A Type 1 Diabetes Genetic Risk Score Predicts Progression of Islet Autoimmunity and Development of Type 1 Diabetes in Individuals at Risk
Author:
Redondo Maria J.1ORCID, Geyer Susan2, Steck Andrea K.3ORCID, Sharp Seth4, Wentworth John M.5ORCID, Weedon Michael N.4, Antinozzi Peter6, Sosenko Jay7ORCID, Atkinson Mark8, Pugliese Alberto7, Oram Richard A.4, Antinozzi P., Atkinson M., Battaglia M., Becker D., Bingley P., Bosi E., Buckner J., Colman P., Gottlieb P., Herold K., Insel R., Kay T., Knip M., Marks J.B., Moran A., Palmer J., Peakman M., Philipson L., Pugliese A., Raskin P., Rodriguez H., Roep B., Russell W., Schatz D.A., Wherrett D., Wilson D., Winter W., Ziegler A., Benoist C., Blum J., Chase P., Clare-Salzler M., Clynes R., Eisenbarth G., Fathman C.G., Grave G., Hering B., Kaufman F., Leschek E., Mahon J., Nanto-Salonen K., Nepom G., Orban T., Parkman R., Pescovitz M., Peyman J., Roncarolo M., Simell O., Sherwin R., Siegelman M., Steck A., Thomas J., Trucco M., Wagner J., Greenbaum , Carla J., Bourcier Katarzyna, Insel Richard, Krischer Jeffrey P., Leschek Ellen, Rafkin Lisa, Spain Lisa, Cowie Catherine, Foulkes Mary, Krause-Steinrauf Heidi, Lachin John M., Malozowski Saul, Peyman John, Ridge John, Savage Peter, Skyler Jay S., Zafonte Stephanie J., Kenyon Norma S., Santiago Irene, Sosenko Jay M., Bundy Brian, Abbondondolo Michael, Adams Timothy, Amado Darlene, Asif Ilma, Boonstra Matthew, Bundy Brian, Burroughs Cristina, Cuthbertson David, Deemer Mary, Eberhard Christopher, Fiske Steve, Ford Julie, Garmeson Jennifer, Guillette Heather, Geyer Susan, Hays Brian, Henderson Courtney, Henry Martha, Heyman Kathleen, Hsiao Belinda, Karges Christina, Keaton Nichole, Kinderman Amanda, Law Pat, Leinbach Ashely, Linton Cristin, Liu Shu, Lloyd Jennifer, Malloy Jamie, Maddox Kristin, Martin Julie, Miller Jessica, Milliot Eric, Moore Margaret, Muller Sarah, Nguyen Thuy, O’Donnell Ryan, Oduah Vanessa, Pilger Jennifer, Roberts Amy, Sadler Kelly, Stavros Tina, Tamura Roy, Wood Keith, Xu Ping, Young Kenneth, Alies Persida, Badias Franz, Baker Aaron, Bassi Monica, Beam Craig, Boulware David, Bounmananh London, Bream Susan, Freeman Doug, Gough Jessica, Ginem Jinin, Granger Moriah, Holloway Mary, Kieffer Michelle, Lane Page, Nallamshetty Lavanya, Parrimon Yazandra, Paulus Kate, Ramiro Joy, Ritzie AQesha Luvon, Sharma Archana, Shor Audrey, Song Xiaohong, Terry Amanda, Weinberger Jeanne, Wootten Margaret, Harding Pamela, McDonough Susan, McGee Paula F., Hess Kimberly Owens, Phoebus Donna, Quinlan Scott, Raiden Erica, Batts Emily, Buddy Chris, Kirpatrick Kristin, Ramey Mary, Shultz Ann, Webb Chris, Romesco Melita, Fradkin Judith, Blumberg Emily, Beck Gerald, Brillon David, Gubitosi-Klug Rose, Laffel Lori, Veatch Robert, Wallace Dennis, Braun Jonathan, Lernmark Ake, Lo Bernard, Mitchell Herman, Naji Ali, Nerup Jorn, Orchard Trevor, Steffes Michael, Tsiatis Anastasios, Zinman Bernard, Loechelt Brett, Baden Lindsey, Green Michael, Weinberg Adriana, Marcovina Santica, Palmer Jerry P., Weinberg Adriana, Yu Liping, Babu Sunanda, Winter William, Eisenbarth George S., Bingley Polly, Clynes Raphael, DiMeglio Linda, Eisenbarth George, Hays Brian, Marks Jennifer, Matheson Della, Rodriguez Henry, Wilson Darrell, Redondo Maria J., Gomez David, Zheng Xiati, Pena