Generic placeholder image

Current Diabetes Reviews


ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

Review Article

Genetic Aspects of Latent Autoimmune Diabetes in Adults: A Mini-Review

Author(s): Mette Korre Andersen* and Torben Hansen

Volume 15, Issue 3, 2019

Page: [194 - 198] Pages: 5

DOI: 10.2174/1573399814666180730123226

Price: $65


Diabetes is a multifactorial disease, caused by a complex interplay between environmental and genetic risk factors. Genetic determinants of particularly Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D) have been studied extensively, whereas well-powered studies of Latent Autoimmune Diabetes in Adults (LADA) are lacking. So far available studies support a clear genetic overlap between LADA and T1D, however, with smaller effect sizes of the T1D-risk variants in LADA as compared to T1D. A genetic overlap between LADA and T2D is less clear. However, recent studies, including large numbers of LADA patients, provide different lines of evidence to support a genetic overlap between T2D and LADA. The genetic predisposition to LADA is yet to be explored in a study design, like a genome- wide association study, which allows for analyses of the genetic predisposition independently of prior hypothesis about potential candidate genes. This type of study may facilitate the discovery of risk variants associated with LADA independently of T1D and T2D, and is central in order to determine if LADA should be considered as an independent diabetic subtype. Extended knowledge about the genetic predisposition to LADA may also facilitate stratification of the heterogeneous group of LADA patients, which may assist the choice of treatment. This mini-review summarizes current knowledge of the genetics of LADA, and discusses the perspectives for future studies.

Keywords: LADA, latent autoimmune diabetes in adults, Genetics, HLA, PTPN22, TCF7L2, family history.

