Adiponectin gene variant RS rs266729: Relation to lipid profile changes and circulating adiponectin after bariatric surgery

Background

ADIPOQ rs266729 have been associated with body mass index and metabolic parameters.

脂氧酶12 编码区遗传变异与胃癌发病的关系

目的：探讨位于脂氧酶12（LOX12）基因编码区Arg261Gln单核苷酸多态与胃癌发病风险的关系。方法：用聚合酶链反应-限制性片段长度多态性分析（PCR-RFLP）方法检测148例胃癌患者和148例无肿瘤正常对照人群的LOX12的基因型,并以Logistic回归模型计算各基因型与胃癌发病风险的关系。结果：LOX12 Arg261Gln等位基因频率在胃癌组中（0.544）高于正常组（0.443）。与Arg/Arg基因型携带者相比,Gln/Gln基因型携带者发生胃癌的风险增加（OR=2.26,95%CI=1.15~4.46,P=0.018）,而杂合基因型Arg/Gln不增加胃癌发病风险（OR=1.37,95%CI=0.77~2.44,P=0.284）。结论：LOX12编码区Arg261Gln遗传变异可能是胃癌发病的重要遗传易感因素。     

Adiponectin genetic variability, plasma adiponectin, and cardiovascular risk in patients with type 2 diabetes

Adiponectin is an adipocyte-derived hormone that has shown anti-inflammatory and antiatherogenic effects. We assessed the associations of variants in the adiponectin gene (ADIPOQ) with circulating adiponectin levels and cardiovascular risk among women with type 2 diabetes. Of 989 diabetic women from the Nurses' Health Study, 285 developed cardiovascular disease (CVD) during follow-up through 2000. We genotyped five ADIPOQ polymorphisms in the CVD case and control subjects. A promoter polymorphism -11365C-->G was significantly associated with lower plasma adiponectin levels (P = 0.004). The homozygotes of allele -4034C were significantly associated with approximately 60% increased cardiovascular risk (odds ratio 1.62 [95% CI 1.07-2.45]). Adjustment for age, BMI, and other covariates did not appreciably change the associations. In addition, a common haplotype possessing allele +276T (CAATT) was associated with a significantly lower CVD risk than the most common haplotype (CAATG) (0.70 [0.50-0.98]). In our meta-analysis of 827 CVD case and 1,887 CVD-free control subjects, polymorphism +276G-->T was significantly associated with approximately 45% (20-62%) decreased CVD risk under a recessive inheritance mode in diabetic patients. In conclusion, ADIPOQ promoter polymorphism -11365C-->G was associated with plasma adiponectin levels, whereas polymorphisms -4034A-->C and +276G-->T were associated with CVD risk in diabetic patients.     

Reduced gene expression of adiponectin in fat tissue from patients with end-stage renal disease

BACKGROUND: Cardiovascular disease (CVD) is the main cause of death in end-stage renal disease (ESRD) patients. It has been suggested that inflammation plays a key role in the development of both atherosclerosis and malnutrition (MIA), a combination of complications associated with poor outcome. Although plasma levels of adiponectin, a recently discovered anti-inflammatory and antiatherogenic adipocytokine, are markedly elevated in ESRD, gene expression of adiponectin (ApM1) has not been analyzed in ESRD patients. METHODS: We analyzed the ApM1 gene expression in adipose tissue from 18 ESRD patients of whom 9 (7 males, 60 +/- 8 years, BMI 24 +/- 6 kg/m(2)) had a high prevalence of MIA complications, and 9 age- (55 +/- 9 years), gender- (7 males) and BMI- (24 +/- 2 kg/m(2)) matched ESRD patients had few MIA complications. The results were compared with age- (59 +/- 11 years), gender- (7 males), and BMI- (24 +/- 6 kg/m(2)) matched healthy control patients. Information on CVD was obtained at the recruitment based on a detailed medical history. Malnutrition was defined as a subjective global assessment (SGA) score >1. Inflammation was defined as CRP >/=10 mg/L. Gene expression analysis was performed using the in situ hybridization technique. RESULTS: Gene expression of ApM1 was lower in ESRD patients compared with healthy control patients (P= 0.001). On the other hand, when comparing the gene expression between ESRD patients with and without MIA complications, respectively, no difference in the ApM1 gene expression was detected. CONCLUSION: Adiponectin gene expression is significantly down-regulated in ESRD patients compared with healthy control patients. We propose that the decrease in expression may be the result of a negative feedback regulation, as a result of elevated levels of circulating adiponectin caused by renal failure.     

Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone

RANK (receptor activator of nuclear factor‐κB), encoded by TNFRSF11A, is a key protein in osteoclastogenesis. TNFRSF11A mutations cause Paget's disease of bone (PDB)–like diseases (ie, familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early‐onset PDB) and an osteoclast‐poor form of osteopetrosis. However, no TNFRSF11A mutations have been found in classic PDB, neither in familial nor in isolated cases. To investigate the possible relationship between TNFRSF11A polymorphisms and sporadic PDB, we conducted an association study including 32 single‐nucleotide polymorphisms (SNPs) in 196 Belgian sporadic PDB patients and 212 control individuals. Thirteen SNPs and 3 multimarker tests (MMTs) turned out to have a p value of between .036 and 3.17 × 10^?4, with the major effect coming from females. Moreover, 6 SNPs and 1 MMT withstood the Bonferroni correction (p < .002). Replication studies were performed for 2 nonsynonymous SNPs (rs35211496 and rs1805034) in a Dutch and a British cohort. Interestingly, both SNPs resulted in p values ranging from .013 to 8.38 × 10^?5 in both populations. Meta‐analysis over three populations resulted in p = .002 for rs35211496 and p = 1.27 × 10^?8 for rs1805034, again mainly coming from the female subgroups. In an attempt to identify the underlying causative SNP, we performed functional studies for the coding SNPs as well as resequencing efforts of a 31‐kb region harboring a risk haplotype within the Belgian females. However, neither approach resulted in significant evidence for the causality of any of the tested genetic variants. Therefore, further studies are needed to identify the real cause of the increased risk to develop PDB shown to be present within TNFRSF11A. © 2010 American Society for Bone and Mineral Research.     

Adiponectin and cardiovascular remodeling in end-stage renal disease and co-morbid diabetes mellitus

OBJECTIVES AND METHODS: Altered plasma high-sensitivity C-reactive protein (hs-CRP) and adiponectin (ADP) may contribute to increased vascular inflammation and accelerated atherosclerosis in patients with end-stage renal disease (ESRD) and co-morbid diabetes. Common carotid artery intima-media thickness (CCA-IMT) and atherosclerotic plaque occurrence, left-ventricular mass index (LVMI), and pulse wave velocity of the proximal aorta (PWVr) were determined by ultrasound imaging in 120 ESRD (55 diabetic) patients, and 83 age-, sex-, and blood pressure-matched controls. Also, plasma levels of ADP and hs-CRP were determined and their relationships with the above cardiovascular alterations were analyzed. RESULTS: LVMI, PWVr, CCA-IMT and atherosclerotic plaque occurrence were all increased in ESRD patients compared to controls (all p < 0.001). LVMI (p < 0.05), PWVr (p < 0.001), CCA-IMT (p < 0.001) and atherosclerotic plaque occurrence (p < 0.001) were increased in diabetic compared to nondiabetic ESRD patients. Hs-CRP levels were increased and ADP levels were decreased in diabetic compared to nondiabetic ESRD patients (both p < 0.001). ADP levels correlated inversely with hs-CRP (r = -0.473, p < 0.0001) in ESRD patients. Hs-CRP was positively correlated with LVMI (r = 0.365, p < 0.0001), PWVr (r = 0.42, p < 0.0001) and CCA-IMT (r = 0.18, p = 0.047) while ADP inversely correlated with PWVr (r = -0.263, p = 0.0035) and CCA-IMT (r = -0.207, p = 0.022) in ESRD patients. CONCLUSION: The present results indicate diabetic disease-specific alterations in the biochemical parameters of hs-CRP and ADP in ESRD patients. The above biochemical parameters were intimately linked to the cardiovascular measurements of LVMI, PWVr and CCA-IMT in patients with ESRD and co-morbid diabetes mellitus.     

