Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes

Bone Mineral Density in Childhood Study

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Abstract

Background: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes. Methods: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls. Results: Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted. Conclusion: LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.

Original languageEnglish (US)
Article number88
Pages (from-to)1
Number of pages1
JournalBMC Medicine
Volume15
Issue number1
DOIs
StatePublished - Apr 25 2017

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Genetic Loci
Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Major Histocompatibility Complex
Latent Autoimmune Diabetes in Adults
Genetic Load
Alleles
Genome-Wide Association Study

All Science Journal Classification (ASJC) codes

  • Medicine(all)

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Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes. / Bone Mineral Density in Childhood Study.

In: BMC Medicine, Vol. 15, No. 1, 88, 25.04.2017, p. 1.

Research output: Contribution to journalArticle

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title = "Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes",
abstract = "Background: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes. Methods: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls. Results: Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted. Conclusion: LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.",
author = "{Bone Mineral Density in Childhood Study} and Rajashree Mishra and Alessandra Chesi and Cousminer, {Diana L.} and Hawa, {Mohammad I.} and Bradfield, {Jonathan P.} and Hodge, {Kenyaita M.} and Guy, {Vanessa C.} and Hakon Hakonarson and Didac Mauricio and Schloot, {Nanette C.} and Yderstr{\ae}de, {Knud B.} and Voight, {Benjamin F.} and Stanley Schwartz and Boehm, {Bernhard O.} and Leslie, {Richard David} and Grant, {Struan F.A.} and Kalkwarf, {Heidi J.} and Lappe, {Joan M.} and Vicente Gilsanz and Oberfield, {Sharon E.} and Shepherd, {John A.} and Andrea Kelly and Zemel, {Babette S.}",
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T1 - Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes

AU - Bone Mineral Density in Childhood Study

AU - Mishra, Rajashree

AU - Chesi, Alessandra

AU - Cousminer, Diana L.

AU - Hawa, Mohammad I.

AU - Bradfield, Jonathan P.

AU - Hodge, Kenyaita M.

AU - Guy, Vanessa C.

AU - Hakonarson, Hakon

AU - Mauricio, Didac

AU - Schloot, Nanette C.

AU - Yderstræde, Knud B.

AU - Voight, Benjamin F.

AU - Schwartz, Stanley

AU - Boehm, Bernhard O.

AU - Leslie, Richard David

AU - Grant, Struan F.A.

AU - Kalkwarf, Heidi J.

AU - Lappe, Joan M.

AU - Gilsanz, Vicente

AU - Oberfield, Sharon E.

AU - Shepherd, John A.

AU - Kelly, Andrea

AU - Zemel, Babette S.

PY - 2017/4/25

Y1 - 2017/4/25

N2 - Background: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes. Methods: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls. Results: Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted. Conclusion: LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.

AB - Background: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes. Methods: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls. Results: Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted. Conclusion: LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.

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