Kaprio J, Tuomilehto J, Koskenvuo M, et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 1992; 35(11): 1060-7.
Kyvik KO, Green A, Beck-Nielsen H. Concordance rates of insulin dependent diabetes mellitus: A population based study of young Danish twins. BMJ 1995; 311(7010): 913-7.
Newman B, Selby JV, King MC, Slemenda C, Fabsitz R, Friedman GD. Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 1987; 30(10): 763-8.
Medici F, Hawa M, Ianari A, Pyke DA, Leslie RD. Concordance rate for type II diabetes mellitus in monozygotic twins: Actuarial analysis. Diabetologia 1999; 42(2): 146-50.
Poulsen P, Kyvik KO, Vaag A, Beck-Nielsen H. Heritability of type II (non-insulin-dependent) diabetes mellitus and abnormal glucose tolerance--a population-based twin study. Diabetologia 1999; 42(2): 139-45.
Redondo MJ, Yu L, Hawa M, et al. Heterogeneity of type I diabetes: Analysis of monozygotic twins in Great Britain and the United States. Diabetologia 2001; 44(3): 354-62.
Hjort R, Alfredsson L, Andersson T, et al. Family history of type 1 and type 2 diabetes and risk of Latent Autoimmune Diabetes in Adults (LADA). Diabetes Metab 2017; 43(6): 536-42.
Lundgren VM, Isomaa B, Lyssenko V, et al. GAD antibody positivity predicts type 2 diabetes in an adult population. Diabetes 2010; 59(2): 416-22.
Carlsson S, Midthjell K, Grill V. Influence of family history of diabetes on incidence and prevalence of latent autoimmune diabetes of the adult: Results from the Nord-Trondelag Health Study. Diabetes Care 2007; 30(12): 3040-5.
Weires MB, Tausch B, Haug PJ, Edwards CQ, Wetter T, Cannon-Albright LA. Familiality of diabetes mellitus. Exp Clin Endocrinol Diabetes 2007; 115(10): 634-40.
Scott RA, Langenberg C, Sharp SJ, et al. The link between family history and risk of type 2 diabetes is not explained by anthropometric, lifestyle or genetic risk factors: the EPIC-InterAct study. Diabetologia 2013; 56(1): 60-9.
Lundgren VM, Andersen MK, Isomaa B, Tuomi T. Family history of Type 1 diabetes affects insulin secretion in patients with “Type 2” diabetes. Diabet Med 2013; 30(5): e163-9.
Cooper JD, Smyth DJ, Smiles AM, et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet 2008; 40(12): 1399-401.
Bradfield JP, Qu HQ, Wang K, et al. A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet 2011; 7(9): e1002293.
Evangelou M, Smyth DJ, Fortune MD, et al. A method for gene-based pathway analysis using genomewide association study summary statistics reveals nine new type 1 diabetes associations. Genet Epidemiol 2014; 38(8): 661-70.
Voight BF, Kang HM, Ding J, et al. The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits. PLoS Genet 2012; 8(8): e1002793.
Morris AP, Voight BF, Teslovich TM, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 2012; 44(9): 981-90.
Fuchsberger C, Flannick J, Teslovich TM, et al. The genetic architecture of type 2 diabetes. Nature 2016; 536(7614): 41-7.
Scott RA, Scott LJ, Mägi R, et al. An expanded genome-wide association study of type 2 diabetes in europeans. Diabetes 2017; 66(11): 2888-902.
Mahajan A, Go MJ, Zhang W, et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet 2014; 46(3): 234-44.
Dooley J, Tian L, Schonefeldt S, et al. Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes. Nat Genet 2016; 48(5): 519-27.
Raj SM, Howson JM, Walker NM, et al. No association of multiple type 2 diabetes loci with type 1 diabetes. Diabetologia 2009; 52(10): 2109-16.
Johansen A, Jensen DP, Bergholdt R, et al. IRS1, KCNJ11, PPARgamma2 and HNF-1alpha: Do amino acid polymorphisms in these candidate genes support a shared aetiology between type 1 and type 2 diabetes? Diabetes Obes Metab 2006; 8(1): 75-82.
Eftychi C, Howson JM, Barratt BJ, et al. Analysis of the type 2 diabetes-associated single nucleotide polymorphisms in the genes IRS1, KCNJ11, and PPARG2 in type 1 diabetes. Diabetes 2004; 53(3): 870-3.
Andersen MK, Sterner M, Forsén T, et al. Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes. Diabetologia 2014; 57(9): 1859-68.
Qu HQ, Polychronakos C. The TCF7L2 locus and type 1 diabetes. BMC Med Genet 2007; 8: 51.
Field SF, Howson JM, Smyth DJ, Walker NM, Dunger DB, Todd JA. Analysis of the type 2 diabetes gene, TCF7L2, in 13,795 type 1 diabetes cases and control subjects. Diabetologia 2007; 50(1): 212-3.
Qu HQ, Grant SF, Bradfield JP, et al. Association analysis of type 2 diabetes Loci in type 1 diabetes. Diabetes 2008; 57(7): 1983-6.
Field SF, Howson JM, Walker NM, Dunger DB, Todd JA. Analysis of the obesity gene FTO in 14,803 type 1 diabetes cases and controls. Diabetologia 2007; 50(10): 2218-20.
Winkler C, Raab J, Grallert H, Ziegler AG. Lack of association of type 2 diabetes susceptibility genotypes and body weight on the development of islet autoimmunity and type 1 diabetes. PLoS One 2012; 7(4): e35410.
Tuomi T, Carlsson A, Li H, et al. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 1999; 48(1): 150-7.
Andersen MK, Lundgren V, Turunen JA, et al. Latent autoimmune diabetes in adults differs genetically from classical type 1 diabetes diagnosed after the age of 35 years. Diabetes Care 2010; 33(9): 2062-4.
Desai M, Zeggini E, Horton VA, et al. An association analysis of the HLA gene region in latent autoimmune diabetes in adults. Diabetologia 2007; 50(1): 68-73.
