The presence of a polymorphism at the translation initiation site of the vitamin D receptor gene is associated with low bone mineral density in postmenopausal mexican-American women

Abstract

We examined the association of bone mineral density (BMD) with a polymorphism in the gene encoding the vitamin D receptor (VDR) that causes a change in the predicted protein sequence. The polymorphism results from a C-to-T transition and creates an initiation codon (ATG) three codons proximal to a downstream start site. The polymorphism can be defined by a restriction fragment length polymorphism (RFLP) using the restriction endonuclease FokI. The presence of a FokI site, designated f, allows protein translation to initiate from the first ATG. The allele lacking the site (designated F), initiates from a second ATG site. Thus, translation products from these alleles are predicted to differ by three amino acids with the f variant elongated. In a group of 100 postmenopausal Mexican-American Caucasian women, subjects with the ff genotype (15% of the study population) had a 12.8% lower BMD at the lumbar spine than FF subjects (37% of the population) (p = 0.01). Heterozygote (Ff) subjects (48% of the population) had an intermediate BMD. This association between BMD and genotype was not apparent at the femoral neck or forearm. Over a 2-year follow-up period, a decrease in BMD at the femoral neck was greater in ff compared with FF subjects (-4.7% vs. -0.5%, p = 0.005). This trend was not apparent at the lumbar spine or forearm. There were no differences between genotype groups in measurements of 25-hydroxyvitamin D (25(OH)D), calcitriol, parathyroid hormone (PTH), osteocalcin, or urinary pyridinolines. We conclude that the FokI polymorphism of the VDR gene correlates significantly with decreased BMD at the lumbar spine and with an increased rate of bone loss at the hip in ff subjects. We emphasize that these initial data should be interpreted with caution but that the utility of this polymorphism as a genetic marker to determine BMD and osteoporosis risk warrants further study in larger populations with subjects of diverse ethnic backgrounds.

Hereditary vitamin D–resistant rickets (HVDRR) owing to a heterozygous mutation in the vitamin D receptor

“…(11,24) Based on these findings, we cloned and sequenced the patient's individual cDNAs representing the two FokI (f/F) polymorphic alleles in order to further demonstrate that the patient had only a single heterozygous mutation in the VDR gene and to rule out the presence of an additional mutation. Sequencing showed that the E420A mutation was present on the f/M1 allele and therefore was inherited from the father.…”

“…Sequencing also showed that the patient and her father were heterozygous for the FokI polymorphism (F/f) located in the translation initiation start site (data not shown). (11,24) To further demonstrate that the patient had only a single heterozygous mutation in the VDR gene, we cloned and sequenced the VDR cDNAs that were generated from the two different F/f site alleles. The cDNA sequence from the patient's f site allele had the E420A mutation, like the father, whereas the cDNA sequence from the F site allele was completely normal, like the mother.…”

Vitamin D receptor polymorphisms and prognosis of patients with epithelial ovarian cancer

“…Similarly, Colin et al (2000) showed a significantly lower (50%) effective dose of 1,25-(OH) 2 D 3 in the FokI C/C genotype than in FokI C/T genotype. By switching from ATG (FokI T) to ACG (FokI C) polymorphism, the first potential start site moves to the 3 0 direction, resulting in proteins that are three amino acids shorter and more functional (Gross et al, 1996). Thus, patients with FokI C/C may react more to vitamin D, resulting in a higher survival rate.…”

The Association between Vitamin D Receptor FokI Gene Polymorphism and Osteoporosis in Postmenopausal Women: A Meta-Analysis

“…Gross et al [15] conducted a study in postmenopausal Mexican-American women, showed that FokI polymorphism of the VDR gene correlates significantly with decreased BMD at the lumbar spine and an increased rate of bone loss at the hip in ff subjects. In another study of postmenopausal Italian women population, Gennari L [16] observed a weak association between FokI polymorphism and lumbar BMD (p = 0.06) but no reveland to femoral neck BMD(p = 0.5).…”