Evaluation of the causality of the low-density lipoprotein receptor gene (LDLR) for serum lipids in pigs

A significant quantitative trait locus (QTL) for low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) was identified around the LDLR gene on chromosome 2 (SSC2) in a White DurocxErhualian F-2 resource population and Sutai pigs in our previous study. However, in previous reports, the causality of LDLR with serum lipids is controversial in pigs. To systematically assess the causality of LDLR with serum lipids, association analyses were successively performed in three populations: Sutai pigs, a White DurocxErhualian F-2 resource population and a Durocx(LandracexLarge White) population. We first performed a haplotype-based association study with 60K SNP genotyping data and evidenced the significant association with LDL-C and TC around the LDLR gene region. We also found that there is more than one QTL for LDL-C and TC on SSC2. Then, we evaluated the causalities of two missense mutations, c.1812C>T and c.1520A>G, with LDL-C and TC. We revealed that the c.1812C>T SNP showed the strongest association with LDL-C (P=5.40x10(-11)) and TC (P=3.64x10(-8)) and explained all the QTL effect in Sutai pigs. Haplotype analysis found that two missense SNPs locate within a 1.93-Mb haplotype block. One major haplotype showed the strongest significant association with LDL-C (P=4.62x10(-18)) and TC (P=1.06x10(-9)). However, the c.1812C>T SNP was not identified in the White DurocxErhualian intercross, and the association of c.1520A>G with both LDL-C and TC did not achieve significance in this F-2 population, suggesting population heterogeneity. Both missense mutations were identified in the Durocx(LandracexLarge White) population and showed significant associations with LDL-C and TC. Our data give evidence that the LDLR gene should be a candidate causative gene for LDL-C and TC in pigs, but heterogeneity exists in different populations.