The Genetic Architecture of Diabetes in Pregnancy: Implications for Clinical Practice

Jeffrey W. Kleinberger; Kristin A. Maloney; Toni I. Pollin

doi:10.1055/s-0036-1592078

American Journal of Perinatology, Inhaltsverzeichnis

Am J Perinatol 2016; 33(13): 1319-1326
DOI: 10.1055/s-0036-1592078

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Genetic Architecture of Diabetes in Pregnancy: Implications for Clinical Practice

Jeffrey W. Kleinberger

¹Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland

,

Kristin A. Maloney

¹Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland

,

Toni I. Pollin

¹Program for Personalized and Genomic Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland

²Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland

› Institutsangaben

Abstract

The genetic architecture of diabetes mellitus in general and in pregnancy is complex, owing to the multiple types of diabetes that comprise both complex/polygenic forms and monogenic (largely caused by a mutation in a single gene) forms such as maturity-onset diabetes of the young (MODY). Type 1 diabetes (T1D) and type 2 diabetes (T2D) have complex genetic etiologies, with over 40 and 90 genes/loci, respectively, implicated that interact with environmental/lifestyle factors. The genetic etiology of gestational diabetes mellitus has largely been found to overlap that of T2D. Genetic testing for complex forms of diabetes is not currently useful clinically, but genetic testing for monogenic forms, particularly MODY, has important utility for determining treatment, managing risk in family members, and pregnancy management. In particular, diagnosing MODY2, caused by GCK mutations, indicates that insulin should not be used, including during pregnancy, with the possible exception of an unaffected pregnancy during the third trimester to prevent macrosomia. A relatively simple method for identifying women with MODY2 has been piloted. MODY1, caused by HNF4A mutations, can paradoxically cause neonatal hyperinsulinemic hypoglycemia and macrosomia, indicating that detecting these cases is also clinically important. Diagnosing all MODY types provides opportunities for diagnosing other family members.

