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Figure 1.
Effect of Prepregnancy Parental Low-Density Lipoprotein Cholesterol (LDL-C) Level on Adult Offspring LDL-C Level
Effect of Prepregnancy Parental Low-Density Lipoprotein Cholesterol (LDL-C) Level on Adult Offspring LDL-C Level

A, Maternal factors influencing adult offspring LDL-C exposure. B, In the comparison groups, paternal prepregnancy LDL-C level exhibits similar pathways except for the in utero exposures and subsequent epigenetic modifications. Concurrent parental LDL-C levels share an adulthood environment and genetic variants. The in utero pathway between prepregnancy LDL-C levels and adult offspring LDL-C levels would not be applicable in the paternal prepregnancy comparison group, as indicated by the “X.” Neither comparison group would be expected to demonstrate an association between parental and offspring LDL-C levels due to in utero LDL-C exposure after adjusting for the confounding pathways. BMI indicates body mass index; SNPs, single-nucleotide polymorphisms.

Figure 2.
Flowchart of Study Sample Inclusions for Analyses
Flowchart of Study Sample Inclusions for Analyses

FHS indicates Framingham Heart Study.

Figure 3.
Risk for Elevated Adult Offspring Low-Density Lipoprotein Cholesterol (LDL-C) Levels
Risk for Elevated Adult Offspring Low-Density Lipoprotein Cholesterol (LDL-C) Levels

Odds ratios (ORs) for elevated adult offspring LDL-C levels (solid line) and 95% CIs (dashed lines) across a range of maternal (A) and paternal (B) prepregnancy LDL-C levels (to convert LDL-C to millimoles per liter, multiply by 0.0259). An OR of 1 indicates no increase in risk.

Table 1.  
Characteristics of Mother-Offspring and Father-Offspring Pairs With Characteristics of Parents at the Prebirth Examination
Characteristics of Mother-Offspring and Father-Offspring Pairs With Characteristics of Parents at the Prebirth Examination
Table 2.  
Association of Adult Offspring LDL-C Level With Parental LDL-C Level at Prepregnancy Examinations
Association of Adult Offspring LDL-C Level With Parental LDL-C Level at Prepregnancy Examinations
Table 3.  
Association of Adult Offspring LDL-C Level With Parental LDL-C Level at Concurrent Examinations
Association of Adult Offspring LDL-C Level With Parental LDL-C Level at Concurrent Examinations
Supplement.

eMethods. Assessments and Analyses

eResults. Comparison of Maternal vs Paternal Prepregnancy Contribution

eTable 1. LDL-C Genetic Risk Score (GRS) Components, Effect Sizes and Genotyping Details

eTable 2. Characteristics of Maternal and Paternal Study Sample at the Concurrent Examination With Adult Offspring LDL-C Measurement

eTable 3. Descriptives of All Participants of the Framingham Heart Study Offspring and Third Generation Cohorts

eTable 4. Full Model Output From Successive Linear Regression Models With Adult Offspring LDL-C (mg/dL) Specified as the Dependent Variable and Maternal Prepregnancy LDL-C (mg/dL) as the Independent Variable of Interest

eTable 5. Full Model Output From Successive Logistic Regression Models With Adult Offspring LDL-C (>130 mg/dL) Specified as the Dependent Variable and Maternal Prepregnancy LDL-C (>130 mg/dL) as the Independent Variable of Interest

eTable 6. Full Model Output From Successive Linear Regression Models With Adult Offspring LDL-C (mg/dL) Specified as the Dependent Variable and Paternal Prepregnancy LDL-C (mg/dL) as the Independent Variable of Interest

eTable 7. Full Model Output From Successive Logistic Regression Models With Adult Offspring LDL-C (>130 mg/dL) Specified as the Dependent Variable and Paternal Prepregnancy LDL-C (>130 mg/dL) as the Independent Variable of Interest

eTable 8. Distribution of HDL Cholesterol and Triglycerides Among Study Sample

eTable 9. Relationship Between Parental HDL Cholesterol and Adult Offspring HDL Cholesterol at Pre-Birth (A) and Concurrent Examinations (B)

eTable 10. Relation Between Adult Offspring Triglycerides and Parental Triglycerides at Pre-Birth (A) and Concurrent Examinations (B)

eTable 11. Sensitivity Analysis Using a Correction Factor (1.35) to Estimate Untreated LDL-C Among Individuals on Lipid-Lowering Medication

eTable 12. Range of Scenarios for the Effect Size and Distribution of Unmeasured Confounding Required to Explain the Association Between Elevated Maternal Prepregnancy LDL-C and Elevated Adult Offspring LDL-C

eFigure 1. Scatterplot of Maternal Prepregnancy LDL-C vs Adult Offspring LDL-C

eFigure 2. Scatterplot of Paternal LDL-C vs Adult Offspring LDL-C

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Original Investigation
April 2016

