Unraveling the etiology of congenital heart defects – The role of maternal genetics and cardiovascular disease as a risk factor

Informations projet

FINNPEDHEART

N° de convention de subvention: 101076986

DOI

10.3030/101076986

Date de signature de la CE 30 Mai 2023

Date de début 1 Juillet 2023

Date de fin 30 Juin 2028

Financé au titre de

• European Research Council (ERC)

Coût total

€ 1 495 845,00

Contribution de l’UE

€ 1 495 845,00

Coordonné par

HELSINGIN YLIOPISTO
Finland

Periodic Reporting for period 1 - FINNPEDHEART (Unraveling the etiology of congenital heart defects – The role of maternal genetics and cardiovascular disease as a risk factor)

Période du rapport: 2023-07-01 au 2025-12-31

Résumé du contexte et des objectifs généraux du projet

One in a hundred infants is born with a congenital heart defect (CHD). Both genetic and environmental risk factors, such as maternal diabetes and obesity, are known to cause CHD, however, little is known about the disease mechanisms behind these risks. CHD can occur as an element of a syndrome, in conjunction with other anomalies, or as an isolated defect. I propose that there is an etiologically distinct “environmental CHD” subgroup, where in addition to the child’s genes, maternal genetics and gene expression play a major role in disease development. Moreover, I propose that in these cases the genetic risk profile predisposes the woman for both having offspring with CHD and having early onset atherosclerotic disease.

My objective is to study how maternal genetics and maternal cardiovascular morbidity as an environmental risk contribute to the risk for having offspring with CHD. In addition, the multifactorial aetiology in terms of the presence of both risk factors, will be studied using a unique dataset available only in Finland.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Three different substudies will be conducted: 1) Finnish national registers gathering health related information of all Finns from birth to death will be used to determine the presence of atherosclerosis and related traits, such as hypertension and coronary artery disease, in mothers who have offspring with CHD compared to those without (tot. N = 1 million). 2) Maternal genetic risk loci for having CHD in the offspring will be sought in the FinnGen study (tot. N = 0.5 million). 3) Maternal 1st trimester serum samples from pregnancies with and without CHD will be analysed to identify CHD associated biomarkers (tot. N = 3200).

Our preliminary results indicate that both mothers and fathers, whose offspring have CHD, have increased risk for getting cardiovascular diagnoses than controls, and they get their diagnoses significantly earlier than controls. When analysing specific diagnoses, offsprings CHD increased the risk for atrial fibrillation/ flutter and hypertension in both parents. Offsprings CHD did not increase the risk fo CVD related death in the parents in this population. In addition, in our preliminary genetic analyses, we have identified specific genetic loci, which associate both with left ventricular outflow tract obstruction -type of CHD and either atrial fibrillation and flutter or hypertension. These findings may indicate shared genetic predisposition.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The study results will provide important information on how the combination of maternal genetic and environmental risk factors contribute to cardiac developmental defects during early pregnancy and offer new insights for future research on the cellular and molecular mechanisms of cardiac development.

Our results thus far indicate 1) partially shared genetic risk for CHD and other cardiovascular disease, and 2) increased cardiovascular morbidity risk in parents who have offspring with CHD. Our results indicate that parents with offspring with CHD may benefit from early primary prevention and counselling to reduce the risk of premature CVD.