Ciociola, Stefano Romeo, Serena Pelusi, Jole Costanza, Giorgio Soardo, Anna Ludovica Fracanzani, Epidemic study investigators, Guido Baselli, Luca Miele, Salvatore Petta, Rosellina Margherita Mancina, Elisabetta Bugianesi, Cristiana Bianco, Luca Valenti, Marco Maggioni, Umberto Vespasiani, and A. Cespiati

Subjects
medicine.medical_specialty, medicine.diagnostic_test, business.industry, Fatty liver, medicine.disease, Chronic liver disease, Gastroenterology, Pathogenesis, Liver disease, Ballooning degeneration, Liver biopsy, Internal medicine, Hepatocellular carcinoma, medicine, Steatosis, business
Abstract

Background&Aims: Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease and has a strong heritable component. The aim of this study was to identify new genes involved in NAFLD pathogenesis. Methods: We examined rare variants captured by whole-exome sequencing in individuals with severe fibrosis or hepatocellular carcinoma due to NAFLD (severe NAFLD, n=301) after variant prioritization. We replicated the results in the UK Biobank and the Liver biopsy cohort (n=2268). Results: We observed an enrichment of the p.P426L variant (rs143545741 C>T; OR=7.2, 2.3-17.3; p C; MAF=0.060 vs. 0.035; OR=1.7, 1.2-2.5; p=0.003). In the UK Biobank cohort, the p.V471A variant was associated with NAFLD (p=0.009) and liver disorders (p=0.004). In the Liver biopsy cohort, the p.V471A variant was linked with severe fibrosis, particularly in those with severe steatosis (p=0.002). Moreover, p.V471A was an independent predictor of hepatocellular ballooning (p=0.007). Hepatic ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers (n=125 with available transcriptomic). ATG7 protein localized to non-parenchymal cells and predominantly in periportal hepatocytes, more so in the presence of ballooning. Finally, we confirmed that in vitro the p.P426L and p.V471A variants result in a protein loss-of-function. Conclusion: We identified novel rare and low-frequency ATG7 variants contributing to severe NAFLD. The underlying mechanism may involve impairment of autophagy and facilitation of hepatocellular ballooning degeneration.

Published
2021
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31. A polygenic risk score for progressive non-alcoholic fatty liver disease risk stratification

Author

Cristiana Bianco, Serena Pelusi, Guido Alessandro Baselli, Irene Zanoni, Alice Taliento, Paola Dongiovanni, Raffaela Rametta, Vittorio Borroni, Alessandro Federico, Umberto Vespasiani Gentilucci, Roberta D’Ambrosio, Elisabetta Bugianesi, Salvatore Petta, Luca Miele, Helen L. Reeves, Anna Ludovica Fracanzani, Giorgio Soardo, Daniele Prati, and Luca Valenti

Subjects
Hepatology, N/A, Settore MED/12 - GASTROENTEROLOGIA
Published
2020

32. Noninvasive risk stratification in nonalcoholic fatty liver disease: a polygenic risk score

Author

Cristiana Bianco, I. Zanoni, A.E. Taliento, Serena Pelusi, Luca Miele, V. Borroni, A.L. Fracanzani, Luca Valenti, S. Petta, Roberta D'Ambrosio, Umberto Vespasiani-Gentilucci, Guido Baselli, R. Rametta, Giorgio Soardo, Elisabetta Bugianesi, Alessandro Federico, Paola Dongiovanni, Helen L. Reeves, and Daniele Prati

Subjects
medicine.medical_specialty, Hepatology, business.industry, Internal medicine, Nonalcoholic fatty liver disease, Risk stratification, Gastroenterology, medicine, Polygenic risk score, medicine.disease, business
Published
2020
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33. Whole exome sequencing for the diagnosis of rare genetic conditions in patients with unexplained liver disease and complex clinical presentation

Author

Guido Baselli, Serena Pelusi, Francesco Malvestiti, C. Santaniello, Daniele Prati, Lucio Santoro, W. Barcellini, Roberta D'Ambrosio, Luca Valenti, M. Miozzo, Cristiana Bianco, and Giorgio Soardo

Subjects
Liver disease, Hepatology, business.industry, Gastroenterology, Medicine, In patient, Presentation (obstetrics), business, medicine.disease, Bioinformatics, Exome sequencing
Published
2021
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34. Definition of healthy ranges for alanine aminotransferase levels: a 2020 update

