Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+l)-to-A mutation(Intl4 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exonl4/intronl4 boundary (Intl4 T) and a missense mutation (Asp'2 to Gly) within exon 15 (D442G).The Intl4 T mutation was only found in one family. However, the D442G and Intl4 A mutations were highly prevalent in subjects with HDL-C . 60 mg/dl, with combined allele frequencies of 9%, 12%, 21%, and 43% for HDL-C 60-79, 80-99, 100-119, and . 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Intl4 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Intl4 T and Intl4 A) was similar to that of Intl4 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Intl4 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86±26 mg/dl) were lower than in Intl4 A homozygotes (158±35 mgldl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91±23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Intl4 A heterozygotes (69±15 mg/dl). Thus, the D442G mutation acts differently to the null mutations A portion of this paper was presented at the Asian-Pacific Congress on coronary heart disease risk factor held in Hong Kong, January 1994.

Background-To date, no prospective studies have examined the association between serum homocysteine levels and the risk of stroke and stroke subtypes in Asian populations. Methods and Results-A prospective, nested, case-control study of Japanese subjects 40 to 85 years of age was conducted by using frozen serum samples from 11 846 participants in cardiovascular risk surveys collected from 1984 to 1995 for one community and 1989 to 1995 for the other two communities. By the end of 2000, we identified 150 incident strokes, the subtypes of which were confirmed by imaging studies. Three control subjects per case were selected by matching for sex, age, community, year of serum storage, and fasting status. Serum total homocysteine levels were measured by high-performance liquid chromatography. Compared with control subjects, total (nϭ150), hemorrhagic (nϭ52), and ischemic (nϭ98) strokes had higher geometric mean values of total homocysteine and higher proportions of homocysteine Ն11.0 mol/L. The multivariate odds ratios (95% CI) for highest (Ն11.0 mol/L) versus lowest quartiles (Ͻ7.0 mol/L) of homocysteine after adjustment for body mass index, smoking, alcohol intake, hypertension, serum total cholesterol, and other cardiovascular risk factors were 2.99 (1.51 to 5.93) for total stroke, 3.89 (1.60 to 9.46) for ischemic stroke, 3.36 (1.27 to 8.90) for lacunar infarction, and 1.63 (0.44 to 6.00) for hemorrhagic stroke. The respective multivariate odds ratios associated with a 5-mol/L increase in homocysteine were 1.40 (1.09 to 1.80), 1.52 (1.07 to 2.14), 1.48 (1.01 to 2.18), and 1.10 (0.76 to 1.59). The excess risk of total and ischemic strokes did not vary significantly according to sex, age, smoking status, or hypertensive status. Conclusions-High total homocysteine concentrations were associated with the increased risk of total stroke, more specifically ischemic stroke and lacunar infarction, among Japanese men and women.

No abstract

No abstract