Sandra, Pietropaolo Massimo, Batts Emily, Brown Tyler, Buckner Jane, Dove Angela, Hammond Marissa, Hefty Deborah, Klein Jani, Kuhns Kristen, Letlau McKenzie, Lord Sandra, McCulloch-Olson Marli, Miller Lisa, Nepom Gerald, Odegard Jared, Ramey Mary, Sachter Elaine, St. Marie Marissa, Stickney Kimberly, VanBuecken Dana, Vellek Ben, Webber Christine, Allen Laurie, Bollyk Jenna, Hilderman Nicole, Ismail Hebatullah, Lamola Steve, Sanda Srinath, Vendettuoli Heather, Tridgell David, Monzavi Roshanak, Bock Meredith, Fisher Lynda, Halvorson Mary, Jeandron Debra, Kim Mimi, Wood Jamie, Geffner Mitchell, Kaufman Francine, Parkman Robertson, Salazar Christine, Goland Robin, Clynes Raphael, Cook Steve, Freeby Matthew, Gallagher Mary Pat, Gandica Rachelle, Greenberg Ellen, Kurland Amy, Pollak Sarah, Wolk Amy, Chan Mary, Koplimae Linda, Levine Elizabeth, Smith Kelly, Trast Jeniece, DiMeglio Linda, Blum Janice, Evans-Molina Carmella, Hufferd Robin, Jagielo Bonnie, Kruse Christy, Patrick Vanessa, Rigby Mark, Spall Maria, Swinney Kim, Terrell Jennifer, Christner Lyla, Ford LeeAnn, Lynch Sheryl, Menendez Martha, Merrill Patricia, Pescovitz Mark, Rodriguez Henry, Alleyn Cielo, Baidal David, Fay Steve, Gaglia Jason, Resnick Brittany, Szubowicz Sarah, Weir Gordon, Benjamin Ronald, Conboy Debbie, deManbey Andrea, Jackson Richard, Jalahej Heyam, Orban Tihmar, Ricker Alyne, Wolfsdorf Joseph, Zhang Hui H., Wilson Darrell, Aye Tandy, Baker Bonita, Barahona Karen, Buckingham Bruce, Esrey Kerry, Esrey Trudy, Fathman Garry, Snyder Radhika, Aneja Beenu, Chatav Maya, Espinoza Oralia, Frank Eliana, Liu Jenny, Perry Jennifer, Pyle Rebecca, Rigby Alison, Riley Kristin, Soto Adriana, Gitelman Stephen, Adi Saleh, Anderson Mark, Berhel Ashley, Breen Kathy, Fraser Kathleen, Gerard-Gonzalez Andrea, Jossan Paula, Lustig Robert, Moassesfar Sara, Mugg Amy, Ng David, Prahalod Priya, Rangel-Lugo Martha, Sanda Srinath, Tarkoff Joshua, Torok Christine, Wesch Rebecca, Aslan Ivy, Buchanan Jeanne, Cordier Jennifer, Hamilton Celia, Hawkins Louise, Ho Thu, Jain Anjali, Ko Karen, Lee Theresa, Phelps Shelly, Rosenthal Stephen, Sahakitrungruang Taninee, Stehl Lorraine, Taylor Lisa, Wertz Marcia, Wong Jenise, Philipson Louis, Briars Rosemary, Devine Nancy, Littlejohn Elizabeth, Grant Tiffany, Gottlieb Peter, Klingensmith Georgeanna, Steck Andrea, Alkanani Aimon, Bautista Kimberly, Bedoy Ruth, Blau Aaron, Burke Betsy, Cory Laraine, Dang MyLinh, Fitzgerald-Miller Lisa, Fouts Alex, Gage Vicky, Garg Satish, Gesauldo Patricia, Gutin Raymond, Hayes Cory, Hoffman Michelle, Ketchum Kaitlin, Logsden-Sackett Nyla, Maahs David, Messer Laurel, Meyers Lisa, Michels Aaron, Peacock Stesha, Rewers Marian, Rodriguez Perla, Sepulbeda Flor, Sippl Rachel, Steck Andrea, Taki Iman, Tran Bao-Khan, Tran Tuan, Wadwa R. Paul, Zeitler Philip, Barker Jennifer, Barry Sandra, Birks Laurie, Bomsburger Leah, Bookert Terra, Briggs Leah, Burdick Patricia, Cabrera Rosio, Chase Peter, Cobry Erin, Conley Amy, Cook Gabrielle, Daniels Joseph, DiDomenico Dominic, Eckert Jennifer, Ehler Angelica, Eisenbarth George, Fain Pamela, Fiallo-Scharer Rosanna, Frank Nicole, Goettle Hannah, Haarhues Michelle, Harris Sherrie, Horton Lauren, Hutton John, Jeffrrey Joy, Jenison Rachael, Jones Kelly, Kastelic Whitney, King Maria Amelia, Lehr