Genetic risk score in diabetes associated with chronic pancreatitis versus type 2 diabetes mellitus

Mark O. Goodarzi; Tanvi Nagpal; Phil Greer; Jinrui Cui; Yii Der I. Chen; Xiuqing Guo; James S. Pankow; Jerome I. Rotter; Samer Alkaade; Stephen T. Amann; John Baillie; Peter A. Banks; Randall E. Brand; Darwin L. Conwell; Gregory A. Cote; Christopher E. Forsmark; Timothy B. Gardner; Andres Gelrud; Nalini Guda; Jessica LaRusch; Michele D. Lewis; Mary E. Money; Thiruvengadam Muniraj; Georgios I. Papachristou; Joseph Romagnuolo; Bimaljit S. Sandhu; Stuart Sherman; Vikesh K. Singh; C. MelWilcox; Stephen J. Pandol; Walter G. Park; Dana K. Andersen; Melena D. Bellin; Phil A. Hart; Dhiraj Yadav; David C. Whitcomb

doi:10.14309/ctg.0000000000000057

Genetic risk score in diabetes associated with chronic pancreatitis versus type 2 diabetes mellitus

Mark O. Goodarzi, Tanvi Nagpal, Phil Greer, Jinrui Cui, Yii Der I. Chen, Xiuqing Guo, James S. Pankow, Jerome I. Rotter, Samer Alkaade, Stephen T. Amann, John Baillie, Peter A. Banks, Randall E. Brand, Darwin L. Conwell, Gregory A. Cote, Christopher E. Forsmark, Timothy B. Gardner, Andres Gelrud, Nalini Guda, Jessica LaRuschMichele D. Lewis, Mary E. Money, Thiruvengadam Muniraj, Georgios I. Papachristou, Joseph Romagnuolo, Bimaljit S. Sandhu, Stuart Sherman, Vikesh K. Singh, C. MelWilcox, Stephen J. Pandol, Walter G. Park, Dana K. Andersen, Melena D. Bellin, Phil A. Hart, Dhiraj Yadav, David C. Whitcomb

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

INTRODUCTION: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM.We approached this question froma unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. METHODS: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. RESULTS: The mean GRSwas identical between 321 subjects with CP-DM and 423 subjects withT2DM(66.53 vs 66.42, P50.95), and theGRS of both diabetic groups was significantly higher than that of nondiabetic controls (n 5 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreasspecific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. DISCUSSION: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.

Original language	English
Article number	e-00057
Journal	Clinical and Translational Gastroenterology
Volume	10
Issue number	7
DOIs	https://doi.org/10.14309/ctg.0000000000000057
State	Published - 2019

Bibliographical note

Publisher Copyright:
© 2019 The Author(s).

Funding

Guarantor of the article: Mark O. Goodarzi, MD, PhD. Specific author contributions: Study conception and design: M.O.G. and D.C.W. Acquisition and assembly of data: M.O.G., T.N., P.G., J.C., Y.-D.I.C., X.G., J.S.P., J.I.R., S.A., S.T.A., J.B., P.A.B., R.E.B., D.L.C., G.A.C., C.E.F., T.B.G., A.G., N.G., J.L., M.D.L., M.E.M., T.M., G.I.P., J.R., B.S.S., S.S., V.K.S., C.M.W., M.D.B., D.Y., and D.C.W. Statistical analysis: M.O.G., T.N., P.G., and J.C. Drafting of the manuscript: M.O.G. and D.C.W. Critical revision of the manuscript: P.G., Y.-D.I.C., J.S.P., T.M., S.J.P., W.G.P., D.K.A., and P.A.H. All authors approved the final manuscript. Financial support: This research was partly supported by NIH grants R01 DK061451 (D.C.W.), R01 DK077906 (D.Y.), U01 DK108314 (M.O.G.), U01 DK108327 (D.L.C., P.A.H.), U01 DK108320 (C.E.F.), U01 DK108306 (D.C.W., D.Y.), U01 DK108323 (S.S.), and P30 DK063491 (M.O.G., J.I.R.) and the Eris M. Field Chair in Diabetes Research (M.O.G.). This publication was made possible in part by Grant Numbers UL1 RR024153 and UL1TR000005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research (University of Pittsburgh. PI, Steven E Reis, MD). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or NIH. The MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for the MESA is provided by contracts HHSN268201500003I, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. The study sponsors had no role in the study design, collection, analysis or interpretation of data, in the writing of the report, or in the decision to submit the report for publication. Potential competing interests: D.C.W. is a consultant for AbbVie, Regeneron, and Ariel Precision Medicine and has equity in Ariel Precision Medicine. N.G. is a consultant to Boston Scientific. M.D.B. serves on the medical advisory board of Ariel Precision Medicine. The other authors have no conflicts to disclose.