Alpha-1-antitrypsin levels and genetic variation of the alpha-1-antitrypsin gene in Peyronie's disease

OBJECTIVES: Alpha-1-antitrypsin (alpha1-antitrypsin) is a major protease inhibitor controlling tissue degradation. Reduced alpha1-antitrypsin levels could result in a change of collagen metabolism. Previous studies have described decreased alpha1-antitrypsin levels in patients with Peyronie's disease. However, only a small number of patients were analyzed, and the reason for the decreased alpha1-antitrypsin levels remained unclear. This study investigated prospectively the levels of alpha1-antitrypsin in patients with Peyronie's disease, as well as genetic variation in the coding region of the alpha1-antitrypsin gene. METHODS: Alpha1-antitrypsin levels were determined prospectively in 94 patients with Peyronie's disease and compared to healthy controls. Analysis of the alpha1-antitrypsin gene (S, Z variants; single nucleotid polymorphisms [SNPs]: T-395A, M2, M3, G6118A) was done in 141 Peyronie's patients including 43 patients with investigated alpha1-antitrypsin serum levels and compared to healthy controls. RESULTS: In patients with Peyronie's disease, the alpha1-antitrypsin levels seemed to be decreased significantly compared to healthy controls. However, in the age matched approach no significant differences occurred. Moreover, a significant (p < 0.002) decrease of the alpha1-antitrypsin level with increasing age was observed, explaining the initial differences between the two groups. In confirmation with these findings, no significant association of the alpha1-antitrypsin gene variants with Peyronie's disease was detectable. CONCLUSIONS: The results of this study do not indicate a significant association between Peyronie's disease and decreased alpha1-antitrypsin levels. Low alpha1-antitrypsin levels in Peyronie's patients are, rather, an age-related phenomenon, as revealed by the comparison with aged matched healthy controls. The decrease of the alpha1-antitrypsin serum level with increasing age has not been described before.     

Regional variation in end-stage renal disease

Regional variations in end-stage renal disease have been found within a country, even within a race. Since diabetic nephropathy is the leading cause of end-stage renal disease in developed countries, first of all, regional differences in diabetic nephropathy must be considered. Although the incidence of end-stage renal disease due to diabetic nephropathy has been found to differ among different areas within a country, there are no data on regional variations in the incidence of type II diabetes or diabetic nephropathy without renal failure. Such regional variations could hardly be explained by local differences in gene pools alone, which suggests an important role of environmental factors. It is not clear at present how regional variations in the incidence of end-stage renal disease are generated. If we can identify the factors that contribute to the regional differences, we can take these into account in future treatment strategies for renal disease. Thus, much effort is required in further analysis of regional differences in end-stage renal disease dynamics.     

Diffuse renal cystic disease in children: morphologic and genetic correlations

During a 5-year period, we evaluated seven infants and two fetuses who presented with enlarged, hyperechoic kidneys. In each, the initial clinical diagnosis was autosomal recessive polycystic kidney disease (ARPKD). Among the seven unrelated infants were three Caucasian and four African-American infants. No syndromic stigmata were evident in any of these infants. At the time of the initial evaluation, the family data were incomplete for four infants. The two fetuses were presumed to be at-risk for ARPKD based on the diagnosis in previous siblings. Renal histopathology was evaluated in all nine cases and revealed a spectrum of cystic disease ranging from ARPKD to glomerulocystic kidney disease to autosomal dominant polycystic kidney disease to diffuse cystic dysplasia. In the eight cases for whom liver histopathology was available, varying degrees of biliary dysgenesis were evident. We present a detailed analysis of the key histopathological features in each case and discuss the histopathological findings in an embryological context. In addition, we address the current role of molecular genetics in the diagnostic evaluation. Received May 14, 1997; received and accepted in revised form September 22, 1997     

桂西地区中老年人脂联素基因多态性与骨质疏松症的相关性

目的 探讨桂西地区中老年人脂联素基因多态性与骨质疏松症的相关性。方法 选取桂西地区中老年人志愿者623名,进行超声骨密度测量、脂联素基因多态性位点分析及SNPs位点的连锁不平衡分析。结果 同年龄（55岁以上）男性骨量值高于女性（P＜0.05）,骨量正常的个体比例随年龄的增长而下降,而骨质疏松症的患病率则随年龄增长而增加。脂联素基因5个SNPs位点均达到Hardy-Weinberg平衡（P＞0.05）,其中SNP位点rs1063539的CG基因型在骨质疏松病例组分布高于正常组,而GG基因型在病例组中的分布则低于正常组。CG型可能是骨密度的一个保护基因型,等位基因C可能与骨质疏松症的发生呈负相关。SNP位点rs3774261的AA基因型在病例组中的分布高于正常组。连锁不平衡检测发现,脂联素基因的5个SNP位点之间不存在连锁关系。结论 脂联素基因的SNP位点rs1063539和rs3774261与桂西地区中老年人群的骨质疏松有密切关系。     

Adiponectin in chronic kidney disease is related more to metabolic disturbances than to decline in renal function.

