E.J. Schaefer

Homozygous Tangier disease and cardiovascular disease

Decreased levels of plasma high density lipoprotein (HDL) cholesterol have been associated with premature cardiovascular disease (CVD). Tangier disease is an autosomal co-dominant disorder in which homozygotes have a marked deficiency of HDL cholesterol and apolipoprotein (apo) A-I levels (both < 10 mg/dl), decreased low density lipoprotein (LDL) cholesterol levels (about 40% of normal), and mild hypertriglyceridemia. Homozygotes develop cholesterol ester deposition in tonsils (orange tonsils), liver, spleen, gastrointestinal tract, lymph nodes, bone marrow, and Schwann cells. Our purpose was to assess the prevalence of CVD in Tangier disease. We reviewed published clinical information on 51 cases of homozygous Tangier disease, report 3 new cases and provide autopsy information on 3 cases. Mean (+/- S.D.) lipid values of all cases were as follows: total cholesterol 68 +/- 30 mg/dl (32% of normal), triglycerides 201 +/- 118 mg/dl (162% of normal), HDL cholesterol 3 +/- 3 mg/dl (6% of normal) and LDL cholesterol 50 +/- 38 mg/dl (37% of normal). The most common clinical finding in these subjects (n = 54) was peripheral neuropathy which was observed in 54% of cases versus < 1% of control subjects (n = 3130). CVD was observed in 20% of Tangier patients versus 5% of controls (P < 0.05), and in those that were between 35 and 65 years of age, 44% (11 of 25) had evidence of CVD (either angina, myocardial infarction or stroke) versus 6.5% in 1533 male controls and 3.2% in 1597 female controls in this age group (P < 0.01). In 9 patients who died, 2 died prior to age 20 of probable infectious diseases, 3 of documented coronary heart disease at ages 48, 64, and 72, 2 of stroke at ages 56 and 69, one of valvular heart disease, and 1 of cancer. In three autopsy cases, significant diffuse atherosclerosis was observed in one at age 64, moderate atherosclerosis and cerebral infarction in another at age 56, but no atherosclerosis was noted in the third case who died of lymphoma at age 62. In one patient with established coronary heart disease, none of the lipid lowering agents used (niacin, gemfibrozil, estrogen or lovastatin) raised HDL cholesterol levels above 5 mg/dl. However, these agents did have significant effects on lowering triglyceride and LDL cholesterol levels. Our data indicate that there may be heterogeneity in these patients with regard to CVD risk, that peripheral neuropathy is a major problem in many patients, and that CVD is a significant clinical problem in middle aged and elderly Tangier homozygotes.(ABSTRACT TRUNCATED AT 400 WORDS)

The BsmI Vitamin D Receptor Restriction Fragment Length Polymorphism (bb) Influences the Effect of Calcium Intake on Bone Mineral Density

Previous studies of the vitamin D receptor (VDR) polymorphisms and bone mineral density (BMD) have suggested that there may be differences in calcium absorption among groups of women with different VDR genotypes, and that the association may be stronger in younger women. To investigate the association between the VDR polymorphisms and BMD, this study was undertaken in the Framingham Study Cohort and a group of younger volunteers. Subjects from the Framingham Study (ages 69–90 years) included those who underwent BMD testing and who had genotyping for the VDR alleles (n = 328) using polymerase chain reaction methods and restriction fragment length polymorphisms with BsmI (B absence, b presence of cut site). A group of younger volunteer subjects (ages 18–68) also underwent BMD testing and VDR genotyping (n = 94). In Framingham Cohort subjects with the bb genotype, but not the Bb or BB genotypes, there were significant associations between calcium intake and BMD at five of six skeletal sites, such that BMD was 7–12% higher in those with dietary calcium intakes greater than 800 mg/day compared with those with intakes <500 mg/day. The data also suggested that BMD was higher in persons with the bb genotype only in the group with calcium intakes above 800 mg/day. No significant differences were found in the Framingham Cohort for age‐, sex‐, and weight‐adjusted BMD at any skeletal site between those with the BB genotype and those with the bb genotype regardless of 25‐hydroxyvitamin D levels or country of origin. In the younger volunteers, BMD of the femoral neck was 5.4% higher (p < 0.05) in the bb genotype group compared with the BB group and 11% higher (p < 0.05) in males with the bb genotype compared with the BB group. There were no significant differences at the lumbar spine. In this study, the association between calcium intake and BMD appeared to be dependent upon VDR genotype. The finding of an association between dietary calcium intake and BMD only in the bb genotype group suggests that the VDR genotype may play a role in the absorption of dietary calcium. Studies that do not consider calcium intake may not detect associations between VDR genotype and BMD. In addition, the association between VDR alleles and BMD may become less evident in older subjects.

Two common mutations (D9N, N291S) in lipoprotein lipase : a cumulative analysis of their influence on plasma lipids and lipoproteins in men and women

We assessed the effect of two common mutations in the lipoprotein lipase gene (LPL), D9N and N291S, which have been shown to modulate plasma lipids in a wide spectrum of patients.A total of 1 114 men and 1 144 women from the Framingham Offspring Study (FOS) were analyzed for these two LPL variants. Subsequently, the association with fasting plasma lipids and risk of coronary artery disease (CHD) was determined. We extended our study by calculating weighed means of lipids and lipoproteins in carriers and non‐carriers for these LPL mutations in patients with genetic dyslipidemias, CHD patients and healthy controls.In the FOS sample, the D9N and N291S alleles were associated with lower high‐density lipoprotein‐cholesterol (HDL‐C) (Δ=−0.07 mmol/l, p=0.03) and a trend towards increased triglycerides (Δ=0.25 mmol/l, p=0.07). In women, a trend towards the high triglyceride, low HDL‐C phenotype was evident (Δ=−0.02 mmol/l for HDL‐C and Δ=0.14 mmol/l for triglycerides, respectively). Cumulative analysis of other studies of male carriers of the D9N and N291S revealed higher levels of triglycerides (D291N; 2.60(1.85) mmol/l vs. 1.62(1.18) mmol/l: p<0.0001) (D9N; 1.94 (1.19) mmol/l vs. 1.74(1.17) mmol/l: p<0.001) and lower HDL‐C (N291S; 1.04(0.32) mmol/l vs. 1.15(0.28) mmol/l: p<0.0001) (D9N; 1.08(0.24) mmol/l vs. 1.16(0.28) mmol/l: p<0.0001). In females, results differed with higher TG levels (N291S; 1.70(0.99) mmol/l vs. 1.10(0.63) mmol/l: p<0.001) (D9N; 1.08(0.76) mmol/l vs. 0.96(0.51) mmol/l: p<0.01) and lower HDL‐C levels (N291S; 1.27(0.33) mmol/l vs. 1.51(0.32) mmol/l: p<0.0001); however, the HDL‐C levels for D9N carriers were similar to non‐carriers (D9N; 1.52(0.29) mmol/l vs. 1.53(0.35) mmol/l: p=0.83).Our data provide evidence that common variants of the LPL gene are significant modulators of lipid and lipoprotein levels in both men and women.

A case report of a diabetic woman with very low HDL cholesterol

Lipid patterns of low high-density lipoprotein cholesterol (HDLc) and high triglycerides (TGs), particularly in patients with diabetes mellitus, are of concern to the physician. This is particularly true when plasma lowdensity lipoprotein (LDL) cholesterol is within the normal range or elevated. This is a report of a diabetic patient with low HDLc and high TGs but a very low total plasma cholesterol. The abnormal HDL particle composition and the response to treatment was thought to be of interest to lipidologists.