Mishra R, Chesi A, Cousminer DL, et al. Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes. BMC Med 2017; 15(1): 88.
Cousminer DL, Mishra R, Ahlqvist E, et al. First genome-wide association study of latent autoimmune diabetes in adults provides novel insights [abstract]. In: American Diabetes Association 77th Scientific Sessions; June 9-13, San Diego, California, USA:Abstract 181-OR
Caillat-Zucman S, Garchon HJ, Timsit J, et al. Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. J Clin Invest 1992; 90(6): 2242-50.
Sabbah E, Savola K, Ebeling T, et al. Genetic, autoimmune, and clinical characteristics of childhood- and adult-onset type 1 diabetes. Diabetes Care 2000; 23(9): 1326-32.
Graham J, Kockum I, Sanjeevi CB, et al. Negative association between type 1 diabetes and HLA DQB1*0602-DQA1*0102 is attenuated with age at onset. Swedish Childhood Diabetes Study Group. Eur J Immunogenet 1999; 26(2-3): 117-27.
Pettersen E, Skorpen F, Kvaloy K, Midthjell K, Grill V. Genetic heterogeneity in latent autoimmune diabetes is linked to various degrees of autoimmune activity: Results from the Nord-Trondelag Health Study. Diabetes 2010; 59(1): 302-10.
Luo S, Lin J, Xie Z, et al. HLA genetic discrepancy between latent autoimmune diabetes in adults and type 1 diabetes: LADA China Study No. 6. J Clin Endocrinol Metab 2016; 101(4): 1693-700.
Cervin C, Lyssenko V, Bakhtadze E, et al. Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes 2008; 57(5): 1433-7.
Petrone A, Suraci C, Capizzi M, et al. The protein tyrosine phosphatase nonreceptor 22 (PTPN22) is associated with high GAD antibody titer in latent autoimmune diabetes in adults: Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study 3. Diabetes Care 2008; 31(3): 534-8.
Hermann R, Lipponen K, Kiviniemi M, et al. Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes. Diabetologia 2006; 49(6): 1198-208.
Chelala C, Duchatelet S, Joffret ML, et al. PTPN22 R620W functional variant in type 1 diabetes and autoimmunity related traits. Diabetes 2007; 56(2): 522-6.
Hakonarson H, Qu HQ, Bradfield JP, et al. A novel susceptibility locus for type 1 diabetes on Chr12q13 identified by a genome-wide association study. Diabetes 2008; 57(4): 1143-6.
Smyth DJ, Plagnol V, Walker NM, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 2008; 359(26): 2767-77.
Onengut-Gumuscu S, Chen WM, Burren O, et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet 2015; 47(4): 381-6.
Desai M, Zeggini E, Horton VA, et al. The variable number of tandem repeats upstream of the insulin gene is a susceptibility locus for latent autoimmune diabetes in adults. Diabetes 2006; 55(6): 1890-4.
Laine AP, Knip M, Ilonen J. Finnish Pediatric Diabetes Register, Transmission disequilibrium analysis of 31 type 1 diabetes susceptibility loci in Finnish families. Tissue Antigens 2013; 82(1): 35-42.
Laine AP, Holmberg H, Nilsson A, et al. Finnish paediatric diabetes registry, two insulin gene single nucleotide polymorphisms associated with type 1 diabetes risk in the Finnish and Swedish populations. Dis Markers 2007; 23(3): 139-45.
Graham J, Hagopian WA, Kockum I, et al. Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 2002; 51(5): 1346-55.
Reddy MPL, Wang H, Liu S, et al. Association between type 1 diabetes and GWAS SNPs in the southeast US Caucasian population. Genes Immun 2011; 12(3): 208-12.
Klinker MW, Schiller JJ, Magnuson VL, et al. Single-nucleotide polymorphisms in the IL2RA gene are associated with age at diagnosis in late-onset Finnish type 1 diabetes subjects. Immunogenetics 2010; 62(2): 101-7.
Howson JM, Walker NM, Smyth DJ, Todd JA. Type 1 Diabetes Genetics Consortium. Analysis of 19 genes for association with type I diabetes in the Type I Diabetes Genetics Consortium families. Genes Immun 2009; 10: S74-84.
Rajasalu T, Haller K, Salur L, et al. Insulin VNTR I/III genotype is associated with autoantibodies against glutamic acid decarboxylase in newly diagnosed type 1 diabetes. Diabetes Metab Res Rev 2007; 23(7): 567-71.
Howson JM, Rosinger S, Smyth DJ, Boehm BO. ADBW-END Study Group, Todd JA. Genetic analysis of adult-onset autoimmune diabetes. Diabetes 2011; 60(10): 2645-53.
Dong F, Yang G, Pan HW, et al. The association of PTPN22 rs2476601 polymorphism and CTLA-4 rs231775 polymorphism with LADA risks: A systematic review and meta-analysis. Acta Diabetol 2014; 51(5): 691-703.
Lukacs K, Hosszufalusi N, Dinya E, Bakacs M, Madacsy L, Panczel P. The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study. Diabetologia 2012; 55(3): 689-93.
Zampetti S, Spoletini M, Petrone A, et al. Association of TCF7L2 gene variants with low GAD autoantibody titre in LADA subjects (NIRAD Study 5). Diabet Med 2010; 27(6): 701-4.
Zheng J, Erzurumluoglu AM, Elsworth BL, et al. LD Hub: A centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics 2017; 33(2): 272-9.
Ng MC, Shriner D, Chen BH, et al. Meta-analysis of genome-wide association studies in African Americans provides insights into the genetic architecture of type 2 diabetes. PLoS Genet 2014; 10(8): e1004517.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy