Sabine Kotschan

BACKGROUND: Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. Strong interindividual variations of VEGF plasma levels have been reported previously. Aim of the present study was to search for mutations in the 3' untranslated region (3'-UTR) of the VEGF gene and to analyze their relation to VEGF plasma levels. METHODS: The complete 3'-UTR (nucleotide 700-2622) of the VEGF gene was screened for sequence variations by single-strand conformation polymorphism (SSCP) analysis. Frequencies of mutated alleles were determined in 119 healthy subjects; VEGF plasma levels were analyzed in a subgroup of 23 healthy men aged 18-36 years. RESULTS: Three novel mutations (702 C/T, 936 C/T, 1612 G/A) were found, allele frequencies of 702T, 936T and 1612A were of 0.017, 0.160 and 0.471, respectively. VEGF plasma levels were significantly lower in carriers of the 936T allele (9.1 +/- 2.7 pg/ml, mean +/- SEM) than in noncarriers (28.0 +/- 5.5 pg/ml, p = 0.033), whereas the 702 C/T and the 1612 G/A mutations showed no association with VEGF plasma levels. The 936 C/T exchange led to the loss of a potential binding site for transcription factor AP-4, although the functionality of this binding site remains unclear. CONCLUSION: We have found three common mutations in the VEGF gene; one of them, a 936 C/T exchange, may be an important determinant of VEGF plasma levels.

Osteoporosis is a systemic disorder of decreased skeletal mass as measured by bone mineral density (BMD), and disturbed skeletal architecture and function which results in an increased risk for bone fractures with consecutively increased morbidity and mortality. Twin and family studies have shown an important genetic component of BMD of about 40-60%. This exceeds other well known factors influencing BMD such as environmental factors like dietary calcium, physical activity or several drugs and diseases. Therefore, interest increased in the genetic background of bone mineral density. Polymorphisms of the Vitamin D receptor gene were the first to be published in this area. Studies on other loci or candidate genes such as the estrogen receptor gene or the collagen type I alpha1 gene also showed associations with bone mineral density that could explain at least a part of the genetic background of osteoporosis. Recently published data suggest that these genetic markers of bone metabolism are important in interaction with each other or in certain bone-affecting diseases. In the future, genetic studies on osteoporosis will have to screen further relevant genes and markers for bone metabolism as well as to evaluate the complex interactions of genetic influences, so that it would be possible to calculate a patient's individual risk for osteoporosis in the context of environmental influences.

Decreased bone mineral density (BMD) at the hip is an important risk factor for hip fractures, which are a major socioeconomic problem in the elderly. The incidence of congenital hip dysplasia (CHD) is about 7-13% in the Middle European population. We assessed the question of whether a conservatively treated CHD may be a risk factor for low BMD at the hip in adult women. We evaluated prospectively 240 premenopausal women (33 +/- 7 years). Past medical history was recorded including the presence or absence of CHD. Lumbar and femoral BMD using dual-energy X-ray absorptiometry (DXA) and biochemical parameters of bone metabolism were measured. X-rays of the pelvis were performed in CHD patients. Thirty-one (12.9%) of the patients had a history of conservatively treated CHD, four (1.2%) had undergone surgery; all other patients served as control group. Patients and controls were comparable for anthropometric data, lifestyle factors, and hip axis length. BMD in CHD patients was significantly lower at the hip (difference by 1 STD) but comparable at the spine. OC was significantly higher in patients with CHD than in controls. In a logistic regression model, CHD was associated with a 6.3-fold increased risk for low BMD at the hip. We therefore conclude that a history of conservatively treated CHD may be a major risk factor for low BMD at the hip in about 1 out of 10 women. Whether this translates into an increased risk for future hip fractures will have to be assessed in further prospective studies.