Debbie, Lungaro Jenna, Mason Kendra, Maurer Heather, Nguyen Luy, Proto Allison, Realsen Jaime, Schmitt Kristina, Schwartz Mara, Skovgaard San, Smith Jennifer, Vanderwel Brandon, Voelmle Mary, Wagner Rebecca, Wallace Amy, Walravens Philip, Weiner Laurie, Westerhoff Becky, Westfall Emily, Widmer Katina, Wright Hali, Schatz Desmond, Abraham Annie, Atkinson Mark, Cintron Miriam, Clare-Salzler Michael, Ferguson Jessica, Haller Michael, Hosford Jennifer, Mancini Diane, Rohrs Hank, Silverstein Janet, Thomas Jamie, Winter William, Cole Gloria, Cook Roberta, Coy Ryan, Hicks Elena, Lewis Nancy, Marks Jennifer, Pugliese Alberto, Blaschke Carlos, Matheson Della, Sanders-Branca Natalia, Sosenko Jay, Arazo Luz, Arce Ray, Cisneros Mario, Sabbag Samir, Moran Antoinette, Gibson Carrie, Fife Brian, Hering Bernhard, Kwong Christine, Leschyshyn Janice, Nathan Brandon, Pappenfus Beth, Street Anne, Boes Mary Ann, Eck Sarah Peterson, Finney Lois, Fischer Theresa Albright, Martin Andrea, Muzamhindo Chenai Jacqueline, Rhodes Missy, Smith Jennifer, Wagner John, Wood Bryan, Becker Dorothy, Delallo Kelli, Diaz Ana, Elnyczky Barbara, Libman Ingrid, Pasek Beata, Riley Karen, Trucco Massimo, Copemen Brian, Gwynn Diane, Toledo Frederico, Rodriguez Henry, Bollepalli Sureka, Diamond Frank, Eyth Emily, Henson Danielle, Lenz Anne, Shulman Dorothy, Raskin Phillip, Adhikari Soumya, Dickson Brian, Dunnigan Erin, Lingvay Ildiko, Pruneda Lourdes, Ramos-Roman Maria, Raskin Philip, Rhee Chanhaeng, Richard John, Siegelman Mark, Sturges Daytheon, Sumpter Kathryn, White Perrin, Alford Marilyn, Arthur Jamie, Aviles-Santa M. Larissa, Cordova Erica, Davis Renee, Fernandez Stefani, Fordan Steve, Hardin Tauri, Jacobs Aris, Kaloyanova Polina, Lukacova-Zib Ivanna, Mirfakhraee Sasan, Mohan Alok, Noto Hiroshi, Smith Oralenda, Torres Nenita, Wherrett Diane, Balmer Diana, Eisel Lesley, Kovalakovska Roze, Mehan Mala, Sultan Farah, Ahenkorah Brenda, Cevallos Jose, Razack Natasha, Ricci Mary Jo, Rhode Angela, Srikandarajah Mithula, Steger Rachel, Russell William E., Black Margo, Brendle Faith, Brown Anne, Moore Daniel, Pittel Eric, Robertson Alyssa, Shannon April, Thomas James W., Herold Kevan, Feldman Laurie, Sherwin Robert, Tamborlane William, Weinzimer Stuart, Toppari Jorma, Kallio Tiina, Kärkkäinen Maarit, Mäntymäki Elina, Niininen Tiina, Nurmi Birgitta, Rajala Petro, Romo Minna, Suomenrinne Sointu, Näntö-Salonen Kirsti, Simell Olli, Simell Tuula, Bosi Emanuele, Battaglia Manuela, Bianconi Eleonora, Bonfanti Riccardo, Grogan Pauline, Laurenzi Andrea, Martinenghi Sabina, Meschi Franco, Pastore Matteo, Falqui Luca, 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L.A., Marshall I., Cerracchio L., Cruz J., Viswanathan A., Wilson J., Chalew S., Valley S., Layburn S., Lala A., Clesi P., Genet M., Uwaifo G., Charron A., Allerton T., Cefalu W., Melendez-Ramirez L., Richards R., Alleyn C., Gustafson E., Lizanna M., Wahlen J., Aleiwe S., Hansen M., Wahlen H., Levy C.J., Bonaccorso A., Rapaport R., Tomer Y., Chia D., Goldis M., Iazzetti L., Klein M., Levister C., Waldman L., Wallach E., Regelmann M.O., Antal Z., Aranda M., Reynholds C., Leech N., Wake D., Owens C., Burns M., Wotherspoon J., Murray A., Short K., Curry G., Kelsey S., Lawson J., Porter J., Stevens S., Thomson E., Winship S., Wynn L., Wiltshire E., Krebs J., Cresswell P., Faherty H., Ross C., Vinik A., Barlow P., Bourcier M., Nevoret M.L., Couper J., Beresford S., Thalagne N., Roper H., Gibbons J., Hill J., Balleaut S., Brennan C., Ellis-Gage J., Fear L., Gray T., Jones L., McNerney C., Pointer L., Price N., Few K., Tomlinson D., Denvir L., Drew J., Randell T., Mansell P., Bell S.A., 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Affiliation:
1. Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 2. University of South Florida, Tampa, FL 3. Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora, CO 4. Institute of Biomedical and Clinical Science, University of Exeter, Exeter, U.K. 5. Walter and Eliza Hall Institute of Medical Research and Royal Melbourne Hospital, Parkville, Victoria, Australia 6. Wake Forest School of Medicine, Winston-Salem, NC 7. University of Miami, Miami, FL 8. University of Florida, Gainesville, FL
Abstract
OBJECTIVE
We tested the ability of a type 1 diabetes (T1D) genetic risk score (GRS) to predict progression of islet autoimmunity and T1D in at-risk individuals.
RESEARCH DESIGN AND METHODS
We studied the 1,244 TrialNet Pathway to Prevention study participants (T1D patients’ relatives without diabetes and with one or more positive autoantibodies) who were genotyped with Illumina ImmunoChip (median [range] age at initial autoantibody determination 11.1 years [1.2–51.8], 48% male, 80.5% non-Hispanic white, median follow-up 5.4 years). Of 291 participants with a single positive autoantibody at screening, 157 converted to multiple autoantibody positivity and 55 developed diabetes. Of 953 participants with multiple positive autoantibodies at screening, 419 developed diabetes. We calculated the T1D GRS from 30 T1D-associated single nucleotide polymorphisms. We used multivariable Cox regression models, time-dependent receiver operating characteristic curves, and area under the curve (AUC) measures to evaluate prognostic utility of T1D GRS, age, sex, Diabetes Prevention Trial–Type 1 (DPT-1) Risk Score, positive autoantibody number or type, HLA DR3/DR4-DQ8 status, and race/ethnicity. We used recursive partitioning analyses to identify cut points in continuous variables.
RESULTS
Higher T1D GRS significantly increased the rate of progression to T1D adjusting for DPT-1 Risk Score, age, number of positive autoantibodies, sex, and ethnicity (hazard ratio [HR] 1.29 for a 0.05 increase, 95% CI 1.06–1.6; P = 0.011). Progression to T1D was best predicted by a combined model with GRS, number of positive autoantibodies, DPT-1 Risk Score, and age (7-year time-integrated AUC = 0.79, 5-year AUC = 0.73). Higher GRS was significantly associated with increased progression rate from single to multiple positive autoantibodies after adjusting for age, autoantibody type, ethnicity, and sex (HR 2.27 for GRS >0.295, 95% CI 1.47–3.51; P = 0.0002).
CONCLUSIONS
The T1D GRS independently predicts progression to T1D and improves prediction along T1D stages in autoantibody-positive relatives.
Funder
National Institute of Diabetes and Digestive and Kidney Diseases Diabetes UK Harry Keen Fellowship
Publisher
American Diabetes Association
Subject
Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
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