ClinVar Genomic variation as it relates to human health

Nevin et al. (1994) reported that mutations in the LPL gene, including D9N, are present in a subgroup of FCHL patients (144250). Reymer et al. (1995) claimed that 20% of Dutch hyperlipidemic individuals have the N291S mutation (609708.0033). De Bruin et al. (1996) screened a group of 28 probands with familial combined hyperlipidemia and group of 91 population controls for the 2 LPL gene mutations, D9N and N291S. In this way, 2 pedigrees from probands with the D9N mutation and 2 pedigrees from probands with the N291S mutation were studied, representing a total of 24 subjects. Both LPL gene mutations were associated with a significant effect on plasma lipids and apolipoproteins. Presence of the D9N mutation (n = 7) was associated with hypertriglyceridemia and reduced plasma high-density lipoprotein cholesterol concentrations. LPL-D9N carriers had higher diastolic blood pressure than noncarriers. Linkage analysis revealed no significant relationship between the D9N or N291S LPL gene mutations and the FCH phenotype (hypertriglyceridemia, hypercholesterolemia, or increased apo-B concentrations). De Bruin et al. (1996) concluded that the LPL gene did not represent the major single gene causing familial combined hyperlipidemia in the 4 pedigrees studied, but that the D9N and N291S mutations had significant additional effects on lipid and apolipoprotein phenotype. Wittrup et al. (1999) undertook to test the hypothesis that the D9N substitution and the -93T-G mutation (609708.0038) in the promoter of the LPL gene affect plasma lipid levels and thereby the risk of IHD. They genotyped 9,033 men and women from a general population sample and 940 patients with IHD. The frequency of both the G allele and the asn9 allele in the general population sample was approximately 0.015 for both men and women. These 2 mutations appeared together in 95% of carriers. The average triglyceride-raising effect associated with double heterozygosity for the 2 mutations was 0.28 mmol/L (p = 0.004) and 0.16 mmol/L (p = 0.10) in men and women, respectively. Of the overall risk of IHD in men in the general population, the fraction attributable to double heterozygosity was 3%, similar to the 5% attributable to diabetes mellitus. The results demonstrated that the D9N substitution is in linkage disequilibrium with the -93T-G mutation and that the double-heterozygous carrier status is associated with elevated plasma triglycerides and an increased risk of IHD in men. Boer et al. (1999) studied the interaction between the common D9N mutation in the LPL gene and physical activity, as well as other lifestyle factors, on lipid traits in a population-based sample of 379 Dutch men and women. Nonfasting blood samples were used for determination of lipid traits and the D9N genotype. Fifteen subjects (4%) were found to have the mutation; all 15 had higher levels of total cholesterol, apoB, and triglycerides as compared to noncarriers. While no interactions with overweight, alcohol consumption, and smoking were found, a strong interaction between the D9N mutation and physical activity was apparent. The 5 physically inactive D9N carriers had significantly higher total cholesterol and apoB levels as compared to noncarriers, whereas their HDL cholesterol concentrations were lower. The same was not the case for the 10 physically active carriers. (less)