Sex-Specific Parental Effects on Offspring Lipid Levels

Background Plasma lipid levels are highly heritable traits, but known genetic loci can only explain a small portion of their heritability. Methods and Results In this study, we analyzed the role of parental levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs) in explaining the values of the corresponding traits in adult offspring. We also evaluated the contribution of nongenetic factors that influence lipid traits (age, body mass index, smoking, medications, and menopause) alone and in combination with variability at the genetic loci known to associate with TC, LDL-C, HDL-C, and TG levels. We performed comparisons among different sex-specific regression models in 416 families from the Framingham Heart Study and 304 from the SardiNIA cohort. Models including parental lipid levels explain significantly more of the trait variation than models without these measures, explaining up to ≈39% of the total trait variation. Of this variation, the parent-of-origin effect explains as much as ≈15% and it does so in a sex-specific way. This observation is not owing to shared environment, given that spouse-pair correlations were negligible (<1.5% explained variation in all cases) and is distinct from previous genetic and acquired factors that are known to influence serum lipid levels. Conclusions These findings support the concept that unknown genetic and epigenetic contributors are responsible for most of the heritable component of the plasma lipid phenotype, and that, at present, the clinical utility of knowing age-matched parental lipid levels in assessing risk of dyslipidemia supersedes individual locus effects. Our results support the clinical utility of knowing parental lipid levels in assessing future risk of dyslipidemia.

[1]  Carlo Sidore,et al.  Rare variant genotype imputation with thousands of study-specific whole-genome sequences: implications for cost-effective study designs , 2014, European Journal of Human Genetics.

[2]  R. Frikke-Schmidt,et al.  Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease , 2014 .

[3]  He Zhang,et al.  Loss-of-function mutations in APOC3, triglycerides, and coronary disease. , 2014, The New England journal of medicine.

[4]  B. Nordestgaard,et al.  Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. , 2014, The New England journal of medicine.

[5]  David M. Evans,et al.  Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index , 2014, PLoS genetics.

[6]  Yongtao Guan,et al.  Maternal nutrition at conception modulates DNA methylation of human metastable epialleles , 2014, Nature Communications.

[7]  R. Mott,et al.  The Architecture of Parent-of-Origin Effects in Mice , 2014, Cell.

[8]  Tanya M. Teslovich,et al.  Discovery and refinement of loci associated with lipid levels , 2013, Nature Genetics.

[9]  M. Laakso,et al.  Genetic Screening for the Risk of Type 2 Diabetes , 2013, Diabetes Care.

[10]  C. Napoli,et al.  Maternal Immunization Affects In Utero Programming of Insulin Resistance and Type 2 Diabetes , 2012, PloS one.

[11]  C. Napoli,et al.  Maternal-foetal epigenetic interactions in the beginning of cardiovascular damage. , 2011, Cardiovascular research.

[12]  J. Fox,et al.  Insulin resistance and metabolic hepatocarcinogenesis with parent-of-origin effects in A×B mice. , 2011, The American journal of pathology.

[13]  J. Rutherford.  Maternal heterozygous familial hypercholesterolemia and its consequences for mother and child. , 2011, Circulation.

[14]  D. Gaudet,et al.  Dyslipidemia of Mothers With Familial Hypercholesterolemia Deteriorates Lipids in Adult Offspring , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[15]  Sharon R Grossman,et al.  Integrating common and rare genetic variation in diverse human populations , 2010, Nature.

[16]  Tanya M. Teslovich,et al.  Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids , 2010, Nature.

[17]  Teri A Manolio,et al.  Genomewide association studies and assessment of the risk of disease. , 2010, The New England journal of medicine.

[18]  Jason H. Moore,et al.  Missing heritability and strategies for finding the underlying causes of complex disease , 2010, Nature Reviews Genetics.

[19]  Nancy R Cook,et al.  Association between a literature-based genetic risk score and cardiovascular events in women. , 2010, JAMA.

[20]  S. Humphries,et al.  Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study , 2010, BMJ : British Medical Journal.

[21]  P. Ridker,et al.  Forty-Three Loci Associated with Plasma Lipoprotein Size, Concentration, and Cholesterol Content in Genome-Wide Analysis , 2009, PLoS genetics.

[22]  C. Napoli,et al.  Influence of Maternal Dysmetabolic Conditions During Pregnancy on Cardiovascular Disease , 2009, Journal of cardiovascular translational research.

