Genetic Variation in Immune Response and Vitamin D Metabolism and Developmental Origins of Cardiometabolic Risk

Abstract

The developmental origins of cardiovascular and metabolic risk (CMR) may involve interactions of genetic variants, the intrauterine environment, and life course exposures. While accumulating evidence supports the roles of the immune system and vitamin D metabolism in CMR, the role of immune- and vitamin D-related candidate gene variants in the developmental origins of CMR is not well-described. We conducted a candidate single nucleotide polymorphism (SNP) study among mother-offspring dyads representing a subset of the Jerusalem Perinatal Study birth cohort. We selected 122 SNPs in 51 genes characterizing immune or vitamin D-related genes and imprinted regions. We investigated nine CMR-related phenotypes measured in adult offspring: cytomegalovirus antibody titer (CMV IgG), 25-hydroxyvitamin D (25[OH]D) concentration, body mass index (BMI), fasting glucose, HDL cholesterol, LDL cholesterol, triglycerides, systolic blood pressure (BP), and diastolic BP. We used weighted linear regression with robust variance estimates to examine associations of 1) offspring genotype, 2) maternal genotype, and 3) maternal-offspring genotype interactions with adult offspring CMR. We also evaluated genotype-CMV IgG and genotype-25[OH]D interactions on CMR. Multiple testing adjustments were performed using the Benjamini-Hochberg False Discovery Rate. The offspring minor allele of rs10894157 in CNTN5 was associated with BMI (β = -1.35, SE = 0.30, p = 0.00002). Two offspring SNPs in SLC2A1, rs841858 (β = -7.33, SE = 2.10, p = 0.0005) and rs3820548 (β = -5.84, SE = 1.75, p = 0.0009) were associated with lower LDL cholesterol, and rs841858 was also associated with lower natural-log transformed triglycerides (β = -0.12, SE 0.03, p = 0.0004). We found interactions between offspring rs3771170 in IL-18R1 and 25[OH]D on LDL cholesterol (p = 0.0001), and offspring rs1950902 in MTHFD1 and 25[OH]D on systolic blood pressure (p = 0.0004). We also found evidence for interactions at maternal rs4987853 in BCL2 with offspring CMV IgG on offspring HDL (p = 0.0003), maternal rs4851522 in IL-1R2 with offspring 25[OH]D on offspring LDL (p < 0.0001), and maternal rs13143866 in IL-21 with offspring 25[OH]D on offspring HDL (p = 0.0002). We found evidence of maternal-offspring genotype interactions at a SNP in MTRR on diastolic and systolic BP, and MTHFD1 on triglycerides, though these latter interactions were not statistically significant after taking into account multiple comparisons. If replicated in future studies, our findings provide evidence that maternal and offspring immune- and vitamin D metabolism- related genetic variants, and their interactions, may play a role in the developmental origins of offspring CMR. Further research in family-based genetic studies with long-term follow-up will enhance our understanding of early life origins of CMR.