Association of Maternal Prepregnancy Dyslipidemia With Adult Offspring Dyslipidemia in Excess of Anthropometric, Lifestyle, and Genetic Factors in the Framingham Heart Study

Author Affiliations
  • 1Framingham Heart Study, Boston University School of Medicine, Boston, Massachusetts
  • 2Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 3Population Studies Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
  • 4Department of Mathematics and Statistics, Boston University, Boston, Massachusetts
  • 5Center for Population Genomics, Veteran’s Administration Healthcare System, Boston, Massachusetts
  • 6Cardiovascular Epidemiology and Human Genomics Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
  • 7Department of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Cardiol. 2016;1(1):26-35. doi:10.1001/jamacardio.2015.0304
Abstract

Importance  Dyslipidemia in young adults in the United States during their childbearing years is common, and the consequences for the next generation are poorly understood. Further understanding of the harmful consequences of elevated low-density lipoprotein cholesterol (LDL-C) levels in young adults may help to inform population screening and management strategies.

Objective  To examine whether adult levels of serum LDL-C are associated with maternal prepregnancy LDL-C levels beyond that attributable to inherited genetic sequence polymorphisms, diet, physical activity, and body mass index.

Design, Setting, and Participants  The Framingham Heart Study is a multigenerational, population-based inception cohort initiated in 1948 in Framingham, Massachusetts. In this study of families, the analyses included 538 parent-offspring pairs with parental LDL-C levels measured in the study prior to the offspring’s birth. Parental prebirth, parental concurrent, and adult offspring assessments occurred in 1971-1983, 1998-2001, and 2002-2005, respectively. Data analyses were conducted between March 1, 2013, and May 30, 2015.

Exposures  Maternal prepregnancy LDL-C levels compared with paternal prepregnancy and parental concurrent LDL-C levels in association with adult offspring LDL-C levels.

Main Outcomes and Measures  Adult offspring LDL-C levels were examined as both a continuous and dichotomous outcome (using a threshold of 130 mg/dL).

Results  Among the 538 parent-offspring pairs, there were 241 mother-offspring and 297 father-offspring pairs with a mean (SD) offspring age of 26 (3) years. Adult offspring LDL-C levels were associated with maternal prepregnancy LDL-C levels after adjustment for family relatedness and offspring lifestyle, anthropometric factors, and inherited genetic variants (β = 0.32 [SE, 0.05] mg/dL; P < .001). After multivariable adjustment, adults who had been exposed to elevated maternal prepregnancy LDL-C levels were at a 3.8 (95% CI, 1.5-9.8) times higher odds of having elevated LDL-C levels (P = .005) and had an adjusted LDL-C level of 18 mg/dL (95% CI, 9-27 mg/dL) higher than did those without such exposure. Maternal prepregnancy 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.

Conclusions and Relevance  Adult offspring dyslipidemia is associated with maternal prepregnancy dyslipidemia in excess of measured lifestyle, anthropometric, and inherited genetic factors. The findings support the possibility of a maternal epigenetic contribution to cardiovascular disease risk in the general population. Further research is warranted to determine whether ongoing public health efforts to identify and reduce dyslipidemia in young adults prior to their childbearing years may have additional potential health benefits for the subsequent generation.

Introduction

Maternal health and in utero exposures are important determinants of long-term cardiometabolic outcomes among adult offspring, with maternal adiposity and hyperglycemia making up the bulk of the studied effects.1-3 Independent of adiposity and hyperglycemia, elevated low-density lipoprotein cholesterol (LDL-C) level is a well-established causal risk factor for atherosclerotic cardiovascular disease (CVD).4 However, the effect of maternal lipoprotein abnormalities on offspring’s cardiovascular health in the general population has been underexplored, despite the frequent occurrence of dyslipidemia among women of childbearing age.5 In the United States, a quarter of women of childbearing age had an elevated LDL-C level (>130 mg/dL [to convert to micromoles per liter, multiply by 0.0259]) in the 2007-2008 data of US National Health and Nutrition Examination Survey.6

