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Biomedical subjects

A G Uitterlinden

Publications and source records attributed to A G Uitterlinden.

At least 19 recordsLinked to original sources
PubMed2001

Interaction between the vitamin D receptor gene and collagen type Ialpha1 gene in susceptibility for fracture.

Osteoporosis is a common disease with a strong genetic component. Polymorphisms in the vitamin D receptor (VDR) gene have been implicated in osteoporosis but explain only a small part of the genetic effect on bone mineral density (BMD) while their effect on fractures is still uncertain. Recently, a G to T polymorphism in an Sp1 site in the collagen type Ialpha1 (COLIA1) gene was found to be associated with reduced BMD and with increased fracture risk. To analyze the combined influence of polymorphisms in the VDR gene and the COLIA1 gene in determining the susceptibility to osteoporotic fracture, we studied 1004 postmenopausal women. The "baT" VDR haplotype, constructed from three adjacent restriction fragment length polymorphisms, was found to be overrepresented among fracture cases (p = 0.009). This corresponded to an odds ratio (OR) of 1.8 (95% CI, 1.0-3.3) for heterozygous carriers and 2.6 (95% CI, 1.4-5.0) for homozygous carriers of the risk haplotype. The effect was similar for vertebral and nonvertebral fractures and, most importantly, independent of BMD. We observed significant interaction (p = 0.03) between VDR and COLIA1 genotype effects. Fracture risk was not VDR genotype-dependent in the COLIA1 "reference" group (genotype GG) while in the COLIA1 "risk" group (genotypes GT and TT) the risk of fracture was 2.1 (95% CI, 1.0-4.4) for heterozygous and 4.4 (95% CI, 2.0-9.4) for homozygous carriers of the VDR risk haplotype. We conclude that both the VDR and the COLIA1 polymorphisms are genetic markers for osteoporotic fracture in women, independent of BMD. Our data indicate that interlocus interaction is likely to be an important component of osteoporotic fracture risk.

Cohort Studies↗
PubMed2000

Detection of sequence variability of the collagen type IIalpha 1 3' variable number of tandem repeat.

The variable number of tandem repeat (VNTR) 3' of the collagen type II (COL2A1) gene has been shown to be highly variable with a complex molecular structure. In a previous pilot experiment we observed discordance between methods to genotype this informative marker. To further investigate the extent and molecular nature of this discordance, we genotyped a random sample of 207 Caucasian individuals with two genotyping methods and sequenced new alleles. We compared single-strand (SS) analysis, which is based on detection of size differences between the different alleles, and heteroduplex analysis (HA), which is sensitive to both size and sequence differences. Overall, 26% of discordance between the two methods was detected. Approximately two thirds of this discordance was caused by subdivision of SS-alleles 13R1 and 14R2 into HA-alleles 4A + 4B and 3B + 3C, respectively. Sequence analysis of the COL2A1 VNTR alleles 4B and 3C showed that these alleles differed in sequence, but not in size, from already described SS-alleles, which explains why they escape detection by SS. The 4B allele is a frequent allele in the population (14%) and is, therefore, important to distinguish in association studies. We conclude that HA is a reliable method when the described optimized electrophoretic conditions are used. HA is a sensitive genotyping method to document allelic diversity at this locus, which can distinguish more alleles compared to the SS method.

Aged↗
PubMed2000

Adjacent genes, for COL2A1 and the vitamin D receptor, are associated with separate features of radiographic osteoarthritis of the knee.

OBJECTIVE: To study the association of the COL2A1 genotype, in relation to the vitamin D receptor (VDR) genotype, with features of radiographic osteoarthritis (ROA) in a population of elderly men and women. METHODS: In this cross-sectional study, we analyzed a population-based sample of 851 men and women ages 55-80 years from a large cohort study, the Rotterdam Study. We determined the prevalence of ROA of the knee according to the Kellgren/Lawrence (K/L) score and features of ROA (presence of osteophytes and narrowing of the joint space [JSN]) without considering clinical parameters of the disease. Genotypes were determined at a variable-number tandem repeats marker 1 kb downstream of the COL2A1 gene using a newly developed heteroduplexing method. The VDR genotype was previously determined by a direct molecular haplotyping polymerase chain reaction method to establish the phase of alleles at 3 adjacent restriction fragment length polymorphisms for Bsm I, Apa I, and Taq I. RESULTS: We found the COL2A1 genotype to be associated with a 2-fold increased risk for JSN, but not with osteophytes or the K/L score. We had previously found the VDR genotype to be associated with osteophytes and the K/L score, but not with JSN. When the COL2A1 genotype was analyzed in combination with the VDR genotype, we found evidence suggesting that the presence of haplotypes of the 2 genes was associated with increased risk for ROA. CONCLUSION: Our findings demonstrate that both the COL2A1 gene and the VDR gene are involved in ROA, but in separate features. The COL2A1 genotype is associated with JSN, while the VDR genotype is associated with osteophytes.

