IADR Abstract Archives
Gestational Diabetes Genes and the Risk of Orofacial Clefts
Objectives: Gestational diabetes mellitus (GDM) has been associated with risk of orofacial clefts (OFCs). Our objective was to determine the association between GDM genes and the risk of OFCs.
Methods: The GENEVA international consortium study included data on 892 isolated cleft lip with or without cleft palate (CL/P) case-parent trios of Asian ancestry and 665 CL/P trios of European ancestry. Twenty GDM genes were selected based on significant associations with GDM in multiple published studies for each gene. Genotypic transmission disequilibrium tests (gTDT) were used to analyze genetic effects and gene-environment (GxE) interactions with periconceptional maternal multivitamin use (PCMV), smoking, and environmental tobacco smoke (ETS). A gene-level approach to analysis was employed with Bonferroni adjustment of p-values based on the number of SNPs used in each individual gene.
Results: SLC30A8 was associated with CL/P in Asian trios. In Europeans, ADRB3, TNF-α, and ABCC8 were associated with CL/P. Considering interactions with PCMV, associations were found for FTO in Asians and ABCC8 and TNF-α in Europeans. Considering interactions with maternal smoking, associations were found for CDKN2A/2B in Asians and for ABCC8, LEP, and TNF-α in Europeans. In Asians, FTO, HHEX, and PPARG showed evidence of association with OFCs when considering interaction with ETS.
Conclusions: Several genes related to GDM were associated with risk of isolated CL/P through genotypic effects alone and gene-environment interactions with PCMV, maternal smoking, and ETS. These associations do not point to any single major GDM gene associated with OFCs, but support the hypothesis that GDM may be causally related to OFCs via multiple GDM susceptibility genes related to the mechanisms of obesity, metabolic syndrome, systemic inflammation, and pancreatic beta-cell dysfunction and possible interactions with environmental factors.
Methods: The GENEVA international consortium study included data on 892 isolated cleft lip with or without cleft palate (CL/P) case-parent trios of Asian ancestry and 665 CL/P trios of European ancestry. Twenty GDM genes were selected based on significant associations with GDM in multiple published studies for each gene. Genotypic transmission disequilibrium tests (gTDT) were used to analyze genetic effects and gene-environment (GxE) interactions with periconceptional maternal multivitamin use (PCMV), smoking, and environmental tobacco smoke (ETS). A gene-level approach to analysis was employed with Bonferroni adjustment of p-values based on the number of SNPs used in each individual gene.
Results: SLC30A8 was associated with CL/P in Asian trios. In Europeans, ADRB3, TNF-α, and ABCC8 were associated with CL/P. Considering interactions with PCMV, associations were found for FTO in Asians and ABCC8 and TNF-α in Europeans. Considering interactions with maternal smoking, associations were found for CDKN2A/2B in Asians and for ABCC8, LEP, and TNF-α in Europeans. In Asians, FTO, HHEX, and PPARG showed evidence of association with OFCs when considering interaction with ETS.
Conclusions: Several genes related to GDM were associated with risk of isolated CL/P through genotypic effects alone and gene-environment interactions with PCMV, maternal smoking, and ETS. These associations do not point to any single major GDM gene associated with OFCs, but support the hypothesis that GDM may be causally related to OFCs via multiple GDM susceptibility genes related to the mechanisms of obesity, metabolic syndrome, systemic inflammation, and pancreatic beta-cell dysfunction and possible interactions with environmental factors.