There is growing evidence to the effect that steroid hormones are associated with a complex phenotype of metabolic abnormalities usually referred to as the metabolic syndrome. The 3beta-hydroxysteroid dehydrogenases/Delta(4.5)-isomerase (3beta-HSD) is crucial to the biosynthesis of hormonal steroids, including aldosterone, cortisol, and testosterone. The objective of the present study was to examine the potential impact of a T --> C substitution at codon Leu(338) of the type I (HSD3B1) 3beta-HSD gene on obesity, circulating hormones, and estimates of insulin, glucose, and lipid metabolism as well as blood pressure in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification of exon 4 of the HSD3B1 gene followed by digestion with the restriction enzyme Bg/II. The frequency of allele T was 0.44 and that of allele C 0.56. Homozygotes for the C allele (n = 75) had significantly (P < 0.05) higher mean systolic and diastolic blood pressures compared to both heterozygotes (n = 143) and homozygotes for the T allele (n = 45). In addition, the C allele was significantly (P = 0.018) more frequent among subjects with grade 1 hypertension (>140/90 mm Hg) compared to normotensive (<130/85 mm Hg) subjects. These results were all adjusted for the potential confounding effect of body mass index (BMI) and waist-to-hip ratio (WHR). Other measurements such as BMI, WHR, abdominal sagittal diameter, salivary cortisol, total testosterone, serum leptin, fasting insulin and glucose, and serum lipids were not, 38 different across the HSD3B1 genotype groups. In conclusion, a T --> C polymorphism at codon Leu(338) of exon 4 of the HSD3B1 gene is associated with elevated systolic and diastolic blood pressures. The pathogenic mechanism underlying this association is, however, uncertain from the present data and further studies are warranted. (C) 2002 Elsevier Science (USA). All rights reserved.