Aged↗
PubMed2000

COLIA1 polymorphism contributes to bone mineral density to assess prevalent wrist fractures.

Wrist fractures associated with postmenopausal women are only partially explained by osteoporosis. Recent studies have shown that polymorphism of an Spl binding site in the first intron of the collagen I alpha 1 gene (COLIA1) may determine risk for vertebral and nonvertebral fractures in post-menopausal women independent of bone mass. We investigated the relationship between the COLIA1 polymorphism, lumbar spine and femoral neck bone mineral density (BMD), ultrasound stiffness of the heel, anthropometric variables, and risk for wrist fractures in 126 Czech postmenopausal women with low bone mass who suffered one or more wrist fracture in the last 5 years and in 126 postmenopausal women with low bone mass without any fracture. Genotypes for the Spl COLIA1 polymorphism were determined by polymerase chain reaction, digestion with Ball restriction enzyme, and agarose gel electrophoresis. The test discriminates two alleles, S and s, which correspond to the presence of guanine and thymidine, respectively, at the first bases in the Spl-binding site in the first intron of the gene for CO-LIA1. No significant differences were found between the fracture and control group with regard to age, weight, and years since menopause. However, BMD of the lumbar spine and femoral neck and ultrasound stiffness of the heel were significantly lower in patients with prevalent wrist fracture. Femoral neck BMD was the strongest determinant of prevalent fracture of the wrist. COLIA1 genotyping significantly strengthened prediction of prevalent fracture of the wrist. After multivariate adjustment, women in the Ss group had 2.0 times the risk of the women in the SS group (95% confidence interval [CI] = 1.1-3.8), and the women in the ss group had 2.8 times the risk of the women in the SS group (95% CI = 0.5-14.6). The overall gene-dose effect was an odds ratio of 2.1 per copy of the "s" allele (95% CI = 1.2-3.8). In the stepwise logistic regression, COLIA1 acted synergistically with femoral neck BMD and weight in increasing prediction of wrist fracture. The results demonstrate that COLIA1 Sp1 polymorphism is associated with an increased risk of wrist fracture in postmenopausal women independent of BMD and may be helpful in clinical practice by identifying patients with an increased fracture risk.

Bone Density↗
PubMed2000

Consequences of vitamin D receptor gene polymorphisms for growth inhibition of cultured human peripheral blood mononuclear cells by 1, 25-dihydroxyvitamin D3.

OBJECTIVE: In the vitamin D receptor (VDR) gene a BsmI restriction fragment length polymorphism (RFLP) in intron 8 and a translational start-site polymorphism, identified as a FokI RFLP, have been described. Crucial for a proper interpretation of these polymorphisms in association studies is the knowledge whether they have direct consequences for 1,25-(OH)2D3 action at cellular level. The present study was designed to assess functional significance of the FokI and BsmI VDR gene polymorphisms in peripheral blood mononuclear cells (PBMC) with a natural occurring VDR genotype for cell growth inhibition by 1,25-(OH)2D3. DESIGN: PBMC of women were isolated, VDR genotyped and in vitro inhibition by 1,25-(OH)2D3 of Phytohemagglutinin (PHA)-stimulated growth of PBMC was examined in relation to VDR genotype. RESULTS: PHA-stimulated growth and maximal growth inhibition were independent of VDR genotype. However, the FF genotype had a significant lower ED50 than the Ff genotype corresponding to an allele dose effect of 0.32 nM per f allele copy (P = 0.0036). For BsmI genotypes no differences in ED50 were observed. CONCLUSION: The present study demonstrates for the first time in cells with a natural VDR genotype a direct functional consequence of the VDR gene translational start-site polymorphism for the action of 1,25-(OH)2D3. Especially under conditions of vitamin D insufficiency these findings might have clinical implications.

