Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 7/2006

01-07-2006 | Article

Common variants in MODY genes increase the risk of gestational diabetes mellitus

Authors: N. Shaat, E. Karlsson, Å. Lernmark, S. Ivarsson, K. Lynch, H. Parikh, P. Almgren, K. Berntorp, L. Groop

Published in: Diabetologia | Issue 7/2006

Login to get access

Abstract

Aims/hypothesis

Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY. In addition, women with MODY gene mutations often present with GDM, but it is not known whether common variants in MODY genes contribute to GDM.

Subjects and methods

We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-α (HNF1A, commonly known as MODY3) and 4-α (HNF4A commonly known as MODY1) genes in 1,880 Scandinavian women (648 women with GDM and 1,232 pregnant non-diabetic control women).

Results

The A allele of the GCK −30G→A polymorphism was more common in GDM women than in control subjects (odds ratio [OR] 1.28 [95% CI 1.06−1.53], p=0.008, corrected p value, p=0.035). Under a recessive model [AA vs GA+GG], the OR increased further to 2.12 (95% CI 1.21−3.72, p=0.009). The frequency of the L allele of the HNF1A I27L polymorphism was slightly higher in GDM than in controls (1.16 [95% CI 1.001−1.34], p=0.048, corrected p value, p=0.17). However, the OR increased under a dominant model (LL+IL vs II; 1.31 [95% CI 1.08−1.60], p=0.007). The rs2144908, rs2425637 and rs1885088 variants, which are located downstream of the primary beta cell promoter (P2) of HNF4A, were not associated with GDM.

