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 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 9/2010

01-09-2010 | Article

Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight

Authors: E. A. Andersson, K. Pilgaard, C. Pisinger, M. N. Harder, N. Grarup, K. Færch, P. Poulsen, D. R. Witte, T. Jørgensen, A. Vaag, T. Hansen, O. Pedersen

Published in: Diabetologia | Issue 9/2010

Login to get access

Abstract

Aims/hypothesis

The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies.

Methods

Midwife records from the Danish State Archives provided information on mother’s age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes.

Results

Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (β = −33 g [95% CI −55, −10], p = 0.004) and CDKAL1 rs7756992 (β = −22 g [95% CI −43, −1], p = 0.04). The association for the latter locus was confirmed in a meta-analysis (n = 24,885) (β = −20 g [95% CI −29, −11], p = 5 × 10−6). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p = 0.09); however, in a meta-analysis (n = 25,164) this type 2 diabetes risk allele was associated with lower birthweight (β = −16 g [95% CI −24, −8], p = 8 × 10−5). On average, individuals with high genetic risk (≥25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (β = −35 g [95% CI −69, −2], p = 0.037).

Conclusions/interpretation

We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.
Appendix
Available only for authorised users
Literature
1.
Frayling TM, Hattersley AT (2001) The role of genetic susceptibility in the association of low birth weight with type 2 diabetes. Br Med Bull 60:89–101CrossRefPubMed
2.
Hales CN, Barker DJ, Clark PM et al (1991) Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303:1019–1022CrossRefPubMed
3.
Harder T, Rodekamp E, Schellong K, Dudenhausen JW, Plagemann A (2007) Birth weight and subsequent risk of type 2 diabetes: a meta-analysis. Am J Epidemiol 165:849–857CrossRefPubMed
4.
Poulsen P, Vaag AA, Kyvik KO, Moller Jensen D, Beck-Nielsen H (1997) Low birth weight is associated with NIDDM in discordant monozygotic and dizygotic twin pairs. Diabetologia 40:439–446CrossRefPubMed
5.
Hattersley AT, Tooke JE (1999) The fetal insulin hypothesis: an alternative explanation of the association of low birthweight with diabetes and vascular disease. Lancet 353:1789–1792CrossRefPubMed
6.
Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S (1998) Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet 19:268–270CrossRefPubMed
7.
Slingerland AS, Hattersley AT (2006) Activating mutations in the gene encoding Kir6.2 alter fetal and postnatal growth and also cause neonatal diabetes. J Clin Endocrinol Metab 91:2782–2788CrossRefPubMed
8.
Edghill EL, Bingham C, Ellard S, Hattersley AT (2006) Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet 43:84–90CrossRefPubMed
9.
Stoy J, Edghill EL, Flanagan SE et al (2007) Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A 104:15040–15044CrossRefPubMed
10.
Pearson ER, Boj SF, Steele AM et al (2007) Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 4:e118CrossRefPubMed
11.
Steinthorsdottir V, Thorleifsson G, Reynisdottir I et al (2007) A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39:770–775CrossRefPubMed
12.
Bouatia-Naji N, Bonnefond A, Cavalcanti-Proenca C et al (2009) A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat Genet 41:89–94CrossRefPubMed
13.
Dupuis J, Langenberg C, Prokopenko I et al (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42:105–116
14.
Lyssenko V, Nagorny CL, Erdos MR et al (2009) Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat Genet 41:82–88CrossRefPubMed
15.
Prokopenko I, Langenberg C, Florez JC et al (2009) Variants in MTNR1B influence fasting glucose levels. Nat Genet 41:77–81CrossRefPubMed
16.
Altshuler D, Hirschhorn JN, Klannemark M et al (2000) The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76–80CrossRefPubMed
17.
Gloyn AL, Weedon MN, Owen KR et al (2003) Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52:568–572CrossRefPubMed
18.
Nielsen EM, Hansen L, Carstensen B et al (2003) The E23K variant of Kir6.2 associates with impaired post-OGTT serum insulin response and increased risk of type 2 diabetes. Diabetes 52:573–577CrossRefPubMed
19.
Grant SF, Thorleifsson G, Reynisdottir I et al (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323CrossRefPubMed
20.
Saxena R, Voight BF, Lyssenko V et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336CrossRefPubMed
21.
Scott LJ, Mohlke KL, Bonnycastle LL et al (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345CrossRefPubMed
22.
Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885CrossRefPubMed
23.
Zeggini E, Scott LJ, Saxena R et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638–645CrossRefPubMed
24.
Zeggini E, Weedon MN, Lindgren CM et al (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341CrossRefPubMed
25.
Yasuda K, Miyake K, Horikawa Y et al (2008) Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet 40:1092–1097CrossRefPubMed
26.
Unoki H, Takahashi A, Kawaguchi T et al (2008) SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 40:1098–1102CrossRefPubMed
27.
Sandhu MS, Weedon MN, Fawcett KA et al (2007) Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet 39:951–953CrossRefPubMed
28.
Gudmundsson J, Sulem P, Steinthorsdottir V et al (2007) Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet 39:977–983CrossRefPubMed
