Search

Background: The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis. Methods: In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed-and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls. Results: The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (a = 0.05). Conclusion: This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase. [ABSTRACT FROM AUTHOR]

Osteoporosis is a bone disease leading to an increased fracture risk. It is considered a complex multifactorial genetic disorder with interaction of environmental and genetic factors. As a candidate gene for osteoporosis, we studied vitamin D binding protein (DBP, or group-specific component, Gc), which binds to and transports vitamin D to target tissues to maintain calcium homeostasis through the vitamin D endocrine system. DBP can also be converted to DBP-macrophage activating factor (DBP-MAF), which mediates bone resorption by directly activating osteoclasts. We summarized the genetic linkage structure of the DBP gene. We genotyped two single-nucleotide polymorphisms (SNPs, rs7041 = Glu416Asp and rs4588 = Thr420Lys) in 6,181 elderly Caucasians and investigated interactions of the DBP genotype with vitamin D receptor (VDR) genotype and dietary calcium intake in relation to fracture risk. Haplotypes of the DBP SNPs correspond to protein variations referred to as Gc1s (haplotype 1), Gc2 (haplotype 2), and Gc1f (haplotype3). In a subgroup of 1,312 subjects, DBP genotype was found to be associated with increased and decreased serum 25-(OH)D3 for haplotype 1 ( P = 3 × 10−4) and haplotype 2 ( P = 3 × 10−6), respectively. Similar associations were observed for 1,25-(OH)2D3. The DBP genotype was not significantly associated with fracture risk in the entire study population. Yet, we observed interaction between DBP and VDR haplotypes in determining fracture risk. In the DBP haplotype 1-carrier group, subjects of homozygous VDR block 5-haplotype 1 had 33% increased fracture risk compared to noncarriers ( P = 0.005). In a subgroup with dietary calcium intake <1.09 g/day, the hazard ratio (95% confidence interval) for fracture risk of DBP hap1-homozygote versus noncarrier was 1.47 (1.06–2.05). All associations were independent of age and gender. Our study demonstrated that the genetic effect of the DBP gene on fracture risk appears only in combination with other genetic and environmental risk factors for bone metabolism. [ABSTRACT FROM AUTHOR]

BACKGROUND: Anti-Müllerian hormone (AMH) inhibits primordial follicle recruitment in the mouse ovary. We hypothesize that in women AMH signaling also regulates the usage of the primordial follicle pool and hence influences the onset of menopause. Since age at menopause has a strong genetic component, we investigated the role of AMH signaling using a candidate gene approach. [ABSTRACT FROM PUBLISHER]

Most studies on the genetic determinants of blood pressure and vascular complications of type 2 diabetes have focused on the effects of single genes. These studies often have yielded conflicting results. Therefore, we examined the combined effects of three renin-angiotensin system (RAS) genes and three salt sensitivity genes in relation to blood pressure and atherosclerosis in the total population and type 2 diabetic patients. The study was a part of the Rotterdam Study, a population-based cohort study. We have genotyped three RAS gene polymorphisms and three salt sensitivity gene polymorphisms. Diabetic patients with three risk genotypes of the RAS genes had a 6.9 mmHg higher systolic blood pressure (P for trend = 0.04) and a 6.0 mmHg higher pulse pressure (P for trend = 0.03) than those who did not carry any risk genotypes. Diabetic patients with three risk genotypes of the salt sensitivity genes had a 9.0 mmHg higher systolic blood pressure (P = 0.19) and a 13.1 mmHg higher pulse pressure (P = 0.02). Diabetic patients who carried three risk genotypes for the RAS genes had a higher mean intima-media thickness than those with two risk genotypes (mean difference 0.04 mm, P = 0.02). We found that among type 2 diabetic patients, mean systolic blood pressure, pulse pressure, and risk of hypertension increased with the number of risk genotypes for the RAS genes and the salt sensitivity genes. Diabetes 56:1905-1912, 2007 [ABSTRACT FROM AUTHOR]