Conclusions/interpretation

The −30G→A polymorphism of the beta-cell-specific promoter of GCK and the I27L polymorphism of HNF1A seem to increase the risk of GDM in Scandinavian women.
Appendix
Available only for authorised users
Literature
1.
Metzger BE, Coustan DR (1998) Summary and recommendations of the fourth international workshop-conference on gestational diabetes mellitus. Diabetes Care 21(Suppl 2):B161–B167PubMed
2.
Aberg A, Rydhstroem H, Frid A (2001) Impaired glucose tolerance associated with adverse pregnancy outcome: a population-based study in southern Sweden. Am J Obstet Gynecol 184:77–83PubMedCrossRef
3.
King H (1998) Epidemiology of glucose intolerance and gestational diabetes in women of childbearing age. Diabetes Care 21(Suppl 2):B9–B13PubMed
4.
Ferrara A, Kahn HS, Quesenberry CP, Riley C, Hedderson MM (2004) An increase in the incidence of gestational diabetes mellitus: Northern California, 1991–2000. Obstet Gynecol 103:526–533PubMed
5.
Dabelea D, Snell-Bergeon JK, Hartsfield CL, Bischoff KJ, Hamman RF, McDuffie RS (2005) Increasing prevalence of gestational diabetes mellitus (GDM) over time and by birth cohort: Kaiser Permanente of Colorado GDM Screening Program. Diabetes Care 28:579–584PubMedCrossRef
6.
Buchanan TA (2001) Pancreatic B-cell defects in gestational diabetes: implications for the pathogenesis and prevention of type 2 diabetes. J Clin Endocrinol Metab 86:989–993PubMedCrossRef
7.
Xiang AH, Peters RK, Trigo E, Kjos SL, Lee WP, Buchanan TA (1999) Multiple metabolic defects during late pregnancy in women at high risk for type 2 diabetes. Diabetes 48:848–854PubMedCrossRef
8.
Osei K, Gaillard TR, Schuster DP (1998) History of gestational diabetes leads to distinct metabolic alterations in nondiabetic African-American women with a parental history of type 2 diabetes. Diabetes Care 21:1250–1257PubMedCrossRef
9.
Fajans SS, Bell GI, Polonsky KS (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345:971–980PubMedCrossRef
10.
Frayling TM, Evans JC, Bulman MP et al (2001) Beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes 50(Suppl 1):S94–S100PubMedCrossRef
11.
Pruhova S, Ek J, Lebl J et al (2003) Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4alpha, GCK and HNF-1alpha. Diabetologia 46:291–295PubMed
12.
Stoffel M, Bell KL, Blackburn CL et al (1993) Identification of glucokinase mutations in subjects with gestational diabetes mellitus. Diabetes 42:937–940PubMedCrossRef
13.
Saker PJ, Hattersley AT, Barrow B et al (1996) High prevalence of a missense mutation of the glucokinase gene in gestational diabetic patients due to a founder-effect in a local population. Diabetologia 39:1325–1328PubMedCrossRef
14.
Ellard S, Beards F, Allen LI et al (2000) A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria. Diabetologia 43:250–253PubMedCrossRef
15.
Zouali H, Vaxillaire M, Lesage S et al (1993) Linkage analysis and molecular scanning of glucokinase gene in NIDDM families. Diabetes 42:1238–1245PubMedCrossRef
16.
Weng J, Ekelund M, Lehto M et al (2002) Screening for MODY mutations, GAD antibodies, and type 1 diabetes-associated HLA genotypes in women with gestational diabetes mellitus. Diabetes Care 25:68–71PubMedCrossRef
17.
Thomson KL, Gloyn AL, Colclough K et al (2003) Identification of 21 novel glucokinase (GCK) mutations in UK and European Caucasians with maturity-onset diabetes of the young (MODY). Hum Mutat 22:417–421PubMedCrossRef
18.
Lehto M, Tuomi T, Mahtani MM et al (1997) Characterization of the MODY3 phenotype. Early-onset diabetes caused by an insulin secretion defect. J Clin Invest 99:582–591PubMedCrossRef
19.
Gragnoli C, Stanojevic V, Gorini A, Von Preussenthal GM, Thomas MK, Habener JF (2005) IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes. Metabolism 54:983–988PubMedCrossRef
20.
Marz W, Nauck M, Hoffmann MM et al (2004) G(−30)A polymorphism in the pancreatic promoter of the glucokinase gene associated with angiographic coronary artery disease and type 2 diabetes mellitus. Circulation 109:2844–2849PubMedCrossRef
21.
Rose CS, Ek J, Urhammer SA et al (2005) A −30G>A polymorphism of the {beta}-cell-specific glucokinase promoter associates with hyperglycemia in the general population of whites. Diabetes 54:3026–3031PubMedCrossRef
22.
Chiu KC, Chuang LM, Chu A, Wang M (2003) Transcription factor 1 and beta-cell function in glucose-tolerant subjects. Diabet Med 20:225–230PubMedCrossRef
23.
Silander K, Mohlke KL, Scott LJ et al (2004) Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes. Diabetes 53:1141–1149PubMedCrossRef
24.
Love-Gregory LD, Wasson J, Ma J et al (2004) A common polymorphism in the upstream promoter region of the hepatocyte nuclear factor-4 alpha gene on chromosome 20q is associated with type 2 diabetes and appears to contribute to the evidence for linkage in an Ashkenazi Jewish population. Diabetes 53:1134–1140PubMedCrossRef
25.
Weedon MN, Owen KR, Shields B et al (2004) Common variants of the hepatocyte nuclear factor-4alpha P2 promoter are associated with type 2 diabetes in the U.K. population. Diabetes 53:3002–3006PubMedCrossRef
