High density lipoprotein cholesterol (HDL-C) levels are inversely associated with the incidence of coronary heart disease (CHD) in middle-aged individuals; in the elderly, the association is less clear. Genetic factors, including variations in the cholesteryl ester transfer protein (CETP) gene, play a role in determining HDL-C levels. Controversy remains about whether CETP deficiency and the resultant rise in HDL-C are antiatherogenic, or whether CETP has the opposite effect due to its role in reverse cholesterol transport. In a seven-year follow-up of 2,340 men aged 71-93 in the Honolulu Heart Program, the age-adjusted CHD incidence rates were significantly lower in men with high versus low HDL-C levels. After adjustment for age, hypertension, smoking, and total cholesterol, the relative risk of CHD for those with HDL-C levels у 60 mg/dl, compared with those with HDL-C levels Ͻ 40 mg/dl, was 0.6. Men with a CETP mutation had the lowest rates of CHD, although this was not statistically significant. These data indicate that HDL-C remains an important risk factor for CHD in the elderly. Whether a CETP mutation offers additional protection against CHD warrants further investigation.

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 Duroc × Erhualian F2 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 Duroc × Erhualian F2 resource population and a Duroc × (Landrace × Large 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 = 5.40 × 10(-11) ) and TC (P = 3.64 × 10(-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 = 4.62 × 10(-18) ) and TC (P = 1.06 × 10(-9) ). However, the c.1812C>T SNP was not identified in the White Duroc × Erhualian intercross, and the association of c.1520A>G with both LDL-C and TC did not achieve significance in this F2 population, suggesting population heterogeneity. Both missense mutations were identified in the Duroc × (Landrace × Large 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.

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