Maternal hypercholesterolemia has been linked to abnormal offspring cholesterol regulation in a fetal pathology case series,7 a pediatric observational cohort,8 and among adults with familial hypercholesterolemia (FH), a mendelian disorder of lipoprotein metabolism.9-11 For example, individuals with FH have significantly elevated LDL-C levels throughout life. Adult offspring with a maternal history of heterozygous FH, and therefore higher in utero exposure to LDL-C, were found in some studies9,10 to have higher LDL-C levels compared with those with paternal inheritance of FH. Subsequently, a higher mortality rate was observed among offspring with maternal compared with paternal inheritance of the same FH genetic variant.12 Similarly, a higher burden of offspring atherosclerosis has been seen in animal models of maternal hypercholesterolemia.13-15 It is unknown whether higher prepregnancy maternal LDL-C levels are associated with increased offspring dyslipidemia and CVD risk in the general population. Exposure to elevated maternal LDL-C levels may explain an additional component of interindividual variation in LDL-C levels beyond that attributable to lifestyle factors and inherited genetic sequence variation.16

The paucity of evidence on the effect of maternal dyslipidemia on adult offspring outcomes is likely the result of the lack of cholesterol screening or routine measurement of cholesterol levels in young, healthy women prior to pregnancy in previous generations. The Framingham Heart Study (FHS), a multigenerational, population-based cohort initiated in 1948 in Framingham, Massachusetts, provides a unique opportunity to examine lipoprotein levels in adulthood among a subset of participants whose parents had LDL-C levels assessed in the study prior to the birth of the present subset.

Methods
Study Design

We conducted an analysis of prospectively collected clinical and laboratory data from the Offspring and Third Generation cohorts of the FHS. The design of the FHS has been previously described17; briefly, in 1971, a total of 5124 children and spouses of children of the original cohort were enrolled in the FHS Offspring cohort. In 2002, a total of 4095 Third Generation cohort participants who had at least 1 parent in the Offspring cohort were enrolled and underwent standard clinical examinations.18 The present study analyses drew on participant data from Offspring cohort examination cycles 1 (1971-1975) and 2 (1979-1983), Offspring cohort examination cycle 7 (1998-2001), and Third Generation cohort examination cycle 1 (2002-2005). Details of the FHS examinations and protocols are available at http://www.framinghamheartstudy.org/researchers/.

The present study examined the association between elevated maternal prepregnancy LDL-C levels (participants from the FHS Offspring cohort) and adult offspring LDL-C levels (participants from the FHS Third Generation cohort) with successive adjustments for potential confounders (body mass index [BMI], smoking, diet, physical activity, and inherited genetic sequence variants known to be associated with LDL-C levels). Potential confounders were identified based on established mechanisms in published studies19 and depicted in Figure 1. Paternal prepregnancy LDL-C levels were examined as a comparison of a parental association lacking the in utero exposure but having a similar contribution of inherited genetic sequence variation and shared early-life environment. Parental (maternal and paternal) LDL-C levels measured concurrently with the adult offspring’s LDL-C levels were examined as an additional comparison to demonstrate the contribution of shared adulthood environmental factors and genetic components. The purpose of the multiple adjustments and comparisons was to determine whether there is a residual association of maternal prepregnancy and adult offspring LDL-C levels in excess of shared early and later life environment, learned behaviors (diet and physical activity), anthropometric features (BMI), and inherited genetic sequence variation—a contribution that may be attributable to maternal intergenerational, epigenetic transmission. The hypothesis that maternal prepregnancy dyslipidemia may impart an effect on adult offspring dyslipidemia beyond that of measured confounders and genetic factors and of a greater magnitude compared with paternal prepregnancy dyslipidemia was prespecified prior to the start of the analyses.

The Boston University Medical Center institutional review board approved the main study protocols and all participants signed written informed consent. Participants did not receive financial compensation.