Keywords

genetics - diabetes - pregnancy - gestational diabetes - MODY

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References
1 American Diabetes Association. 2. Classification and diagnosis of diabetes. Diabetes Care 2016; 39 (Suppl. 01) S13-S22
2 Centers for Disease Control and Prevention. 2014 National Diabetes Statistics Report. Available at: http://www.cdc.gov/diabetes/data/statistics/2014statisticsreport.html . Accessed April 25, 2016
3 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) 354-362
4 Tisch R, McDevitt H. Insulin-dependent diabetes mellitus. Cell 1996; 85 (3) 291-297
5 Carmichael SK, Johnson SB, Baughcum A , et al. Prospective assessment in newborns of diabetes autoimmunity (PANDA): maternal understanding of infant diabetes risk. Genet Med 2003; 5 (2) 77-83
6 Aas KK, Tambs K, Kise MS, Magnus P, Rønningen KS. Genetic testing of newborns for type 1 diabetes susceptibility: a prospective cohort study on effects on maternal mental health. BMC Med Genet 2010; 11: 112
7 Stene LC, Witsø E, Torjesen PA , et al. Islet autoantibody development during follow-up of high-risk children from the general Norwegian population from three months of age: design and early results from the MIDIA study. J Autoimmun 2007; 29 (1) 44-51
8 Nielsen DS, Krych Ł, Buschard K, Hansen CH, Hansen AK. Beyond genetics. Influence of dietary factors and gut microbiota on type 1 diabetes. FEBS Lett 2014; 588 (22) 4234-4243
9 Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 1984; 33 (2) 176-183
10 Nisticò L, Buzzetti R, Pritchard LE , et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet 1996; 5 (7) 1075-1080
11 Bottini N, Musumeci L, Alonso A , et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 2004; 36 (4) 337-338
12 Pociot F, Akolkar B, Concannon P , et al. Genetics of type 1 diabetes: what's next?. Diabetes 2010; 59 (7) 1561-1571
13 Husebye ES, Anderson MS. Autoimmune polyendocrine syndromes: clues to type 1 diabetes pathogenesis. Immunity 2010; 32 (4) 479-487
14 Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 2002; 39 (8) 537-545
15 Perheentupa J. APS-I/APECED: the clinical disease and therapy. Endocrinol Metab Clin North Am 2002; 31 (2) 295-320 , vi
16 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) 139-145
17 Almgren P, Lehtovirta M, Isomaa B , et al; Botnia Study Group. Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study. Diabetologia 2011; 54 (11) 2811-2819
18 Bonnefond A, Froguel P. Rare and common genetic events in type 2 diabetes: what should biologists know?. Cell Metab 2015; 21 (3) 357-368
19 Kong A, Steinthorsdottir V, Masson G , et al; DIAGRAM Consortium. Parental origin of sequence variants associated with complex diseases. Nature 2009; 462 (7275) 868-874
20 Frayling TM, Timpson NJ, Weedon MN , et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316 (5826) 889-894
21 Florez JC, Jablonski KA, Bayley N , et al; Diabetes Prevention Program Research Group. TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 2006; 355 (3) 241-250
22 Laaksonen DE, Siitonen N, Lindström J , et al; Finnish Diabetes Prevention Study Group. Physical activity, diet, and incident diabetes in relation to an ADRA2B polymorphism. Med Sci Sports Exerc 2007; 39 (2) 227-232
23 Mahajan A, Go MJ, Zhang W , et al; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium; Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium; South Asian Type 2 Diabetes (SAT2D) Consortium; Mexican American Type 2 Diabetes (MAT2D) Consortium; Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet 2014; 46 (3) 234-244
24 Gaulton KJ, Ferreira T, Lee Y , et al; DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nat Genet 2015; 47 (12) 1415-1425
25 Majithia AR, Flannick J, Shahinian P , et al; GoT2D Consortium; NHGRI JHS/FHS Allelic Spectrum Project; SIGMA T2D Consortium; T2D-GENES Consortium. Rare variants in PPARG with decreased activity in adipocyte differentiation are associated with increased risk of type 2 diabetes. Proc Natl Acad Sci U S A 2014; 111 (36) 13127-13132
26 Centers for Disease Control and Prevention. National diabetes fact sheet: National estimates and general information on diabetes and prediabetes in the United States. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention; 2011
27 Zhang C, Bao W, Rong Y , et al. Genetic variants and the risk of gestational diabetes mellitus: a systematic review. Hum Reprod Update 2013; 19 (4) 376-390
28 Stuebe AM, Wise A, Nguyen T, Herring A, North KE, Siega-Riz AM. Maternal genotype and gestational diabetes. Am J Perinatol 2014; 31 (1) 69-76
29 Huerta-Chagoya A, Vázquez-Cárdenas P, Moreno-Macías H , et al. Genetic determinants for gestational diabetes mellitus and related metabolic traits in Mexican women. PLoS ONE 2015; 10 (5) e0126408
30 Huopio H, Cederberg H, Vangipurapu J , et al. Association of risk variants for type 2 diabetes and hyperglycemia with gestational diabetes. Eur J Endocrinol 2013; 169 (3) 291-297
31 Kwak SH, Kim SH, Cho YM , et al. A genome-wide association study of gestational diabetes mellitus in Korean women. Diabetes 2012; 61 (2) 531-541
32 Hayes MG, Urbanek M, Hivert MF , et al; HAPO Study Cooperative Research Group. Identification of HKDC1 and BACE2 as genes influencing glycemic traits during pregnancy through genome-wide association studies. Diabetes 2013; 62 (9) 3282-3291
33 Scott RA, Lagou V, Welch RP , et al; DIAbetes Genetics Replication and Meta-analysis (DIAGRAM) Consortium. Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways. Nat Genet 2012; 44 (9) 991-1005
34 Guo C, Ludvik AE, Arlotto ME , et al. Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. Nat Commun 2015; 6: 6069
35 Stein SA, Maloney KL, Pollin TI. Genetic counseling for diabetes mellitus. . Curr Genet Med Rep 2014; 2 (2) 56-67
36 OMIM: Online Mendelian Inheritance in Man Available at: http://www.omim.org/ . Accessed April 24, 2016