26.
Weedon MN, Owen KR, Shields B et al (2005) A large-scale association analysis of common variation of the HNF1alpha gene with type 2 diabetes in the U.K. Caucasian population. Diabetes 54:2487–2491PubMedCrossRef
27.
Winckler W, Burtt NP, Holmkvist J et al (2005) Association of common variation in the HNF1{alpha} gene region with risk of type 2 diabetes. Diabetes 54:2336–2342PubMedCrossRef
28.
Winckler W, Graham RR, de Bakker PI et al (2005) Association testing of variants in the hepatocyte nuclear factor 4alpha gene with risk of type 2 diabetes in 7,883 people. Diabetes 54:886–892PubMedCrossRef
29.
Lind T, Phillips PR (1991) Influence of pregnancy on the 75-g OGTT. A prospective multicenter study. The Diabetic Pregnancy Study Group of the European Association for the Study of Diabetes. Diabetes 40(Suppl 2):8–13PubMed
30.
Shaat N, Ekelund M, Lernmark A et al (2005) Association of the E23K polymorphism in the KCNJ11 gene with gestational diabetes mellitus. Diabetologia 48:2544–2551PubMedCrossRef
31.
Shaat N, Ekelund M, Lernmark A et al (2004) Genotypic and phenotypic differences between Arabian and Scandinavian women with gestational diabetes mellitus. Diabetologia 47:878–884PubMedCrossRef
32.
Lernmark B, Elding-Larsson H, Hansson G, Lindberg B, Lynch K, Sjoblad S (2004) Parent responses to participation in genetic screening for diabetes risk. Pediatr Diabetes 5:174–181PubMedCrossRef
33.
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRef
34.
35.
Matschinsky F, Liang Y, Kesavan P et al (1993) Glucokinase as pancreatic beta cell glucose sensor and diabetes gene. J Clin Invest 92:2092–2098PubMedCrossRef
36.
Stone LM, Kahn SE, Fujimoto WY, Deeb SS, Porte D Jr (1996) A variation at position −30 of the beta-cell glucokinase gene promoter is associated with reduced beta-cell function in middle-aged Japanese-American men. Diabetes 45:422–428PubMedCrossRef
37.
Zaidi FK, Wareham NJ, McCarthy MI et al (1997) Homozygosity for a common polymorphism in the islet-specific promoter of the glucokinase gene is associated with a reduced early insulin response to oral glucose in pregnant women. Diabet Med 14:228–234PubMedCrossRef
38.
Weedon MN, Frayling TM, Shields B et al (2005) Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene. Diabetes 54:576–581PubMedCrossRef
39.
Allan CJ, Argyropoulos G, Bowker M et al (1997) Gestational diabetes mellitus and gene mutations which affect insulin secretion. Diabetes Res Clin Pract 36:135–141PubMedCrossRef
40.
Chiu KC, Go RC, Aoki M et al (1994) Glucokinase gene in gestational diabetes mellitus: population association study and molecular scanning. Diabetologia 37:104–110PubMedCrossRef
41.
Ryffel GU (2001) Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences. J Mol Endocrinol 27:11–29PubMedCrossRef
42.
Holmkvist J, Cervin C, Almgren P, Lyssenko V, Cilio C, Groop L (2005) Common variants in the HNF-1a gene increase susceptibility to type 2 diabetes [abstract]. Diabetologia 48(Suppl 11):A127
43.
Duncan SA, Manova K, Chen WS et al (1994) Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Proc Natl Acad Sci USA 91:7598–7602PubMedCrossRef
44.
Thomas H, Jaschkowitz K, Bulman M et al (2001) A distant upstream promoter of the HNF-4alpha gene connects the transcription factors involved in maturity-onset diabetes of the young. Hum Mol Genet 10:2089–2097PubMedCrossRef
45.
Hansen SK, Parrizas M, Jensen ML et al (2002) Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function. J Clin Invest 110:827–833PubMed
46.
Hansen SK, Rose CS, Glumer C et al (2005) Variation near the hepatocyte nuclear factor (HNF)-4alpha gene associates with type 2 diabetes in the Danish population. Diabetologia 48:452–458PubMedCrossRef
Metadata
Title
Common variants in MODY genes increase the risk of gestational diabetes mellitus
Authors
N. Shaat
E. Karlsson
Å. Lernmark
S. Ivarsson
K. Lynch
H. Parikh
P. Almgren
K. Berntorp
L. Groop
Publication date
01-07-2006
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 7/2006
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-006-0258-8

Other articles of this Issue 7/2006

Diabetologia 7/2006 Go to the issue

For Debate

Neel revisited: the adipocyte, seasonality and type 2 diabetes

Article

Plasma apolipoprotein A5 and triglycerides in type 2 diabetes

Letter-comment

Comment to: Martin S, Schneider B, Heinemann L et al (2006) Self-monitoring of blood glucose in type 2 diabetes and long-term outcome: an epidemiological cohort study. Diabetologia 49:271–278

Letter

Comment to: Hoi-Hansen T, Pedersen-Bjergaard U, Thorsteinsson B (2005) The Somogyi phenomenon revisited using continuous glucose monitoring in daily life. Diabetologia 48:2437–2438

Short communication

Estimating glomerular filtration rate in diabetes: a comparison of cystatin-C- and creatinine-based methods

Article

Common polymorphisms of calpain-10 are associated with abdominal obesity in subjects at high risk of type 2 diabetes
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits