The Immunosignature of MotherFetus Couples in Gestational Diabetes Mellitus: Role of HLA-G 14 bp insdel and PAPP-A AC Polymorphisms in the Uterine Inflammatory Milieu

Abstract EN

We enrolled 151 healthy mother/newborn couples and 26 with gestational diabetes mellitus (GDM).

HLA-G and PAPP-A plasma levels were measured by ELISA at first and second trimesters, at delivery, and in cord blood.

HLA-G 14 bp ins/del and PAPP-A A/C polymorphisms were genotyped.

HLA-G del/del and PAPP-A C/C genotypes were more frequent among GDM mothers than controls.

We observed a genetic epistasis between the two polymorphisms: the HLA-G del/del and PAPP-A C/C combination was carried by 8% of GDM mothers and 1.3% of controls (OR = 9.5, 95% CI = 0.8–109, p=0.07).

GDM mothers showed increased sHLA-G levels compared to controls (p=0.004), and those carrying the HLA-G del/del genotype produced more sHLA-G at the second trimester and at delivery (p=0.014).

A genetic pressure by fetal genotype on maternal sHLA-G production was observed in GDM mothers with heterozygous HLA-G del/ins newborns (p=0.02).

Babies born to GDM mothers showed higher sHLA-G concentrations compared to those born to healthy mothers, and those carrying HLA-G del/del showed the highest sHLA-G levels (p=0.013).

PAPP-A amounts significantly increased along pregnancy (p<0.001), but the median levels at the first and second trimesters were significantly lower in GDM (p=0.03).

Our findings first suggest an involvement of HLA-G and PAPP-A gene-protein interaction in GDM and highlight a possible contribution of the fetus in balancing maternal inflammation.