Funders	Funder number
Colorado Mesa University
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)	N02-HL-64278
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Research Resources
National Center for Advancing Translational Sciences (NCATS)	UL1TR001881
National Center for Advancing Translational Sciences (NCATS)
University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh

ASJC Scopus subject areas

Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.14309/ctg.0000000000000057

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Goodarzi, M. O., Nagpal, T., Greer, P., Cui, J., Chen, Y. D. I., Guo, X., Pankow, J. S., Rotter, J. I., Alkaade, S., Amann, S. T., Baillie, J., Banks, P. A., Brand, R. E., Conwell, D. L., Cote, G. A., Forsmark, C. E., Gardner, T. B., Gelrud, A., Guda, N., ... Whitcomb, D. C. (2019). Genetic risk score in diabetes associated with chronic pancreatitis versus type 2 diabetes mellitus. Clinical and Translational Gastroenterology, 10(7), Article e-00057. https://doi.org/10.14309/ctg.0000000000000057

@article{5075a78d8db0420fb475174fd52af58d,

title = "Genetic risk score in diabetes associated with chronic pancreatitis versus type 2 diabetes mellitus",

abstract = "INTRODUCTION: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM.We approached this question froma unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. METHODS: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. RESULTS: The mean GRSwas identical between 321 subjects with CP-DM and 423 subjects withT2DM(66.53 vs 66.42, P50.95), and theGRS of both diabetic groups was significantly higher than that of nondiabetic controls (n 5 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreasspecific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. DISCUSSION: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.",

author = "Goodarzi, {Mark O.} and Tanvi Nagpal and Phil Greer and Jinrui Cui and Chen, {Yii Der I.} and Xiuqing Guo and Pankow, {James S.} and Rotter, {Jerome I.} and Samer Alkaade and Amann, {Stephen T.} and John Baillie and Banks, {Peter A.} and Brand, {Randall E.} and Conwell, {Darwin L.} and Cote, {Gregory A.} and Forsmark, {Christopher E.} and Gardner, {Timothy B.} and Andres Gelrud and Nalini Guda and Jessica LaRusch and Lewis, {Michele D.} and Money, {Mary E.} and Thiruvengadam Muniraj and Papachristou, {Georgios I.} and Joseph Romagnuolo and Sandhu, {Bimaljit S.} and Stuart Sherman and Singh, {Vikesh K.} and C. MelWilcox and Pandol, {Stephen J.} and Park, {Walter G.} and Andersen, {Dana K.} and Bellin, {Melena D.} and Hart, {Phil A.} and Dhiraj Yadav and Whitcomb, {David C.}",

note = "Publisher Copyright: {\textcopyright} 2019 The Author(s).",

year = "2019",

doi = "10.14309/ctg.0000000000000057",

language = "English",

volume = "10",

journal = "Clinical and Translational Gastroenterology",

issn = "2155-384X",

publisher = "Nature Publishing Group",

number = "7",

}

Goodarzi, MO, Nagpal, T, Greer, P, Cui, J, Chen, YDI, Guo, X, Pankow, JS, Rotter, JI, Alkaade, S, Amann, ST, Baillie, J, Banks, PA, Brand, RE, Conwell, DL, Cote, GA, Forsmark, CE, Gardner, TB, Gelrud, A, Guda, N, LaRusch, J, Lewis, MD, Money, ME, Muniraj, T, Papachristou, GI, Romagnuolo, J, Sandhu, BS, Sherman, S, Singh, VK, MelWilcox, C, Pandol, SJ, Park, WG, Andersen, DK, Bellin, MD, Hart, PA, Yadav, D & Whitcomb, DC 2019, 'Genetic risk score in diabetes associated with chronic pancreatitis versus type 2 diabetes mellitus', Clinical and Translational Gastroenterology, vol. 10, no. 7, e-00057. https://doi.org/10.14309/ctg.0000000000000057

TY - JOUR

T1 - Genetic risk score in diabetes associated with chronic pancreatitis versus type 2 diabetes mellitus

AU - Goodarzi, Mark O.

AU - Nagpal, Tanvi

AU - Greer, Phil

AU - Cui, Jinrui

AU - Chen, Yii Der I.

AU - Guo, Xiuqing

AU - Pankow, James S.

AU - Rotter, Jerome I.

AU - Alkaade, Samer

AU - Amann, Stephen T.

AU - Baillie, John

AU - Banks, Peter A.

AU - Brand, Randall E.

AU - Conwell, Darwin L.

AU - Cote, Gregory A.

AU - Forsmark, Christopher E.

AU - Gardner, Timothy B.

AU - Gelrud, Andres

AU - Guda, Nalini

AU - LaRusch, Jessica

AU - Lewis, Michele D.

AU - Money, Mary E.

AU - Muniraj, Thiruvengadam

AU - Papachristou, Georgios I.

AU - Romagnuolo, Joseph

AU - Sandhu, Bimaljit S.

AU - Sherman, Stuart

AU - Singh, Vikesh K.

AU - MelWilcox, C.

AU - Pandol, Stephen J.

AU - Park, Walter G.

AU - Andersen, Dana K.

AU - Bellin, Melena D.

AU - Hart, Phil A.

AU - Yadav, Dhiraj

AU - Whitcomb, David C.

PY - 2019

Y1 - 2019

N2 - INTRODUCTION: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM.We approached this question froma unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. METHODS: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. RESULTS: The mean GRSwas identical between 321 subjects with CP-DM and 423 subjects withT2DM(66.53 vs 66.42, P50.95), and theGRS of both diabetic groups was significantly higher than that of nondiabetic controls (n 5 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreasspecific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. DISCUSSION: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.

AB - INTRODUCTION: Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM.We approached this question froma unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. METHODS: We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. RESULTS: The mean GRSwas identical between 321 subjects with CP-DM and 423 subjects withT2DM(66.53 vs 66.42, P50.95), and theGRS of both diabetic groups was significantly higher than that of nondiabetic controls (n 5 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreasspecific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. DISCUSSION: Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.

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DO - 10.14309/ctg.0000000000000057

M3 - Article

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SN - 2155-384X

VL - 10

JO - Clinical and Translational Gastroenterology

JF - Clinical and Translational Gastroenterology

IS - 7

M1 - e-00057

ER -

Genetic risk score in diabetes associated with chronic pancreatitis versus type 2 diabetes mellitus

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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