Study Sample

For the present analysis, we studied participants in the Third Generation cohort (the adult offspring in the present study) who (1) attended the first examination cycle (2002-2005), (2) had at least 1 parent in the Offspring generation cohort who was examined before the Third Generation participant’s birth (Offspring cohort examination cycles 1 and 2 [1971-1983]), and (3) had serum LDL-C measurements available for both the parental prebirth assessment and adult offspring at enrollment. We did not include parents in the Original cohort since LDL-C level was not determined in the early examination cycles (1950s). Biological parent-offspring pairs were identified using self-reported relationships and confirmed with genetic pedigree data to avoid issues of nonpaternity. There were 597 parent-adult offspring pairs with parental prebirth and adult offspring examinations (281 mother-offspring and 316 father-offspring). We excluded pairs with an individual receiving lipid-lowering therapy at either the parental prebirth assessment or adult offspring assessment (5 cases [1 father and 4 adult offspring]); triglyceride level higher than 400 mg/dL (to convert to micromoles per liter, multiply by 0.0113), since LDL-C levels could not be accurately calculated (n = 5); and those with missing parental or offspring lipid measurements (n = 49). After exclusions, there were 538 biological parent-offspring pairs (241 mother-offspring and 297 father-offspring pairs), of which 116 adult children were in both mother-offspring and father-offspring pairs (Figure 2). Parental LDL-C levels measured concurrently with the adult offspring LDL-C levels (parental LDL-C levels from the Offspring cohort examination cycle 7 [1998-2001]) were available for 507 parent-offspring pairs (223 mother-offspring and 284 father-offspring pairs).

Lifestyle, Clinical, Laboratory, and Genetic Assessments

At each study visit, participants underwent a medical history interview and routine physical examination, including measurement of height, weight, and blood pressure, using standardized approaches. Details of the covariate measurements are described in the eMethods in the Supplement. In summary, dietary intake was ascertained in the adult offspring (Third Generation cohort) via a 126-item, semiquantitative, self-reported food frequency questionnaire.20-22 A physical activity index, expressed in metabolic equivalents, was calculated by assigning each self-reported activity category a metabolic equivalent value based on the oxygen consumption required to perform activities in the category and deriving a weighted mean of the metabolic equivalent values based on the proportion of time spent on activities in each category.23 Plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels were measured on morning blood samples obtained after an 8-hour fast. The Friedewald equation24 was used to calculate the LDL-C level. The LDL-C genetic risk score for each participant included 37 known LDL-C–related single-nucleotide polymorphisms reported in 2010 by the Global Lipids Genetic Consortium16 that were weighted by summation of genotypes (coded additively for the risk allele) and multiplied by the reported effect-size estimates (eTable 1 in the Supplement).

Statistical Analysis

We generated summary statistics with counts, frequencies, and means (SDs) for the demographic and clinical characteristics of the sample. Generalized estimating equations (GEEs) with a linear (identity) link for continuous outcomes and logit link for binary outcomes were used to account for familial correlations between measurements (PROC GENMOD, REPEATED statement [SAS, version 9.3; SAS Institute Inc]). A compound symmetry correlation matrix was specified with robust variance estimators. For continuous LDL-C exposure and outcomes, GEE models were run with successive adjustment for model 1 (M1), parental age and adult offspring age and sex; M2, previous covariates plus parental and adult offspring BMI and parental smoking status; M3, previous covariates plus adult offspring dietary and physical activity measures; and M4, previous covariates plus the adult offspring’s LDL-C genetic risk score. There were no statistically significant interactions for offspring sex and parental LDL-C levels in any models (P > .10); therefore, sex-pooled analyses are presented.

The LDL-C levels were dichotomized at 130 mg/dL as elevated for both parent and offspring in agreement with published guidelines.25 For dichotomous exposures and outcomes, GEE models were conducted with elevated LDL-C level in the adult offspring as the outcome, elevated LDL-C level in the parent as the predictor of interest, and successive adjustments for the same covariates as described above. For dichotomous exposures and continuous outcomes, the adjusted mean difference in adult offspring LDL-C (M4) for those exposed to elevated parental prepregnancy LDL-C levels compared with unexposed individuals was generated. For continuous exposures and dichotomous outcomes, restricted, penalized cubic splines were used to illustrate the association between the continuous parental prepregnancy LDL-C levels and the fully adjusted (M4) odds ratio (OR) for elevated adult offspring LDL-C.26

The additional association of the maternal prepregnancy LDL-C level compared with paternal prepregnancy LDL-C level was contrasted by including both parental prepregnancy LDL-C values in the same regression model for a subset of participants with LDL-C data on both parents. In addition, we used measures of model improvement to contrast the parental models, namely, the C statistic, net reclassification index, and integrated discrimination index. Details are provided in eMethods in the Supplement. We focused on the dichotomized elevated parental prepregnancy LDL-C level, as opposed to the continuous measure, because it represents a clinically relevant measure to exert a pathologic effect above a homeostatic reference range, is more easily elicited in a clinical medical history interview, and is a current threshold to promote healthy lifestyle changes in young adults.