The COLIA1 Sp1 polymorphism has been associated with bone mineral density (BMD) and fracture. A promoter polymorphism, -1997 G/T, also has been associated with BMD. In this study, we examined whether these polymorphisms alone and in the form of haplotypes influence bone parameters and fracture risk in a large population-based cohort of elderly Caucasians. We determined the COLIA1 -1997 G/T (promoter) and Sp1 G/T (intron) polymorphisms in 6,280 individuals and inferred haplotypes. Femoral neck BMD and BMD change were compared across COLIA1 genotypes at baseline and follow-up (mean 6.5 years). We also investigated the relationship between the COLIA1 polymorphisms and incident nonvertebral fractures, which were recorded during a mean follow-up period of 7.4 years. Vertebral fractures were assessed by radiographs on 3,456 genotyped individuals. Femoral neck BMD measured at baseline was 3.8% lower in women carrying two copies of the T-Sp1 allele ( P for trend = 0.03). No genotype dependent differences in BMD loss were observed. In women homozygous for the T allele of the Sp1 polymorphism, the risk of fragility fracture increased 2.3 times (95% confidence interval 1.4–3.9, P = 0.001). No such association was observed with the promoter polymorphism. In men, no association with either the Sp1 or the -1997 G/T promoter polymorphism was seen with BMD or fracture. High linkage disequilibrium (LD; D′ = 0.99, r 2 = 0.03) exists between the two studied polymorphisms. We observed three haplotypes in our population: haplotype 1 (Gpromoter–Gintron) frequency (f) = 69%, haplotype 2 (Gpromoter–Tintron) f = 17.6%, and haplotype 3 (Tpromoter–Gintron) f = 13.4%. Haplotype 2 was associated with a 2.1-fold increased risk of fragility fracture in women (95% confidence interval 1.2–3.7, P = 0.001). We confirm that the COLIA1 Sp1 polymorphism influences BMD and the risk of fracture in postmenopausal Caucasian women. In contrast, we found no independent effect of the -1997 G/T promoter polymorphism on BMD or fracture. [ABSTRACT FROM AUTHOR]

Purpose. Genetic factors, as well as environmental factors (e.g. physical activity, nutritional intake, and body composition) are considered to influence the regulation of (young) adult bone quality. The association between lumbar bone mineral density (LBMD) and polymorphisms of three genes (i.e. VDR, ER, COLIA1), as well as gene-environment interactions over a period of 10 years were investigated in (young) adult men and women. Basic procedures. The study was conducted in participants of the Amsterdam Growth and Health Longitudinal Study. Longitudinal analyses were performed in Dutch Caucasian males and females, including measurements at their mean ages of 27, 32 and 36 years. LBMD measurements were performed at the L2-L4 region by dual energy X-ray absorptiometry (DEXA). Polymorphism-containing regions were amplified from genomic DNA with the restriction fragment length polymorphism- polymerase chain reaction (RFLP-PCR). Genotyping was performed for the BsmI, ApaI, and TaqI polymorphisms of the VDR, for the PvuII and XbaI polymorphisms of the ER, and for the G-to-T polymorphism in the COLIA1 gene. Main findings. A positive allele-dose effect of the ER haplotype PX on the development of (young) adult LBMD was found. Dietary calcium intake modified the relationship between VDR haplotypes and LBMD, and fat-free mass modified the relationship between COLIA1 polymorphisms and LBMD. Conclusions. An allele-dose relationship with LBMD during the third and fourth decades of life was detected for the PX haplotype allele of the VDR gene. Most Caucasian lumbar bones are likely to benefit from an increased calcium intake, and all will benefit from an increased fat-free mass. [ABSTRACT FROM AUTHOR]

Previously, we have shown that a mutation in the mitochondrial DNA-encoded tRNALeu(UUR) gene is associated with type 2 diabetes. One of the consequences of this mutation is a reduced aminoacylation of tRNALeu(UUR). In this study, we have examined whether variants in the leucyl tRNA synthetase gene (LARS2), involved in aminoacylation of tRNALeu(UUR), associate with type 2 diabetes. Direct sequencing of LARS2 cDNA from 25 type 2 diabetic subjects revealed eight single nucleotide polymorphisms. Two of the variants were examined in 7,836 subjects from four independent populations in the Netherlands and Denmark. A -109 g/a variant was not associated with type 2 diabetes. Allele frequencies for the other variant, H324Q, were 3.5% in type 2 diabetic and 2.7% in control subjects, respectively. The common odds ratio across all four studies was 1.40 (95% CI 1.12-1.76), P = 0.004. There were no significant differences in clinical variables between carriers and noncarriers. In this study, we provide evidence that the LARS2 gene may represent a novel type 2 diabetes susceptibility gene. The mechanism by which the H324Q variant enhances type 2 diabetes risk needs to be further established. This is the first report of association between an aminoacyl tRNA synthetase gene and disease. Our results further highlight the important role of mitochondria in glucose homeostasis. Diabetes 54:1892-1895, 2005 previously, we have shown that an A3243G mutation in the mitochondrial DNA-encoded tRNA[sup Leu(UUR)] gene is associated with maternally inherited diabetes and deafness(1,2). Carriers of the 3243 mutation have a reduced glucose-stimulated insulin secretion. Biochemical studies indicate that mutant mitochondrial TRNA[sup Leucine] is less efficiently aminoacylated in comparison with the wild-type tRNA(2). Furthermore, it has been shown that there is an altered balance between mitochondrial and nuclear-encoded proteins in mutant mitochondria, resulting in mitochondrial dysfunction(2). [ABSTRACT FROM AUTHOR]