Maternal LDL-C levels before pregnancy are associated with adult offspring LDL-C levels

Mendelson MM, Lyass A, O’Donnell CJ, et al.
JAMA Cardiol 2016; published online ahead of print

Background

Pregnant women with hyperglycaemia and adiposity give birth to children with a high CV risk [1,2]. Dyslipidaemia has been frequently reported in women of childbearing age [3], however, the consequences of maternal lipoprotein abnormalities on the health of their offspring has not been adequately explored.
However, animal models of maternal hypercholesterolaemia have a higher burden of offspring atherosclerosis [4]. Furthermore, offspring with maternal, compared with paternal, inheritance of the same familial hypercholesterolaemia (FH) genetic variant, have a higher mortality rate [6] and maternal hypercholesterolaemia has been linked to abnormal offspring cholesterol regulation [7,8].
In previous generations routine cholesterol measurements in young, healthy women prior to pregnancy was not seen as a necessity, therefore, it is not known whether higher maternal LDL-C levels before pregnancy are associated with increased offspring dyslipidemia and CVD risk in the general population.
This study assessed whether adult offspring levels of serum LDL-C are associated with maternal LDL-C levels before pregnancy (not measured based on any indication), beyond that attributable to inherited genetic sequence polymorphisms, diet, physical activity, and body mass index, in a subgroup of individuals who participated the Framingham Heart Study (FHS). Data of 538 parent-offspring pairs (241 mother-offspring and 297 father-offspring) were included.

Main results

• Adult offspring LDL-C levels (exposed to elevated maternal pre-pregnancy LDL-C levels) were associated with maternal pre-pregnancy LDL-C: adjusted β = 0.32; SE: 0.05 mg/dL; P < 0.001

• Adult offspring were at a 3.8 (95%CI: 1.5-9.8) times higher odds of having elevated LDL-C levels (P = 0.005)  and had an adjusted higher LDL-C level of 18mg/dL (95%CI: 9-27mg/dL).

• Maternal pre-pregnancy LDL-C levels explained 13% of the variation in adult offspring LDL-C levels beyond common genetic variants and classic risk factors for elevated LDL-C levels.
• The regression β coefficient for the association of parental pre-pregnancy LDL-C with adult offspring LDL-C levels was approximately twice as high for maternal compared with paternal pre-pregnancy LDL-C levels.

• When both maternal and paternal pre-pregnancy LDL-C levels were added to the same regression model, the maternal pre-pregnancy LDL-C levels remained associated with the adult offspring LDL-C levels, but the paternal pre-pregnancy levels did not (maternal OR: 6.2; 95%CI: 1.6-24; P = 0.009, paternal OR: 0.6; 95%CI: 0.2-2.3; P = 0.49).

Conclusion

Maternal LDL-C levels before pregnancy are associated with adult offspring LDL-C levels, independently of the influence of measured lifestyle, anthropometric, and inherited genetic factors in mother and offspring. These findings may point in the direction of a multifactorial mechanism that may be mediated through direct effects on the developing fetal organ systems and through epigenetic modifications transferred via gametes or introduced in utero under influence of the nutrient milieu.
Better understanding of the CVD risk associated with the intrauterine environment may lead to population-based lifestyle strategies for women in their childbearing years. The authors propose that identification and management of dyslipidemia in these young women may contribute to the reduction of the atherosclerotic burden in the general population.

Editorial comment [9]

In his editorial note, Sabatine comments on the possible explanation of the study findings: “As the investigators correctly note, this observed association does not prove causality. To that end, in this older Framingham Heart Study cohort, maternal dietary habits might have played a greater role than did paternal habits in setting the dietary habits of the offspring. Moreover, studies in the setting of familial hypercholesterolemia have not found any difference between maternal vs paternal carriage of familial hypercholesterolemia and offspring LDL-C levels, both in offspring with and those without familial hypercholesterolemia. However, there is a growing body of evidence that epigenetic regulation of gene expression can be influenced by environmental exposures. To that end, differential DNA methylation has been observed after periconceptional exposure to famine. Determining whether there are epigenetic transmission mechanisms underlying the observations seen in the study by Mendelson and colleagues will be an important next step. Regardless, this study should raise awareness of the effect of parental, and specifically maternal, hypercholesterolemia on the cardiovascular risk profile of offspring.”

Find this article online at JAMA Cardiology

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