Additional analyses were conducted on the other lipid panel components (HDL-C and triglyceride levels). There were insufficient cases of maternal prepregnancy hypertriglyceridemia (triglyceride levels >150 mg/dL; 9 cases) or parental postpregnancy low HDL-C levels (<40 mg/dL in men and <50 mg/dL in women; 18 cases [to convert to millimoles per liter, multiply by 0.0259]) to include in dichotomous models, so only models examining continuous exposure/outcomes are presented.

Several sensitivity analyses were conducted. First, parents who began receiving lipid-lowering therapy after their initial assessment and were receiving lipid-lowering therapy at the concurrent assessment with adult offspring LDL-C (n = 15) were excluded from the successive GEE models, as described above. We conducted an additional sensitivity analysis to account for statin therapy with a second approach. For participants receiving lipid-lowering therapy (at the prebirth parental examination [n = 1], concurrent parental examination [n = 15], or adult offspring examination [n = 4]), we multiplied the treated elevated LDL-C level by 1.35 to account for the mean lowering effect of statin therapy to estimate the untreated elevated LDL-C level.27 For the dichotomous models, individuals receiving statins were included in the elevated LDL-C level group. Successive GEE models that included participants with the estimated untreated elevated LDL-C levels were then conducted. A third sensitivity analysis excluded 21 maternal examinations performed within 9 months before the offspring’s birth (14 [66.7%] within the first trimester) to account for any measurements taken during the pregnancy. Ordinary least-squares linear and logistic regression models (not adjusted for family structure) were conducted, with successive covariate adjustment as described above, resulting in a minimal difference in estimates as compared with the GEE models. A bias factor was calculated to determine the magnitude of unmeasured residual confounding that would have to be present to explain significant associations between maternal prepregnancy LDL-C and adult offspring LDL-C levels.28

All analyses were conducted using SAS, version 9.3. A 2-sided, unpaired value of P < .05 was considered statistically significant. Data analyses were conducted between March 1, 2013, and May 30, 2015.

Results
Study Sample Characteristics

There were a total of 538 parent-offspring pairs (241 mother-offspring and 297 father-offspring). The characteristics of the study sample with parental characteristics at the prepregnancy examination are outlined in Table 1, and parental characteristics at the concurrent examination with the offspring’s LDL-C values are reported in eTable 2 in the Supplement. The mean (SD) age of the fathers was slightly greater than the age of the mothers (29 [5] vs 27 [4] years) with higher BMIs (26.0 vs 22.3 [calculated as weight in kilograms divided by height in meters squared]). Smoking was common in the prepregnancy parental examinations: 110 (45.6%) of mothers and 120 (40.0%) of fathers. Parental concurrent examinations were unavailable for 17 (7.1%) mothers and 14 (4.7%) fathers. As expected, the present study sample differs from the overall FHS sample because the present sample was selected for having a prepregnancy parental examination and is therefore a younger subset (eTable 3 in the Supplement).

Association Between Maternal Prepregnancy and Adult Offspring LDL-C Levels

Maternal prepregnancy LDL-C levels were significantly correlated with adult offspring LDL-C levels (β = 0.38 [SE, 0.06] mg/dL; P < .001) in the age- and sex-adjusted models (M1: scatterplot in eFigure 1 in the Supplement). After successive adjustments for anthropometric, lifestyle, and inherited genetic factors (Table 2), the association between maternal prepregnancy and adult offspring LDL-C levels was attenuated but remained significantly correlated (M4: β = 0.32 [SE, 0.05] mg/dL; P < .001). In excess of those confounding factors, maternal prebirth LDL-C levels explained 13% of the variation in adult offspring LDL-C levels (M4: partial r2 = 0.13). In the fully adjusted models (M4) (Table 2), the odds of elevated LDL-C levels (>130 mg/dL) among adult offspring were 3.8 (95% CI, 1.5-9.8) times higher for individuals exposed to elevated maternal prepregnancy LDL-C levels compared with those who were unexposed (P = .005). The mean adult offspring LDL-C level was 18 mg/dL (95% CI, 9-27 mg/dL) greater among individuals exposed to elevated maternal prebirth LDL-C compared with those unexposed. The association between maternal prepregnancy LDL-C levels and the OR for elevated LDL-C levels in adult offspring is presented in Figure 3A. The full regression model output for all covariates is reported in eTables 4 and 5 in the Supplement.

