BMI at age 8 years is influenced by the type 2 diabetes susceptibility genes HHEX-IDE and CDKAL1.
OBJECTIVE
To determine whether HHEX-IDE and CDKAL1 genes, which are associated with birth weight and susceptibility to type 2 diabetes, continue to influence growth during childhood.


METHODS
BMI, weight, and height at age 8 years expressed as age- and sex-corrected standard deviation scores (SDS) against national reference data and single-nucleotide polymorphism genotyping of HHEX-IDE and CDKAL1 loci were analyzed in 646 prospectively followed children in the German BABYDIAB cohort. All children were singleton full-term births; 386 had mothers with type 1 diabetes, and 260 had fathers with type 1 diabetes and a nondiabetic mother.


RESULTS
Type 2 diabetes risk alleles at the HHEX-IDE locus were associated with reduced BMI-SDS at age 8 years (0.17 SDS per allele; P = 0.004). After stratification for birth weight, both HHEX-IDE and CDKAL1 risk alleles were associated with reduced BMI-SDS (0.45 SDS, P = 0.0002; 0.52 SDS, P = 0.0001) and weight-SDS (0.22 SDS, P = 0.04; 0.56 SDS, P = 0.0002) in children born large for gestational age (>90th percentile) but not children born small or appropriate for gestational age. Within children born large for gestational age, BMI and weight decreased with each additional type 2 diabetes risk allele ( approximately -2 kg per allele; >8 kg overall). Findings were consistent in children of mothers with type 1 diabetes (P < 0.0001) and children of nondiabetic mothers (P = 0.008).


CONCLUSIONS
The type 2 diabetes susceptibility alleles at HHEX-IDE and CDKAL1 loci are associated with low BMI at age 8 years in children who were born large for gestational age.
Winkler
Christiane
C
Institut fuer Diabetes forschung der Forschergruppe Diabetes e.V. at Helmholtz Center Munich, Neuherberg, Germany.
Bonifacio
Ezio
E
Grallert
Harald
H
Henneberger
Lydia
L
Illig
Thomas
T
Ziegler
Anette-Gabriele
AG
D001724:Birth Weight / Q000235:genetics; D015992:Body Mass Index; D002648:Child; D015331:Cohort Studies; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005220:Fathers; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009035:Mothers; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*; D012359:tRNA Methyltransferases
C078492:HHEX protein, human; D018398:Homeodomain Proteins; D014157:Transcription Factors; D012359:tRNA Methyltransferases; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human
Diabetes. 2009 Jun;58(6):1428-33
19228808
Pediatrics. 1999 Sep;104(3):e33
10469816
Circulation. 1996 Dec 15;94(12):3246-50
8989136
J Clin Endocrinol Metab. 2006 Jun;91(6):2153-8
16537681
Am J Epidemiol. 2007 Apr 15;165(8):849-57
17215379
Diabetes Care. 2006 Nov;29(11):2489-97
17065690
J Pediatr. 1977 Jun;90(6):1049-51
859062
BMJ. 1994 Apr 9;308(6934):942-5
8173400
Am J Clin Nutr. 1985 Jul;42(1):57-60
4014067
Nat Genet. 1998 Nov;20(3):284-7
9806549
Diabetes. 2010 Mar;59(3):751-5
19933996
Diabetes. 2001 Mar;50(3):686-9
11246892
Nat Genet. 2008 May;40(5):638-45
18372903
Br J Nutr. 2010 Feb;103(3):386-92
19772682
Pediatrics. 1988 Dec;82(6):828-34
3186371
BMJ. 1996 Feb 17;312(7028):406-10
8601111
Diabetes. 1999 Mar;48(3):460-8
10078544
J Clin Endocrinol Metab. 2009 Oct;94(10):4113-5
19622614
Diabetes. 1980 Dec;29(12):1023-35
7002669
Ann Intern Med. 1999 Feb 16;130(4 Pt 1):278-84
10068385
Diabetes Care. 2003 Feb;26(2):343-8
12547860
Geburtshilfe Frauenheilkd. 1996 Oct;56(10):550-8
9036070
Br Med Bull. 1997 Jan;53(1):81-95
9158286
Diabetes. 2007 Dec;56(12):3101-4
17804762
Am J Hum Biol. 1995;7(3):293-301
28557025
Diabetes. 2007 Dec;56(12):3105-11
17827400
Diabetologia. 2005 Aug;48(8):1496-502
16007414
Diabetes Care. 2004 Oct;27(10):2512-3
15451930
Arch Med Res. 2008 Nov;39(8):796-802
18996294