Aetiological differences between novel subtypes of diabetes derived from genetic associations

Background Type 2 diabetes (T2D) is a multi-organ disease defined by hyperglycemia resulting from different disease mechanisms. Using clinical parameters measured at diagnosis (age, BMI, HbA1c, HOMA2-B, HOMA2-IR and GAD autoantibodies) adult patients with diabetes have been reproducibly clustered into five subtypes, that differed clinically with respect to disease progression and outcomes.[1][1] In this study we use genetic information to investigate if these subtypes have distinct underlying genetic drivers. Methods Genome-wide association (GWAS) and genetic risk score (GRS) analysis was performed in Swedish (N=12230) and Finnish (N=4631) cohorts. Family history was recorded by questionnaires. Results Severe insulin-deficient diabetes (SIDD) and mild obesity-related diabetes (MOD) groups had the strongest family history of T2D. A GRS including known T2D loci was strongly associated with SIDD (OR per 1 SD increment [95% CI]=1.959 [1.814-2.118]), MOD (OR 1.726 [1.607-1.855]) and mild age-related diabetes (MARD) (OR 1.771 [1.671-1.879]), whereas it was less strongly associated with severe insulin-resistant diabetes (SIRD, OR 1.244 [1.157-1.337]), which was similar to severe autoimmune diabetes (SAID, OR 1.282 [1.160-1.418]). SAID showed strong association with the GRS for T1D, whereas the non-autoimmune subtype SIDD was most strongly associated with the GRS for insulin secretion rate ( P <7.43×10−9). SIRD showed no association with variants in TCF7L2 or any GRS reflecting insulin secretion. Instead, only SIRD was associated with GRS for fasting insulin ( P =3.10×10−8). Finally, a T2D locus, rs10824307 near the ZNF503 gene was uniquely associated with MOD (ORmeta=1.266 (1.170-1.369), P =4.3×10−9). Conclusions New diabetes subtypes have partially different genetic backgrounds and subtype-specific risk loci can be identified. Especially the SIRD subtype stands out by having lower heritability and less involvement of beta-cell related pathways in its pathogenesis. Evidence before this study In March 2018 we suggested a novel subclassification of diabetes into five subtypes. This classification was based on clustering using clinical parameters commonly measured at diabetes diagnosis (age at diabetes onset, HbA1c, bodymass index, presence of GAD autoantibodies and HOMA2 indices for insulin resistance and secretion). These subtypes differed with respect to clinical characteristics, disease progression and risk of complications, but it remained unclear to what extent these subtypes have different underlying pathologies. In our original publication we analysed a small set of genetic risk variants for diabetes and found differential associations between subtypes, suggesting potential aetiological differences. Added value of this study In this study we have conducted a full genome analysis of the original ANDIS cohort, including genome-wide association studies and polygenic risk score analysis with replication in an independent cohort. We have also compared heritability and prevalence of having a family history of diabetes in the subtypes. Implications of all the available evidence We demonstrate that stratification into subtypes facilitates identification of genetic risk loci and that the aetiology of the subtypes is at least partially distinct. These results are especially important for the future study and treatment of individuals belonging to the severe insulin-resistant diabetes (SIRD) subtype, whose pathogenesis appears to differ substantially from that of traditional T2D. ### Competing Interest Statement The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. MMcC has served on advisory panels for Pfizer, NovoNordisk and Zoe Global, has received honoraria from Merck, Pfizer, Novo Nordisk and Eli Lilly, and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, MMcC is an employee of Genentech, and a holder of Roche stock. As of January 2020 AM is an employee of Genentech and a holder of Roche stock. JB is an employee and share holder of Pfizer. JCF has received consulting honoraria from Goldfinch Bio and speaking honoraria from Novo Nordisk. ### Funding Statement This study was supported by grants from the Swedish Research Council (project grant 521-2010-3490 and infrastructure grants 2010-5983, 2012-5538, and 2014-6395 to LG; project grant 2017-02688 to EA; Linnaeus grant 349-2006-237; and a strategic research grant 2009-1039 to LG), a European Research Council Advanced Research grant (GA 269045), a Vinnova Swelife grant, and grants from the Academy of Finland (263401and 267882 to LG), Sigrid Juselius Foundation, Novo Nordisk Foundation (NNF18OC0034408 to EA), Scania University Hospital (ALF grant), Diabetes Wellness Sweden (25-420 PG), the Swedish Heart and Lung Foundation, the Swedish Diabetes Foundation, the Crafoord Foundation, the Albert Pahlsson Foundation. This project was also financially supported by the Swedish Foundation for Strategic Research (IRC15-0067). The genotyping of ANDIS was funded by Pfizer Inc. Cambridge, MA, US. DIREVA was supported by the Vasa Hospital district, Jakobstadsnejden Heart Foundation, Folkhalsan Research Foundation, and Ollqvist Foundation (to TT and AK). The Botnia Study (L.G., T.T.) have been financially supported by grants from Folkhalsan Research Foundation, the Sigrid Juselius Foundation, The Academy of Finland (grants no. 263401, 267882, 312063 to LG, 312072 to TT), University of Helsinki, Nordic Center of Excellence in Disease Genetics, EU (EXGENESIS, MOSAIC FP7-600914), Ollqvist Foundation, Swedish Cultural Foundation in Finland, Finnish Diabetes Research Foundation, Foundation for Life and Health in Finland, Signe and Ane Gyllenberg Foundation, Finnish Medical Society, Paavo Nurmi Foundation, State Research Funding via the Helsinki University Hospital, Perklen Foundation, Narpes Health Care Foundation and Ahokas Foundation. The study has also been supported by the Ministry of Education in Finland, Municipal Health Care Center and Hospital in Jakobstad and Health Care Centers in Vasa, Narpes and Korsholm. The research leading to these results has received funding from the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013) / ERC grant agreement no 269045. The genotyping of Botnia was funded by Regeneron Pharmaceuticals Inc. NY, US. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ANDIS and MDC study protocols were approved by the regional ethics review committee in Lund (Dnr. 584/2006, 2012/676, LU 51-90, 532/2006), DIREVA was approved by the ethics committee in Vasa (6/2007). The Botnia studies were approved by the ethical committee at Vasa central hospital (Dnr. 6.4.1989) and ethical committee at Jakobstad hospital (Dnr. 1/95). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The data that support the findings of this study are available upon request but restrictions apply. Individual level data are not publicly available due to ethical and legal restrictions related to the Swedish Biobanks in Medical Care Act (2002:297) and the Personal Data Act (1998:204), EU's General Data Protection Regulation (GDPR) 2016/679, and the Data Protection Act 2018:218. [1]: #ref-1