Comparison of Maternal vs Paternal Prepregnancy Contribution

The association between paternal prepregnancy LDL-C and adult offspring LDL-C levels was attenuated after adjustment for anthropometrics, lifestyle, and genetic factors (Table 2 and scatterplot in eFigure 2 in the Supplement). The regression β coefficient for the association of parental prepregnancy LDL-C with adult offspring LDL-C levels was approximately twice as great for maternal compared with paternal prepregnancy LDL-C levels (M4 in Table 2).

In a second approach to contrast the association between maternal and paternal prepregnancy LDL-C levels, the subset of adult offspring among whom prepregnancy lipid values were available for both parents (n = 116) was examined. When both maternal and paternal prepregnancy LDL-C levels were added to the same regression model, the maternal prepregnancy LDL-C levels remained associated with the adult offspring LDL-C level, but the paternal prepregnancy levels did not (OR, 6.2 [95% CI, 1.6-24]; P = .009 and OR, 0.6 [95% CI, 0.2-2.3]; P = .49 for mothers and fathers, respectively). Results from the analyses comparing model C statistic, net reclassification index, and integrated discrimination index are presented in the eResults in the Supplement. The full regression model output for all covariates is reported in eTables 6 and 7 in the Supplement.

Comparison of Parental Prepregnancy vs Concurrent LDL-C Assessments

There were 507 parent-offspring pairs (223 [44.0%] mother-offspring and 284 [56.0%] father-offspring pairs) in the concurrent parental LDL-C level examination with the adult offspring LDL-C level measurement. There were no parental losses between prebirth and concurrent assessments owing to known coronary heart disease–related deaths. Concurrent parental measurements were not associated with adult offspring LDL-C in the fully adjusted models (M4 in Table 3).

Analyses for Parental-Offspring HDL-C and Triglyceride Levels

Additional models for HDL-C and log-transformed triglyceride level (study sample distributions available in eTable 8 in the Supplement) are presented in eTables 9 and 10 in the Supplement. A differential association for maternal over paternal prepregnancy and prepregnancy vs concurrent examinations was not observed for HDL-C and log triglyceride values.

Sensitivity Analyses

The OR for elevated LDL-C levels in an adult offspring was lower in the sensitivity analysis after excluding parents receiving lipid-lowering therapy at the parental concurrent assessment (OR [95% CI] for elevated adult offspring LDL-C level, 1.3 [0.5-3.5]; P = .63; and 2.1 [0.7-6.2]; P = .19; owing to elevated concurrent maternal and paternal LDL-C levels, respectively). There were no substantial changes in the results after using a correction factor (1.35) to estimate untreated elevated LDL-C levels (eTable 11 in the Supplement). The sensitivity analysis excluding maternal assessment within 9 months before the birth of an offspring had little effect on the OR for maternal prebirth assessment on the adult offspring’s elevated LDL-C level (OR, 3.5 [95% CI, 1.2-10.1]; P = .02).

Bias Factor for Unmeasured Residual Confounding

The bias analyses indicated that a large amount of unmeasured confounding would have been required to account for the association between elevated maternal prepregnancy LDL-C levels and elevated adult offspring LDL-C levels. For example, the unmeasured confounders would be required to result in a more than 3-fold increase in elevated adult offspring LDL-C levels and be present in 70% of exposed vs 30% unexposed offspring (eTable 12 in the Supplement provides a range a bias scenarios).

Discussion

We demonstrated that elevated LDL-C levels in women prior to the birth of a child was associated with an increased risk of elevated LDL-C levels in their adult offspring. The association persisted after adjustment for maternal BMI and smoking, and adjustment for adult offspring lifestyle factors, BMI, and inherited genetic variants known to be associated with elevated LDL-C levels. To our knowledge, this is the first study demonstrating a link in the general population between elevated maternal prepregnancy LDL-C levels and adult offspring LDL-C levels, which is a major contributor to atherosclerotic CVD. The explanation for an enduring risk associated with elevated maternal prepregnancy LDL-C levels beyond genetic variants and lifestyle factors is likely multifactorial and may be mediated by direct effects on the developing fetal organ systems and through epigenetic modifications transferred via gametes or introduced in utero owing to the nutrient milieu.