37 Rubio-Cabezas O, Hattersley AT, Njølstad PR , et al; International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2014. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2014; 15 (Suppl. 20) 47-64
38 De Franco E, Ellard S. Genome, exome, and targeted next-generation sequencing in neonatal diabetes. Pediatr Clin North Am 2015; 62 (4) 1037-1053
39 Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 2008; 4 (4) 200-213
40 Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing?. Diabetologia 2010; 53 (12) 2504-2508
41 Kropff J, Selwood MP, McCarthy MI, Farmer AJ, Owen KR. Prevalence of monogenic diabetes in young adults: a community-based, cross-sectional study in Oxfordshire, UK. Diabetologia 2011; 54 (5) 1261-1263
42 Pihoker C, Gilliam LK, Ellard S , et al; SEARCH for Diabetes in Youth Study Group. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J Clin Endocrinol Metab 2013; 98 (10) 4055-4062
43 Kleinberger JW, Pollin TI. Undiagnosed MODY: Time for Action. Curr Diab Rep 2015; 15 (12) 110
44 Kleinberger JW, Pollin TI. Personalized medicine in diabetes mellitus: current opportunities and future prospects. Ann N Y Acad Sci 2015; 1346 (1) 45-56
45 Clissold R, Shields B, Ellard S, Hattersley A, Bingham C. Assessment of the HNF1B Score as a Tool to Select Patients for HNF1B Genetic Testing. Nephron 2015; 130 (2) 134-140
46 Thanabalasingham G, Pal A, Selwood MP , et al. Systematic assessment of etiology in adults with a clinical diagnosis of young-onset type 2 diabetes is a successful strategy for identifying maturity-onset diabetes of the young. Diabetes Care 2012; 35 (6) 1206-1212
47 Byrne MM, Sturis J, Menzel S , et al. Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes 1996; 45 (11) 1503-1510
48 Yamagata K, Oda N, Kaisaki PJ , et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 1996; 384 (6608) 455-458
49 Yamagata K, Furuta H, Oda N , et al. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Nature 1996; 384 (6608) 458-460
50 Byrne MM, Sturis J, Fajans SS , et al. Altered insulin secretory responses to glucose in subjects with a mutation in the MODY1 gene on chromosome 20. Diabetes 1995; 44 (6) 699-704
51 Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat 2013; 34 (5) 669-685
52 Klupa T, Warram JH, Antonellis A , et al. Determinants of the development of diabetes (maturity-onset diabetes of the young-3) in carriers of HNF-1alpha mutations: evidence for parent-of-origin effect. Diabetes Care 2002; 25 (12) 2292-2301
53 Harries LW, Locke JM, Shields B , et al. The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development. Diabetes 2008; 57 (6) 1745-1752
54 Flannick J, Beer NL, Bick AG , et al. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat Genet 2013; 45 (11) 1380-1385
55 Stoffel M, Duncan SA. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci U S A 1997; 94 (24) 13209-13214
56 Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 2003; 362 (9392) 1275-1281
57 Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT. A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med 2009; 26 (4) 437-441
58 Pearson ER, Boj SF, Steele AM , et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007; 4 (4) e118
59 Fajans SS, Bell GI. Macrosomia and neonatal hypoglycaemia in RW pedigree subjects with a mutation (Q268X) in the gene encoding hepatocyte nuclear factor 4alpha (HNF4A). Diabetologia 2007; 50 (12) 2600-2601
60 Kapoor RR, Locke J, Colclough K , et al. Persistent hyperinsulinemic hypoglycemia and maturity-onset diabetes of the young due to heterozygous HNF4A mutations. Diabetes 2008; 57 (6) 1659-1663
61 Conn JJ, Simm PJ, Oats JJ , et al. Neonatal hyperinsulinaemic hypoglycaemia and monogenic diabetes due to a heterozygous mutation of the HNF4A gene. Aust N Z J Obstet Gynaecol 2009; 49 (3) 328-330
62 Flanagan SE, Kapoor RR, Mali G , et al. Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations. Eur J Endocrinol 2010; 162 (5) 987-992
63 Bacon S, Schmid J, McCarthy A , et al. The clinical management of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young. Am J Obstet Gynecol 2015; 213 (2) 236.e1-236.e7
64 Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Hattersley AT. Intrauterine hyperglycemia is associated with an earlier diagnosis of diabetes in HNF-1alpha gene mutation carriers. Diabetes Care 2002; 25 (12) 2287-2291
65 Chakera AJ, Spyer G, Vincent N, Ellard S, Hattersley AT, Dunne FP. The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: the Atlantic Diabetes in Pregnancy cohort. Diabetes Care 2014; 37 (5) 1230-1236
66 Byrne MM, Sturis J, Clément K , et al. Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest 1994; 93 (3) 1120-1130
67 Chakera AJ, Steele AM, Gloyn AL , et al. Recognition and Management of Individuals With Hyperglycemia Because of a Heterozygous Glucokinase Mutation. Diabetes Care 2015; 38 (7) 1383-1392
68 Stride A, Vaxillaire M, Tuomi T , et al. The genetic abnormality in the beta cell determines the response to an oral glucose load. Diabetologia 2002; 45 (3) 427-435
69 Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA 2014; 311 (3) 279-286
70 Stride A, Shields B, Gill-Carey O , et al. Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia 2014; 57 (1) 54-56
71 Spyer G, Macleod KM, Shepherd M, Ellard S, Hattersley AT. Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med 2009; 26 (1) 14-18
72 Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet 1998; 19 (3) 268-270
73 Spyer G, Hattersley AT, Sykes JE, Sturley RH, MacLeod KM. Influence of maternal and fetal glucokinase mutations in gestational diabetes. Am J Obstet Gynecol 2001; 185 (1) 240-241
74 Shields BM, Spyer G, Slingerland AS , et al. Mutations in the glucokinase gene of the fetus result in reduced placental weight. Diabetes Care 2008; 31 (4) 753-757
75 Rudland VL, Hinchcliffe M, Pinner J , et al. Identifying Glucokinase Monogenic Diabetes in a Multiethnic Gestational Diabetes Mellitus Cohort: New Pregnancy Screening Criteria and Utility of HbA1c. Diabetes Care 2016; 39 (1) 50-52