Aged↗
PubMed1999

Estrogen receptor polymorphism predicts the onset of natural and surgical menopause.

Age at menopause and risk of hysterectomy have strong genetic components, but the genes involved remain ill defined. We investigated whether genetic variation at the estrogen receptor (ER) gene contributes to the variability in the onset of menopause in 900 postmenopausal women, aged 55-80 yr, of the Rotterdam Study, a population-based cohort study in The Netherlands. Gynecological information was obtained, and if women reported surgical menopause, validation of type and indication of surgery was accomplished by checking medical records. The ER genotypes (PP, Pp, and pp) were assessed by PCR using the PvuII endonuclease. Compared with women carrying the pp genotype, homozygous PP women had a 1.1-yr (P < 0.02) earlier onset of menopause. Furthermore, an allele dose effect was observed, corresponding to a 0.5-yr (P < 0.02) earlier onset of menopause per copy of the P allele. The risk of surgical menopause was 2.4 (95% confidence interval, 1.5-3.8) times higher for women carrying the PP genotype compared to those in the pp group, with the most prominent effect in women who underwent hysterectomy due to fibroids or menorrhagia. We conclude that genetic variations of the ER gene are related to the onset of natural menopause and the risk of surgical menopause, especially hysterectomy.

Aged↗
PubMed1998

Relation of alleles of the collagen type Ialpha1 gene to bone density and the risk of osteoporotic fractures in postmenopausal women.

BACKGROUND: Osteoporosis is a common disorder with a strong genetic component. One way in which the genetic component could be expressed is through polymorphism of COLIA1, the gene for collagen type Ialpha1, a bone-matrix protein. METHODS: We determined the COLIA1 genotypes SS, Ss, and ss in a population-based sample of 1778 postmenopausal women using a polymerase-chain-reaction-based assay. We then related the genotypes to bone mineral density and the occurrence of osteoporotic fractures in these women. RESULTS: As compared with the 1194 women with the SS genotype, the 526 women with the Ss genotype had 2 percent lower bone mineral density at the femoral neck (P=0.003) and the lumbar spine (P=0.02); the 58 women with the ss genotype had reductions of 4 percent at the femoral neck (P= 0.05) and 6 percent at the lumbar spine (P=0.005). These differences increased with age (P=0.01 for modification by age of the effect of COLIA1 on femoral-neck bone density, and P=0.004 for modification of the effect on lumbar-spine bone density). Women with the Ss and ss genotypes were overrepresented among the 111 women who had incident nonvertebral fractures (relative risk per copy of the s allele, 1.5; 95 percent confidence interval, 1.1 to 2.1). CONCLUSIONS: The COLIA1 polymorphism is associated with reduced bone density and predisposes women to osteoporotic fractures.

Age Factors↗
PubMed1998

Population analysis of the collagen type IIalpha1 3' variable number of tandem repeat polymorphism by heteroduplex genotyping.

The AT-rich variable number of tandem repeat (VNTR) marker at the 3' end of the collagen type IIalpha1 (COL2A1) gene has been shown to have a complex structure with extensive sequence variations among repeat units. We analyzed this VNTR polymorphism in a large population of 972 Caucasian individuals with a genotyping procedure involving heteroduplex analysis of PCR products using polyacrylamide gel electrophoresis. Seven size alleles were identified, combining to 19 different homoduplex genotypes (heterozygosity = 0.64). These could be further dissected by analysis of heteroduplexes into 85 different heteroduplex genotypes (heterozygosity = 0.84). By systematically heteroduplexing homozygous and heterozygous individuals in vitro, characteristic heteroduplex doublet bands were generated of known allelic composition. A comparison of these doublets with heteroduplex patterns observed in the population allowed us to identify 29 alleles. The degree of correspondence with a different COL2A1 VNTR genotyping system, based on size separation of single-strand VNTR alleles [1], was investigated by the analysis of samples typed with both methods, including samples from reference CEPH pedigrees. This revealed improved genetic resolution by the heteroduplex method including discrimination of frequent alleles considered identical by the single-strand analysis. Our findings demonstrate heteroduplex analysis of the COL2A1 VNTR to be a robust and highly informative genetic marker system. The documented increased genetic variability has important implications in forensic and paternity testing, as well as in linkage and association studies relating genetic variation at this locus to disease endpoints.

