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. 2017 Apr 25;15(1):88.
doi: 10.1186/s12916-017-0846-0.

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

Rajashree Mishra  1 , Alessandra Chesi  1 , Diana L Cousminer  2 , Mohammad I Hawa  3 , Jonathan P Bradfield  4 , Kenyaita M Hodge  1 , Vanessa C Guy  1 , Hakon Hakonarson  1   4   5 ; Bone Mineral Density in Childhood Study; Didac Mauricio  6 , Nanette C Schloot  7 , Knud B Yderstræde  8 , Benjamin F Voight  2   9 , Stanley Schwartz  10 , Bernhard O Boehm  11   12 , Richard David Leslie  13   14 , Struan F A Grant  15   16   17   18   19
Collaborators, Affiliations

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

Rajashree Mishra et al. BMC Med. .

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.

Keywords: Genetic risk scores; Latent autoimmune diabetes in adults.

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Figures

Fig. 1
Fig. 1
Type 1 (T1D) and type 2 diabetes (T2D) genetic risk scores (GRS) tested in latent autoimmune diabetes in adulthood (LADA) cases and controls. Weighted GRS for T1D (black) and T2D (red) were calculated by summing over all the risk alleles (T1D/T2D SNPs). The scores were tested in a 978 LADA cases and 1057 healthy controls; b 309 autoantibody-positive (glutamic acid decarboxylase autoantibodies (GADA) and insulinoma-associated antigen-2 autoantibodies (IA2A)) LADA cases and 1057 controls; c 669 GADA-only autoantibody positive. The ability of the GRS to discriminate between cases and controls was assessed by receiver and operator characteristic analysis. The area under the curve (AUC) was 0.667 and 0.565 for T1D and T2D, respectively, in the set with all LADA cases, 0.76 for T1D and 0.496 for T2D in the GADA, IA2A autoantibody-positive restricted set, and 0.623 for T1D, 0.597 for T2D in the GADA-only autoantibody-positive restricted set. A combination of T1D and T2D SNPs (green) had an AUC of 0.673 for all samples, 0.755 for the GADA+ IA2A+ restricted set, and 0.635 for the GADA-only restricted set
Fig. 2
Fig. 2
Genetic risk score (GRS) distributions between type 1 diabetes (T1D), type 2 diabetes (T2D), latent autoimmune diabetes in adulthood (LADA), and LADA-restricted cases and controls. The GRS distributions were compared across individuals diagnosed with T1D (n = 1990), T2D (n = 1960), LADA (n = 978), LADA restricted (n = 309), LADA GADA-only (n = 669), and Bone Mineral Density in Childhood Study controls (n = 1057). a Violin plots of the distributions of the GRS calculated using the T1D SNPs for the five groups. A multiple comparison test (Wilcoxon rank sum test) was performed to calculate the significance of pair-wise differences. b Violin plots of the distributions of the GRS calculated using the T2D SNPs for the five groups. A multiple comparison test (Wilcoxon rank sum test) was performed to calculate the significance of pair-wise differences. We include some of the significant P values to highlight key differences. (*** P < 10–5, ** P < 0.0001, * P < 0.05)
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