[23]  M. Gillman,et al.  Intrauterine exposure to gestational diabetes, child adiposity, and blood pressure. , 2009, American journal of hypertension.

[24]  C. Hoggart,et al.  Genome-wide association analysis of metabolic traits in a birth cohort from a founder population , 2008, Nature Genetics.

[25]  Cornelia M van Duijn,et al.  Genome-based prediction of common diseases: advances and prospects. , 2008, Human molecular genetics.

[26]  M. Gillman,et al.  Maternal smoking during pregnancy and child overweight: systematic review and meta-analysis , 2008, International Journal of Obesity.

[27]  R. Collins,et al.  Newly identified loci that influence lipid concentrations and risk of coronary artery disease , 2008, Nature Genetics.

[28]  Dolores Corella,et al.  Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans , 2008, Nature Genetics.

[29]  Mario Falchi,et al.  Genome-wide Association Study Identifies Genes for Biomarkers of Cardiovascular Disease: Serum Urate and Dyslipidemia , 2022 .

[30]  C. Napoli,et al.  Developmental programming: maternal hypercholesterolemia and immunity influence susceptibility to atherosclerosis. , 2007, Nutrition reviews.

[31]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[32]  R. D'Agostino,et al.  A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study , 2007, BMC Medical Genetics.

[33]  Marcia M. Nizzari,et al.  Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels , 2007, Science.

[34]  F. P. Villena,et al.  Rescue of the Mouse DDK Syndrome by Parent-of-Origin-Dependent Modifiers1 , 2007, Biology of reproduction.

[35]  G. Abecasis,et al.  Heritability of Cardiovascular and Personality Traits in 6,148 Sardinians , 2006, PLoS genetics.

[36]  Ewout W Steyerberg,et al.  Predictive testing for complex diseases using multiple genes: Fact or fiction? , 2006, Genetics in Medicine.

[37]  M. Abney,et al.  The sex-specific genetic architecture of quantitative traits in humans , 2006, Nature Genetics.

[38]  H. Willard,et al.  Genetic and parent-of-origin influences on X chromosome choice in Xce heterozygous mice , 2005, Mammalian Genome.

[39]  R. Olsen,et al.  GABAA receptor beta3 subunit gene-deficient heterozygous mice show parent-of-origin and gender-related differences in beta3 subunit levels, EEG, and behavior. , 2005, Brain research. Developmental brain research.

[40]  M. Olivier.  A haplotype map of the human genome. , 2003, Nature.

[41]  M. Olivier.  A haplotype map of the human genome , 2003, Nature.

[42]  J. Meulen.  Glucose tolerance in adults after prenatal exposure to famine , 2001, The Lancet.

[43]  L. Lumey.  Glucose tolerance in adults after prenatal exposure to famine , 2001, The Lancet.

[44]  R. Hanson,et al.  Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. , 2000, Diabetes.

[45]  C. Glass,et al.  Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study , 1999, The Lancet.

[46]  M. Kilby,et al.  Fetal and maternal lipoprotein metabolism in human pregnancy complicated by type I diabetes mellitus. , 1998, The Journal of clinical endocrinology and metabolism.

[47]  J L Witztum,et al.  Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. , 1997, The Journal of clinical investigation.

[48]  I. Perry,et al.  Ambulatory blood pressure in pregnancy and fetal growth , 1997, The Lancet.

[49]  T. Wheeler,et al.  Early origin of coronary heart disease , 1995, BMJ.

[50]  M. Kilby,et al.  Fetal and maternal lipoprotein metabolism in human pregnancy. , 1995, Clinical science.

[51]  M. Susser,et al.  Early origin of coronary heart disease (the “Barker hypothesis”) , 1995, BMJ.

[52]  S. Hunt,et al.  Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins. , 1989, American journal of epidemiology.

[53]  C. Osmond,et al.  INFANT MORTALITY, CHILDHOOD NUTRITION, AND ISCHAEMIC HEART DISEASE IN ENGLAND AND WALES , 1986, The Lancet.

[54]  W. Kannel,et al.  The Framingham Offspring Study. Design and preliminary data. , 1975, Preventive medicine.

[55]  R. Levy,et al.  Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. , 1972, Clinical chemistry.

[56]  T. Dawber,et al.  Epidemiological approaches to heart disease: the Framingham Study. , 1951, American journal of public health and the nation's health.

[57]  Christian Gieger,et al.  Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts , 2009, Nature Genetics.

[58]  P. Allhoff,et al.  The Framingham Offspring Study , 1991 .