Aged↗
PubMed1998

Lack of associations between serum leptin, a polymorphism in the gene for the beta 3-adrenergic receptor and glucose tolerance in the Dutch population.

BACKGROUND: The associations between leptin levels and the prevalence of a polymorphism in the beta 3-adrenergic receptor were studied in a cross-sectional analysis of 600 participants in a population-based study, which were stratified for glucose tolerance by an oral glucose tolerance test. METHODS: In a random sample of 600 participants in the Rotterdam study, aged 55-75 years at baseline (309 men, 291 women) the relationships were studied between the presence of Trp64 Arg mutation in the beta 3-adrenergic receptor gene and fasting leptin, glucose and insulin (fasting and after an oral glucose load), and other components of the insulin resistance syndrome. RESULTS: Mean age of the study population was 66.9 years (SD 5.7). Fasting serum leptin levels overall in men and women were 6.1 micrograms/l (SE 0.2) and 21.7 micrograms/l (0.9), respectively, (P < 0.001). These differences were independent of age, body mass index and waist to hip ratio. We identified 73/600 persons who were heterozygotes for the Trp64 Arg polymorphism (allelic frequency 6.1%), but failed to find an association between the presence of this polymorphism and leptin or any measured parameter indicative for obesity, impaired glucose tolerance or type 2 diabetes mellitus. CONCLUSION: Heterozygosity for the Trp64Arg polymorphism of the beta 3-adrenergic receptor gene is not accompanied by obesity, impaired glucose tolerance and type 2 diabetes mellitus in the general elderly Dutch population, and is also not associated with changes in circulating leptin levels.

Aged↗
PubMed1997

Vitamin D receptor genotype is associated with radiographic osteoarthritis at the knee.

Osteoporosis and osteoarthritis are age-related disorders of the skeleton with genetic components. Low bone density is a risk factor for osteoporotic fracture while osteoarthritis is associated with increased bone density. The 1,25-dihydroxyvitamin D3 receptor (VDR) gene locus was previously found to be associated with bone density. We therefore studied the relationship between radiographic osteoarthritis at the knee and VDR genotype in a population-based sample (n = 846), using molecular haplotyping of anonymous intragenic DNA polymorphisms. Radiographic osteoarthritis was defined using the Kellgren score, which is based on the assessment of osteophytes and joint space narrowing (JSN). We show that one VDR haplotype allele is significantly overrepresented in individuals with knee osteoarthritis and associated with a 2.27-fold increased relative risk (95% confidence interval 1.46, 3.52). Adjustment for bone density at the femoral neck did not change these results, indicating that the association is not mediated by bone density. The association appeared to be largely explained by the presence of osteophytes rather than JSN. Our results indicate a role of the VDR gene in the pathogenesis of osteophytes while linkage disequilibrium with another nearby gene, i.e., the collagen type IIa1 gene encoding the most abundant protein in cartilage, might contribute to the association.

Aged↗
PubMed1997

Mapping of 34 minisatellite loci resolved by two-dimensional DNA typing.

Two-dimensional (2-D) DNA typing is based on electrophoretic separation of genomic DNA fragments in two dimensions according to independent criteria (size and base-pair sequence), followed by hybridization analysis using multilocus probes. The technique allows simultaneous visualization of several hundred loci as spots in a 2-D pattern. The majority of the loci resolved are polymorphic. Using linkage analysis in a large CEPH family, this study reports the mapping of 34 loci detected by the minisatellite core probe 33.6. By multipoint linkage analysis, regional chromosome positions of the 33.6 loci could be deduced, showing no evidence of clustering. In the analysis of spot patterns, use was made of a computerized image analysis system specifically designed for 2-D DNA typing. Since experimental variations between different separation patterns were automatically corrected for with this program, rapid and reliable scorings could be obtained. The results presented demonstrate the availability of reliable genetic information throughout the 2-D separation pattern. Adding the use of semiautomated computerized pattern analysis, this study further substantiates the applicability of 2-D DNA typing in genome scanning, not only in theoretical but also in practical terms. Moreover, it can be anticipated that this method will have a specific advantage in studies that scan for trinucleotide repeat expansions and somatic instability, where the repeat sequences detected by appropriate core probes are of particular interest.