Author

Serena Pelusi, Luca Valenti, Roberta D'Ambrosio, Alessandra Berzuini, María Isabel Colombo, L. Iogna Prat, Cristiana Bianco, Daniele Prati, Ferruccio Ceriotti, Emmanuel Tsochatzis, R. Trotti, Guido Baselli, and Mirella Fraquelli

Subjects
medicine.medical_specialty, Endocrinology, Hepatology, business.industry, Internal medicine, Gastroenterology, medicine, Alanine aminotransferase, business
Published
2021
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35. Future counselling of donors and recipients of blood products concerning prion-related diseases

Author

J. O'Riordan, C. P. Engelfriet, K. Nakajima, Harvey G. Klein, M. A. V. Carasa, P. Turek, L. Muylle, James L. Bernat, Cristiana Bianco, R. A. Gallastegui, Tom Krusius, Paolo Rebulla, T. Mäki, T. Shirato, H. W. Reesink, Daniele Prati, Patricia Hewitt, H. M. Dupuis, Peter Flanagan, Ebbe Dickmeiss, C. K. Lin, Roger Y. Dodd, S. Wendel, Gastroenterology and Hepatology, and Other departments

Subjects
Counseling, medicine.medical_specialty, Consensus, business.industry, Blood Donors, Hematology, General Medicine, Prion Diseases, Text mining, Family medicine, Humans, Mass Screening, Medicine, Human medicine, Diagnostic Errors, business, Forecasting
Published
2003

36. Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores

Author

Thomas Berg, Antonio Liguori, Giorgio Soardo, Quentin M. Anstee, Guido Baselli, Umberto Vespasiani-Gentilucci, Paola Dongiovanni, Cristiana Bianco, Salvatore Petta, Jochen Hampe, Felix Stickel, Janett Fischer, Stefano Romeo, Daniele Prati, Anna Ludovica Fracanzani, Luca Miele, R. Spagnuolo, Alessandro Federico, Marica Meroni, Luigi Santoro, Elisabetta Bugianesi, Roberta D'Ambrosio, Anna Alisi, Serena Pelusi, Irene Zanoni, Oveis Jamialahmadi, S. Maier, V. Borroni, Luca Valenti, Helen L. Reeves, Bianco, C., Jamialahmadi, O., Pelusi, S., Baselli, G., Dongiovanni, P., Zanoni, I., Santoro, L., Maier, S., Liguori, A., Meroni, M., Borroni, V., D'Ambrosio, R., Spagnuolo, R., Alisi, A., Federico, A., Bugianesi, E., Petta, S., Miele, L., Vespasiani-Gentilucci, U., Anstee, Q. M., Stickel, F., Hampe, J., Fischer, J., Berg, T., Fracanzani, A. L., Soardo, G., Reeves, H., Prati, D., Romeo, S., Valenti, L., Bianco C., Jamialahmadi O., Pelusi S., Baselli G., Dongiovanni P., Zanoni I., Santoro L., Maier S., Liguori A., Meroni M., Borroni V., D'Ambrosio R., Spagnuolo R., Alisi A., Federico A., Bugianesi E., Petta S., Miele L., Vespasiani-Gentilucci U., Anstee Q.M., Stickel F., Hampe J., Fischer J., Berg T., Fracanzani A.L., Soardo G., Reeves H., Prati D., Romeo S., and Valenti L.

Subjects
0301 basic medicine, Oncology, Liver Cirrhosis, Male, Multifactorial Inheritance, Cirrhosis, 0302 clinical medicine, Risk Factors, Non-alcoholic Fatty Liver Disease, Hepatic fat, Adiposity, education.field_of_study, Fatty liver, Liver Neoplasms, Middle Aged, Prognosis, Europe, Liver, Cohort, 030211 gastroenterology & hepatology, Biomarker, Genetics, Non-alcoholic fatty liver disease, Female, Liver cancer, Cohort study, medicine.medical_specialty, Carcinoma, Hepatocellular, Settore MED/12 - GASTROENTEROLOGIA, Population, Risk Assessment, 03 medical and health sciences, Biomarker, Cirrhosis, Genetics, Hepatic fat, Non-alcoholic fatty liver disease, Cross-Sectional Studies, Europe, Female, Genetic Predisposition to Disease, Humans, Liver, Liver Cirrhosis, Male, Mediation Analysis, Middle Aged, Multifactorial Inheritance, Predictive Value of Tests, Prognosis, Risk Assessment, Risk Factors, Adiposity, Carcinoma, Hepatocellular, Non-alcoholic Fatty Liver Disease, Genetic, Predictive Value of Tests, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, education, Cirrhosi, Mediation Analysis, Hepatology, business.industry, Carcinoma, Case-control study, Hepatocellular, medicine.disease, digestive system diseases, 030104 developmental biology, Cross-Sectional Studies, business
Abstract

Background & Aims: Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification. Methods: We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5). Results: In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p

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37. MAFLD vs NAFLD: Let the contest begin!

