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


METHODS
We genotyped five common variants in the glucokinase (GCK, commonly known as MODY2), hepatocyte nuclear factor 1-alpha (HNF1A, commonly known as MODY3) and 4-alpha (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
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.
Shaat
N
N
Department of Clinical Sciences/Diabetes and Endocrinology, Malmö University Hospital, Lund University, Malmö, Sweden. nael.shaat@med.lu.se
Karlsson
E
E
Lernmark
A
A
Ivarsson
S
S
Lynch
K
K
Parikh
H
H
Almgren
P
P
Berntorp
K
K
Groop
L
L
D000328:Adult; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D016640:Diabetes, Gestational / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005941:Glucokinase / Q000235:genetics*; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D013548:Sweden
C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D005941:Glucokinase