A meta-analysis of genome-wide data from five European isolates reveals an association of COL22A1, SYT1, and GABRR2 with serum creatinine level

Background

Serum creatinine (S_CR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in S_CR level is explicable by genetic factors.

Methods

We performed a meta-analysis of genome-wide association studies of S_CR undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with S_CR (candidate loci) were replicated in two additional population-based samples ('replication cohorts').

Results

After the discovery meta-analysis, 29 loci were selected for replication. Association between S_CR level and polymorphisms in the collagen type XXII alpha 1 (COL22A1) gene, on chromosome 8, and in the synaptotagmin-1 (SYT1) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 × 10^-6 and 1.7 × 10^-4, respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (GABRR2) gene and the ubiquitin-conjugating enzyme E2-J1 (UBE2J1) gene (replication p value = 3.6 × 10^-3). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (UMOD) gene and in the schroom family member 3 (SCHROOM3) gene were also replicated.

Conclusions

While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes SYT1 and GABRR2 corroborate previous findings that highlighted a possible role of the neurotransmitters GABA_A receptors in the regulation of the glomerular basement membrane and a possible interaction between GABA_Areceptors and synaptotagmin-I at the podocyte level.     

Gene polymorphisms of the renin-angiotensin system and early development of hypertension

BACKGROUND: A case-control association study was conducted to investigate a possible involvement of polymorphisms of three renin-angiotensin system genes: ACE (I/D and T-3892C), AGT (M235T and T174M), and AT1R (A1166C) in the early development of hypertension. METHODS: One hundred nineteen hypertensive and 125 normotensive participants aged 18 to 40 years were selected from a broader sample representative of the general population of Croatia. The selection criteria for hypertensive cases were systolic blood pressure (BP) higher than 140 mm Hg or diastolic BP higher than 90 mm Hg and a history of hypertension according to patient interview. RESULTS: Among the polymorphisms investigated, only those located on the ACE gene were associated with hypertension. For ACE I/D, the odds ratio for hypertension of DD versus II homozygote individuals was 2.50 (95% confidence interval [CI] 1.19-5.25) and for ACE T-3892C, the odds ratio of CC versus TT individuals was 2.32 (95% CI 1.05-5.10). Both polymorphisms of the ACE gene were in tight linkage disequilibrium. Of the investigated risk factors for hypertension, only body mass index (BMI) showed an influence on the early development of hypertension, acting independently of the ACE polymorphism. Their additive effect gives rise to 86% of hypertensives in subjects having both the DD genotype and BMI >or=30 kg/m(2). CONCLUSIONS: The present study provides evidence of the association of the ACE gene polymorphisms and premature hypertension. In addition, BMI proved to be another important predictor of the disorder acting independently of the ACE gene.     

Short tandem repeat (STR) variation in eight village populations of the island of Korcula (Croatia)

The aim of this study was to analyse short tandem repeat (STR) variation using the data on nine loci (D3S1358, vWA, FGA, THO1, TPOX, CSF1PO, D5S818, D13S317, D7S820) in the populations from eight villages on the island of Korcula, Croatia, in order to analyse its genetic and population structure. The analysis of STR data in this study indicated an appreciable degree of genetic homogeneity among the studied village populations on the island, even though a so-called 'east-west dichotomy' and differentiation between the inhabitants of the most recent settlement and the remaining ones was indicated with respect to the loci CSF1PO and TPOX, respectively. The validity of STR markers in assessing genetic structure of small populations and especially in determining the relationships among geographically closely related but reproductively isolated groups remains to be further evaluated, especially in terms of a larger number of studied loci in order to possibly find specific markers useful for resolving genetic patterns of variability at regional levels.     

侧脑室外引流术与腰大池持续引流术治疗脑室出血的疗效对比分析

目的 对比分析侧脑室外引流术与腰大池持续引流术治疗脑室出血的效果.方法 回顾性分析106例脑室出血患者临床资料,根据治疗方式分为侧脑室外引流组(67例)和腰大池引流组(39例),比较两组患者治疗效果及预后情况.结果 与腰大池引流组比较,侧脑室外引流组术后3、7d脑脊液蛋白水平均较低[(3.95±0.42)g/L vs.(6.23±0.31)g/L,t=1.698,P=0.029;(0.98±0.41)g/L vs.(3.38±0.39)g/L,t=1.985,P=0.027],术后1、3 d血肿清除率均较高(t=6.130,P=0.032;t=7.690,P=0.019).与腰大池引流组比较,侧脑室外引流组再出血、颅内感染、脑积水、预后不良发生率更高(χ2=0.013,P=0.035;χ2=0.048,P=0.021;χ2=0.061,P=0.017;χ2=2.458,P=0.025).结论 腰大池持续引流治疗脑室出血与侧脑室外引流比较,早期血肿清除较慢,但创伤小,并发症发生率低,预后良好.     