Author

Cristiana Bianco, Michelle T. Long, Luca Valenti, Salvatore Petta, Stefano Romeo, Bianco C., Romeo S., Petta S., Long M.T., and Valenti L.

Subjects
obesity, Hepatology, business.industry, steatosi, MEDLINE, medicine.disease, Bioinformatics, CONTEST, Obesity, Article, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, Non-alcoholic Fatty Liver Disease, 030220 oncology & carcinogenesis, medicine, fatty liver disease, Humans, 030211 gastroenterology & hepatology, Steatosis, Insulin Resistance, business, Human
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38. Genetic predisposition similarities between NASH and ASH: Identification of new therapeutic targets

Author

Luca Valenti, Elia Casirati, Cristiana Bianco, and Francesco Malvestiti

Subjects
SREBP, sterol response element binding protein, Alcoholic liver disease, LDs, lipid droplets, MBOAT7, membrane bound O-acyltransferase domain-containing 7, AA, arachidonic acid, PPAR, peroxisome proliferator-activated receptor, RC799-869, Disease, Review, Bioinformatics, TNF-α, tumour necrosis factor-α, Liver disease, GPR55, G protein-coupled receptor 55, Immunology and Allergy, IL-, interleukin, HFE, homeostatic iron regulator, genetics, GCKR, glucokinase regulator, PNPLA3, patatin like phospholipase domain containing 3, Fatty liver, Gastroenterology, Diseases of the digestive system. Gastroenterology, FGF19, fibroblast growth factor 19, Lipotoxicity, ASH, alcoholic steatohepatitis, PRS, polygenic risk score, FFAs, free fatty acids, HSC, hepatic stellate cells, alcoholic liver disease, IL32, TAG, triacylglycerol, precision medicine, NASH, non-alcoholic steatohepatitis, interleukin-32, HSD17B13, hydroxysteroid 17-beta dehydrogenase 13, steatohepatitis, DNL, de novo lipogenesis, MBOAT7, ER, endoplasmic reticulum, FLD, fatty liver disease, FXR, farnesoid X receptor, Internal Medicine, medicine, Genetic predisposition, PNPLA3, therapy, LPI, lysophosphatidyl-inositol, Hepatology, business.industry, cirrhosis, PUFAs, polyunsaturated fatty acids, non-alcoholic fatty liver disease, medicine.disease, Mitochondrial amidoxime reducing component 1, MARC1, mitochondrial amidoxime reducing component 1, fatty liver disease, Steatohepatitis, business, HCC, hepatocellular carcinoma, DAG, diacylglycerol
Abstract

Summary: Fatty liver disease can be triggered by a combination of excess alcohol, dysmetabolism and other environmental cues, which can lead to steatohepatitis and can evolve to acute/chronic liver failure and hepatocellular carcinoma, especially in the presence of shared inherited determinants. The recent identification of the genetic causes of steatohepatitis is revealing new avenues for more effective risk stratification. Discovery of the mechanisms underpinning the detrimental effect of causal mutations has led to some breakthroughs in the comprehension of the pathophysiology of steatohepatitis. Thanks to this approach, hepatocellular fat accumulation, altered lipid droplet remodelling and lipotoxicity have now taken centre stage, while the role of adiposity and gut-liver axis alterations have been independently validated. This process could ignite a virtuous research cycle that, starting from human genomics, through omics approaches, molecular genetics and disease models, may lead to the development of new therapeutics targeted to patients at higher risk. Herein, we also review how this knowledge has been applied to: a) the study of the main PNPLA3 I148M risk variant, up to the stage of the first in-human therapeutic trials; b) highlight a role of MBOAT7 downregulation and lysophosphatidyl-inositol in steatohepatitis; c) identify IL-32 as a candidate mediator linking lipotoxicity to inflammation and liver disease. Although this precision medicine drug discovery pipeline is mainly being applied to non-alcoholic steatohepatitis, there is hope that successful products could be repurposed to treat alcohol-related liver disease as well.

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