Low-density lipoprotein cholesterol is taken up by the maternal aspect of the placenta, and cholesterol is used as a nutrient source for the developing fetus.29 In humans, low maternal serum cholesterol levels are associated with preterm birth and lower birthweight30; similar results have occurred in experimental studies in mice.31 In contrast, fetal overnutrition with excess cholesterol due to increased LDL-C uptake likely has pathologic effects on the developing fetus. In humans, fetuses of hypercholesterolemic mothers have an increase of aortic fatty streaks7; this finding also replicates results from experimental studies in animals.32 Intrauterine exposure to elevated LDL-C levels may leave lasting effects on organ systems or epigenetic metabolism dysregulation that ultimately influence the ability of the offspring to regulate LDL-C levels in later life, as observed in the present study, with important implications for risk of a higher future burden of atherosclerosis and CVD.

In the FHS, adult offspring without maternal prebirth elevated LDL-C level exposure were observed to have a lower LDL-C level of a clinically relevant degree (18 mg/dL). A meta-analysis33 of randomized trials of statin treatment from the Cholesterol Treatment Trialists’ Collaboration27 revealed that a comparable decrease in LDL-C levels resulted in a 20% decrease in ischemic heart disease events. The elevated LDL-C level outcomes observed in the adult offspring occurred at a relatively young age (mean, 26 years). Available evidence34 demonstrates that early and prolonged exposure to elevated LDL-C levels carries significant adverse CVD consequences beyond those of developing dyslipidemia later in life. It was previously shown in the FHS that an increasing length of exposure to elevated LDL-C levels was associated with increased subclinical atherosclerosis, as measured by coronary artery calcium burden,35 and higher CVD mortality.36 The early development of LDL-C level elevation among adult offspring exposed to maternal prepregnancy elevated LDL-C levels may carry further consequences for the subsequent generation. Early development of dyslipidemia may accelerate a transgenerational cycle as an even greater proportion of young adult offspring go on to develop dyslipidemia in their childbearing years.

The association observed between concurrent parental LDL-C and adult offspring LDL-C levels in the unadjusted model is largely attenuated in the fully adjusted model. This finding suggests that the association is largely accounted for by measurable inherited genetic and lifestyle factors, and the larger maternal effect is observable only when the prebirth level is considered. In the fully adjusted model, maternal prebirth LDL-C level explained 13% of the interindividual variation in adult offspring LDL-C levels. Further study of the underlying mechanisms linking maternal prebirth LDL-C and adult offspring LDL-C levels may reveal novel causal pathways resulting in dyslipidemia that are independent of inherited genetic sequence variants.

The present study has limitations. First, this study was limited to a subset of participants in the FHS because it required participants’ parents to have been enrolled and assessed prior to the present cohort’s birth. Second, we used prepregnancy elevated LDL-C levels as a proxy for intrauterine exposure, and lipid levels are known to increase during pregnancy. It has been demonstrated37 that maternal prepregnancy lipid levels predict those measured during pregnancy and that elevated levels in women at the start of pregnancy remain higher throughout gestation. Further studies with direct measures of LDL-C during pregnancy would further support our findings. However, misclassification of women who did not have elevated prepregnancy LDL-C levels but went on to develop abnormal levels during pregnancy would attenuate and not inflate the observed effect. Third, we only had data on cross-sectional adult offspring diet and physical activity and were not able to include any consideration of childhood diet and physical activity or parental prepregnancy diet and physical activity. Similarly, we had no data on offspring LDL-C levels during childhood. Residual confounding from a larger maternal environmental contribution to offspring LDL-C levels may exist. For example, mothers may play a larger role than fathers in establishing lifelong eating behaviors that contribute to adult offspring LDL-C levels. Fourth, birth outcomes data (eg, birthweight) were not available for the adult offspring in our study; therefore, whether the associations we observed are independent of birthweight and other birth outcomes could not be assessed in this study. Fifth, we were unable to confirm cohabitation of offspring with one or both parents during childhood and development, which may falsely attenuate the concurrent examination analysis results. Sixth, our findings are limited to a population of European descent and may not be generalizable to other ethnicities. Seventh, intergenerational epigenetic transmission is a hypothesized mechanism underlying our findings, and these phenomena (eg, DNA methylation and histone modifications) were not examined directly in this study. Recent evidence38-42 of altered offspring DNA methylation in association with maternal diet and metabolic intrauterine environment supports this premise. Aside from epigenetic mechanisms, the association between maternal prepregnancy and adult offspring LDL-C levels after adjustments may be the result of unmeasured residual confounding (eg, from shared environment, learned behaviors, inheritance of maternal mitochondrial DNA, or unmeasured rare genetic variants).