29.
Winckler W, Weedon MN, Graham RR et al (2007) Evaluation of common variants in the six known maturity-onset diabetes of the young (MODY) genes for association with type 2 diabetes. Diabetes 56:685–693CrossRefPubMed
30.
Rung J, Cauchi S, Albrechtsen A et al (2009) Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 41:1110–1115CrossRefPubMed
31.
Saxena R, Hivert M-F, Langenberg C et al (2010) Genetic variation in GIPR influences the glucose and insulin responses to an oral glucose challenge. Nat Genet 42:142–148
32.
Freathy RM, Bennett AJ, Ring SM et al (2009) Type 2 diabetes risk alleles are associated with reduced size at birth. Diabetes 58:1428–1433CrossRefPubMed
33.
Pulizzi N, Lyssenko V, Jonsson A et al (2009) Interaction between prenatal growth and high-risk genotypes in the development of type 2 diabetes. Diabetologia 52:825–829CrossRefPubMed
34.
Zhao J, Li M, Bradfield JP et al (2009) Examination of type 2 diabetes loci implicates CDKAL1 as a birth weight gene. Diabetes 58:2414–2418CrossRefPubMed
35.
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 54:576–581CrossRefPubMed
36.
Freathy RM, Weedon MN, Bennett A et al (2007) Type 2 diabetes TCF7L2 risk genotypes alter birth weight: a study of 24,053 individuals. Am J Hum Genet 80:1150–1161CrossRefPubMed
37.
Jorgensen T, Borch-Johnsen K, Thomsen TF, Ibsen H, Glumer C, Pisinger C (2003) A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99. Eur J Cardiovasc Prev Rehabil 10:377–386CrossRefPubMed
38.
Glumer C, Jorgensen T, Borch-Johnsen K (2003) Prevalences of diabetes and impaired glucose regulation in a Danish population: the Inter99 study. Diab Care 26:2335–2340CrossRef
39.
RM Freathy US, I Prokopenko, DO Mook-Kanamori, et al. for the Early Growth Genetics Consortium (2009) New loci on chromosomes 3q25 and 3q21 are associated with size at birth. (Abstract # 87). Presented at the 59th Annual Meeting of The American Society of Human Genetics, 23 October 2009, Honolulu, Hawaii. Available at www.​ashg.​org/​2009meeting/​abstracts/​fulltext/​, accessed 1 May 2010
40.
Grarup N, Rose CS, Andersson EA et al (2007) Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects: validation and extension of genome-wide association studies. Diabetes 56:3105–3111CrossRefPubMed
41.
Phillips DI, Barker DJ, Hales CN, Hirst S, Osmond C (1994) Thinness at birth and insulin resistance in adult life. Diabetologia 37:150–154CrossRefPubMed
42.
Freathy RM, Mook-Kanamori DO, Sovio U et al (2010) Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight. Nat Genet 42:430–435
43.
Leech CA, Castonguay MA, Habener JF (1999) Expression of adenylyl cyclase subtypes in pancreatic beta-cells. Biochem Biophys Res Commun 254:703–706CrossRefPubMed
44.
Prentki M, Matschinsky FM (1987) Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion. Physiol Rev 67:1185–1248PubMed
45.
Yan L, Vatner DE, O'Connor JP et al (2007) Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130:247–258CrossRefPubMed
46.
Okumura S, Vatner DE, Kurotani R et al (2007) Disruption of type 5 adenylyl cyclase enhances desensitization of cyclic adenosine monophosphate signal and increases Akt signal with chronic catecholamine stress. Circulation 116:1776–1783CrossRefPubMed
47.
Bernstein IM, Mongeon JA, Badger GJ, Solomon L, Heil SH, Higgins ST (2005) Maternal smoking and its association with birth weight. Obstet Gynecol 106:986–991PubMed
48.
Grunnet L, Vielwerth S, Vaag A, Poulsen P (2007) Birth weight is nongenetically associated with glucose intolerance in elderly twins, independent of adult obesity. J Intern Med 262:96–103CrossRefPubMed
49.
Hypponen E, Smith GD, Power C (2003) Parental diabetes and birth weight of offspring: intergenerational cohort study. BMJ 326:19–20CrossRefPubMed
Metadata
Title
Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight
Authors
E. A. Andersson
K. Pilgaard
C. Pisinger
M. N. Harder
N. Grarup
K. Færch
P. Poulsen
D. R. Witte
T. Jørgensen
A. Vaag
T. Hansen
O. Pedersen
Publication date
01-09-2010
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 9/2010
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-010-1790-0

Other articles of this Issue 9/2010

Diabetologia 9/2010 Go to the issue

Erratum

Erratum to: Consensus guidelines, algorithms and care of the individual patient with type 2 diabetes

Article

Low-intensity physical activity is associated with reduced risk of incident type 2 diabetes in older adults: evidence from the English Longitudinal Study of Ageing

Short Communication

Proteinuria modifies the effects of physical activity on total and cardiovascular disease mortality rates in patients with type 2 diabetes

Article

Diabetes, prediabetes and cancer mortality

Article

Naturally occurring R225W mutation of the gene encoding AMP-activated protein kinase (AMPK)γ3 results in increased oxidative capacity and glucose uptake in human primary myotubes

Article

Evidence of increased islet cell proliferation in patients with recent-onset type 1 diabetes

ACC 2024 Congress Coverage

Cardiology Video

Highlights from the ACC 2024 Congress

Watch now

Watch official videos from the ACC congress summarizing key highlights from the last year in heart failure, cardiomyopathies, valvular disease, pulmonary vascular disease, and pediatric cardiology.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits