Low-density lipoprotein Receptor Related Protein 1B ( LRP1B) is homologous to the gigantic lipoprotein receptor-related protein 1 that belongs to the family of Low-density lipoprotein receptors. Previous genetic association studies of the LRP1B gene have shown its genetic association with obesity. Through exome sequencing of the LRP1B gene from a childhood severe obesity cohort (n = 692), we found novel single nucleotide polymorphism (rs431809) in intron 4, which has been significantly correlated with both body mass index (BMI) and waist-hip-ratio (WHR). Three methylations of CpG sites (cg141441481, cg01852095 and cg141441470) in the same intron were also significantly correlated with BMI and WHR. All CpG methylations had bimodal patterns, and were dependent on rs431809 genotypes. The genetic influences of obesity on the LRP1B gene may be linked to the interplay of CpG methylations in the same intron. Heritability of SNP interacts with epigenetic crosstalk in LRP1B. Genetic and epigenetic crosstalk of LRP1B gene may be implicated in the prevention and therapeutic approach to childhood obesity.