Chromosome Mapping↗
PubMed1997

The effect of vitamin D supplementation on the bone mineral density of the femoral neck is associated with vitamin D receptor genotype.

Recent studies suggest that variations of the vitamin D receptor (VDR) gene are related to bone mineral density (BMD). In this study, we examined the effect of vitamin D3 supplementation on BMD at the femoral neck in relation to VDR genotype. We analyzed 81 women, age 70 years and over, who participated in a placebo-controlled clinical trial on the effect of vitamin D3 supplementation (400 IU daily for at least 2 years) on BMD and fracture incidence. VDR genotype was based on the presence (b) or absence (B) of the BsmI restriction site. Mean BMD of the right and left femoral neck was measured at baseline and after 1 and 2 years. Dietary calcium, body mass index, and years since menopause were assessed at baseline while biochemical markers were measured at baseline and after 1 year. There was no difference among the BB, Bb, and bb genotype for baseline measurements of BMD at the femoral neck (mean and SD, g/cm2: 0.70 (0.10), 0.71 (0.12), and 0.69 (0.10), respectively), nor for any of the biochemical indices. The mean increase of BMD in the vitamin D group relative to the placebo group, expressed as percentage of baseline BMD, was significantly higher (p = 0.03) in the BB (delta BMD: 4.4%, p = 0.04) and Bb genotype (delta BMD: 4.2%, p = 0.007) compared with the bb genotype (delta BMD: -0.3%, p = 0.61). No significant changes were found for any of the other measured parameters. The VDR genotype-dependent effect of vitamin D supplementation in these elderly subjects suggest a functional involvement of VDR gene variants in determining BMD.

Absorptiometry, Photon↗
PubMed1996

Comprehensive and accurate mutation scanning of the CFTR gene by two-dimensional DNA electrophoresis.

The large number of possible disease-causing mutations in the 27 exons of the cystic fibrosis transmembrane conductance regulator (CFTR) gene has severely limited direct diagnosis of cystic fibrosis (CF) patients and carriers by mutation detection. Here we show that in principle testing for mutations in the CFTR gene can be both substantially facilitated and made virtually complete, by two-dimensional DNA electrophoretic separation of polymerase chain reaction (PCR) amplified exons on the basis of size and basepair sequence in denaturing gradient gels. Under a single optimized set of conditions we were able to obtain a pattern of spots representing all 27 exons of the CFTR gene and to readily detect 17 out of 17 identified sequence variations in 9 different exons in DNA from 11 CF patients and carriers. Our results demonstrate the potential of 2-dimensional DNA electrophoresis for comprehensive mutation analysis of the CFTR gene. The approach serves as a model for comprehensive diagnosis of the many other large disease genes for which a variety of mutations have also which been reported.

Cystic Fibrosis↗
PubMed1996

A large-scale population-based study of the association of vitamin D receptor gene polymorphisms with bone mineral density.

Conflicting results have been reported on the association between restriction fragment length polymorphisms (RFLPs) at the vitamin D receptor (VDR) gene locus (i.e., for BsmI, ApaI, and TaqI) and bone mineral density (BMD). We analyzed this association in a large population-based sample (n = 1782) of men and women aged 55-80 years using a novel direct haplotyping polymerase chain reaction (PCR) test to monitor the three polymorphic sites simultaneously. The direct haplotyping test we developed demonstrated a larger degree of genetic polymorphism at the VDR gene locus than described until now. None of the individual RFLPs were associated with BMD at the proximal femur. By analyzing allele dose effects, we identified a VDR haplotype allele weakly associated with low BMD. This allele, as one representative of the group of b alleles, is different from the BsmI allele previously reported by other groups to be associated with low BMD. This suggests allelic heterogeneity at the VDR locus in relation to BMD. Our results indicate at most a small effect of the VDR genotype on BMD in this elderly population. Since anonymous polymorphisms were analyzed, alternative explanations for our results include linkage to another nearby bone-metabolism related gene.

Absorptiometry, Photon↗