Rare genetic variants are likely not a major source of unmeasured confounding; recent studies43,44 show that rare variants explain very little additional interindividual variation in lipid levels in the general population beyond the common variants included here. The bias analysis demonstrates that any unmeasured confounding would need a large effect size and be relatively frequent suggesting that the maternal prebirth LDL-C level association results are fairly robust to unmeasured confounding. We observed a statistically significant association of continuous paternal prebirth LDL-C with adult offspring LDL-C levels with a 2.5-times larger regression coefficient for maternal vs paternal associations in the fully adjusted model (0.32- vs 0.13-mg/dL increase in adult offspring LDL-C level for each 1-mg/dL increase in parental prebirth LDL-C level). The smaller paternal prebirth association is less robust to residual confounding and may be the result of the inability to completely account for inherited lifestyle and genetic factors. However, transgenerational epigenetic inheritance from the paternal line transmitted via sperm has been described in animal models,45,46 and we may be observing this effect, albeit smaller than that for the maternal LDL-C level association.

The strength of the study is that the mothers had lipid measurements obtained at a relatively young age prior to the birth of their children and the testing was not based on any indication (eg, obesity or family history of heart disease), which was not standard practice at the time. The availability of these LDL-C levels allowed us to assess outcomes in adult offspring with no parental testing bias. In addition, father-offspring pairs were confirmed using genetic data, excluding any possibility that nonpaternity issues would artificially reduce the father-offspring associations.

An improved understanding of the CVD risk associated with the intrauterine environment may inform population-based lifestyle strategies for women in their childbearing years to identify those at risk and to direct lipid-specific nutritional and lifestyle interventions or therapeutics. Further research is needed to determine whether the knowledge of the risk associated with maternal prepregnancy dyslipidemia may motivate behavior change in young women of childbearing age driven by considerations of their child’s health beyond the consideration of their own health. Regardless, if the association is driven by epigenetic mechanisms or shared environment and learned behaviors, early lifestyle interventions would have the potential to affect either mechanism. For example, behavioral counseling for young adults with elevated LDL-C levels to increase physical activity and replace saturated and trans fats with polyunsaturated fats is recommended in the American Heart Association/American College of Cardiology guidelines.47 Although further research is required, our results support the possibility of benefits for the subsequent generation, and even beyond into further generations, from interventions in young adults. Additional studies with larger sample sizes would be needed to support our findings and improve the precision and confidence intervals of the effect estimates. Finally, incorporating intrauterine exposures into CVD risk prediction models may improve discriminative properties, although this possibility remains to be formally addressed.

Conclusions

Maternal prepregnancy LDL-C levels are associated with adult offspring LDL-C levels beyond the influence attributable to measured lifestyle, anthropometric, and inherited genetic factors. Intergenerational maternal epigenetic transmission mechanisms, currently poorly understood, may mediate this effect. We postulate that identifying young women of childbearing age with elevated LDL-C levels and initiating lipid-specific interventions may further reduce the transgenerational cycle of dyslipidemia and CVD risk.

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Article Information

Corresponding Author: Daniel Levy, MD, Population Studies Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, 73 Mt Wayte Ave, Ste 2, Framingham, MA 01702 (levyd@nih.gov).

Accepted for Publication: November 19, 2015.

Published Online: March 2, 2016. doi:10.1001/jamacardio.2015.0304.

Author Contributions: Drs Mendelson and Lyass had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Mendelson, O’Donnell, D’Agostino, Levy.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Mendelson, Lyass, D’Agostino.

Critical revision of the manuscript for important intellectual content: Mendelson, O’Donnell, D’Agostino, Levy.

Statistical analysis: Lyass, D’Agostino.

Obtained funding: D’Agostino, Levy.

Administrative, technical, or material support: Mendelson, O’Donnell, Levy.

Study supervision: Levy.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: The Framingham Heart Study is administered by Boston University and is supported by contracts N01-HC-25195 and HHSN268201500001I from the US National Heart, Lung, and Blood Institute. Dr Mendelson is supported by a research fellowship from Boston University and the Tommy Kaplan Fund, Department of Cardiology, Boston Children’s Hospital, Boston, Massachusetts.

Role of the Funder/Sponsor: The funding sources had no role in the current study design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing: Participant-level phenotype and genotype data from the Framingham Heart Study are accessible from the US National Center for Biotechnology Information database of Genotypes and Phenotypes at https://dbgap.ncbi.nlm.nih.gov/ to approved scientific investigators pursuing research questions that are consistent with the informed consent agreements provided by individual research participants.

Additional Contributions: We acknowledge the immense contribution of the participants and staff of the Framingham Heart Study.

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