Primary adenocarcinoma of the duodenum. Report of two cases

Between 1969 and 1982, two patients were treated for malignant primary tumors of the duodenum in the Central Institute for Tumors and Allied Diseases in Zagreb. Adenocarcinoma of the posterior wall of the third part of the duodenum was histologically confirmed in the first patient. Today, 11 years after surgery and radiotherapy, there are no signs of the disease. Invasive papillary adenocarcinoma of the third part of the duodenum was histologically confirmed in the second patient. This patient died in cachexia 2 years after the diagnosis. The autopsy confirmed the initial diagnosis, and metastasis in the liver and periduodenal lymph nodes. When establishing the differential diagnosis of undefined pathologic processes in this region, one should consider a primary tumor of the duodenum. Palliative surgery can also be valuable in the overall outcome of treatment.     

Genetic variation in Brac, Croatia.

A serological survey of the Dalmatian island of Brac (Croatia), based on a total sample of 747 subjects, shows considerable local genetic variation. While the overall gene frequencies are much as expected from the island's geographical position, the local genetic heterogeneity is made up of differences between the inland and coastal villages, differences between the two coastal areas, and variation among the older inland villages. This heterogeneity is interpreted as deriving from the settlement process (founder effect), random differentiation, and the essentially local marriage pattern.     

Molecular recognition and modulation of hepatocyte growth factor activity by heparan and dermatan sulfates

Introduction Hepatocyte growth factor/scatter factor (HGF/SF) is an unusual growth factor in that it binds both heparan sulfate (HS) ( Lyon et al. 1994 ) and dermatan sulfate (DS) ( Lyon et al. 1998 ) glycosaminoglycans (GAGs) with similar high affinities. Both these GAGs act as co‐receptors for HGF/SF in the activation of the Met receptor ( Lyon et al. 2002 ). Our aim was to determine the sequences in HS and DS that specifically interact with and modulate HGF/SF activity. Materials and methods A structurally unique DS, which possesses O‐sulfation at carbon‐6 of the hexosamine residue (and not carbon‐4 as in mammalian DS), was obtained from the sea cucumber, Ascidia nigra. A variety of HS‐ and DS‐like structures were also generated using various chemical modification procedures (specific desulfations and carboxyl reductions). The ability of these various GAG species to compete with cell surface GAGs for HGF/SF binding was tested using radiolabelled HGF/SF and MDCK cells. The modified GAG structures and the A. nigra DS are currently being tested for their ability to act as co‐receptors for the interaction between HGF/SF and Met by studying cell signalling and cellular response assays, using the sulfated GAG‐deficient CHO‐745 cell line. Results Unexpectedly, A. nigra DS was found to bind HGF/SF strongly with a KD of around 1 nm . This interaction is 20‐fold stronger than that of between HGF/SF and mammalian DS, but similar to that of with HS. A. nigra DS also stimulated HGF/SF‐mediated Erk activation and migration in CHO‐745 cells. Studies using the modified GAG species showed that, in the case of HS, 6‐O‐sulfate and N‐sulfate groups are most important for HGF/SF binding. For HGF/SF binding to DS, hexosamine O‐sulfate is most important. HGF/SF was also found to bind 6‐O‐sulfated GAGs more strongly than 4‐O‐sulfated ones. Discussion The data show that there is flexibility in the structures recognized by HGF/SF, and this explains the ability of the growth factor to bind both HS and DS. However, there are still observable preferences in GAG structure, such as 6‐O‐sulfation over 4‐O‐sulfation. Information on HGF/SF‐binding GAG structures is valuable for the design of HGF/SF antagonists that could be useful therapeutically in the treatment of solid tumours where HGF/SF‐Met activity is up‐regulated.