BACKGROUND: Adiponectin, a newly discovered collagen-like protein of the collectin family exclusively produced by adipocytes, possesses anti-inflammatory properties. Plasma adiponectin is associated with a decreased cardiovascular risk in non-renal patients, and is reduced in obesity and insulin-resistant states. Although reports show an increase in the adiponectin level in maintenance haemodialysis, peritoneal dialysis and end-stage renal disease, there is no documentation of adiponectin levels and regulation in the early stages of chronic kidney disease (CKD). METHODS: We prospectively measured glomerular filtration rate (GFR) in 48 patients with CKD using inulin clearance. Fasting blood was drawn to determine insulin, leptin, adiponectin and C-reactive protein (CRP) levels. Body fat mass was calculated using skinfold thickness measurements. RESULTS: The patients' mean GFR was 53.5+/-24.9 (SD) ml/min/1.73 m2. Adiponectin was in the normal range in men (9.8+/-2.9 mg/l) and women (16.6+/-5.0 mg/l) with CKD, being significantly higher in women than men (P<0.001). Serum leptin was above normal (10.4+/-10.7 microg/l), whereas serum insulin and CRP were within their normal ranges (3.5+/-3.3 microU/ml and 2.6+/-5.0 mg/l, respectively). In linear regression analysis, adiponectin was negatively correlated with GFR (P = 0.02), fat mass (P = 0.03) and body mass index (P = 0.002), and strongly positively correlated with serum leptin (P = 0.003). A positive relationship was also found between plasma adiponectin and the urinary albumin/creatinine ratio (P = 0.007). No relationship was found between adiponectin and insulin or adiponectin and CRP. In multiple regression analysis, adiponectin was significantly positively correlated with leptin (P<0.0001), negatively with body mass index (P<0.0001) and only weakly with GFR (P = 0.04). CONCLUSIONS: Despite an adverse metabolic environment in chronic renal insufficiency, serum adiponectin increases in non-obese patients when renal function deteriorates. Adiponectin is only weakly affected by renal function per se, but appears influenced by proteinuria, and more significantly by body mass index and the change in serum leptin that accompanies decline in renal function.     

Adiponectin gene polymorphisms and susceptibility to diabetic nephropathy: a meta-analysis

Adiponectin (ADIPOQ) plays an important role in the pathogenesis of diabetic nephropathy (DN) and previous studies regarding the association between ADIPOQ polymorphisms and DN risk reported conflicting results. To derive a more precise estimation of this association, we performed a meta-analysis to assess the association between four ADIPOQ polymorphisms [?11391G?>?A (rs17300539), ?11377C?>?G (rs266729), +45T?>?G (rs2241766), and +276G?>?T (rs1501299)] and risk for DN. Odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were pooled to assess the association between four aforementioned polymorphisms and susceptibility to DN. Based on the included criteria, we selected 13 articles, among which 7 studies (cases/controls: 2749/7585) for ?11391G?>?A, 8 studies for ?11377C?>?G (3074/3842), 9 studies for +45T?>?G (2654/7710), and 10 studies for +276G?>?T (2812/7821), respectively. Our meta-analysis indicated no evidence heterogeneity among the included studies; thus, the fixed-effects model was used. Overall, there was an association between ADIPOQ ?11391A allele with increased DN risk (OR?=?1.186, 95% CI: 1.051–1.338, p?=?0.006). Subgroup by ethnicity suggested significant association between +45T?>?G polymorphism and DN risk among Caucasians (OR?=?1.122, 95% CI: 1.007–1.250, p?=?0.038). Sensitivity analysis suggested exclusion of any single study did not materially alter the overall pooled ORs above. Future studies are needed to validate these findings.     

The relationship of cigarette smoking to end-stage renal disease

Cigarette smoking (CS) has been associated with augmented progression of nephropathies responsible for the 4 major causes of end-stage renal disease (ESRD) in the United States. CS has well-described ways by which it causes tissue injury in other organ systems and the mechanisms by which it adversely affects nephropathy progression might be similar. Therefore, exploring the mechanisms for CS-induced nephropathy or progression thereof might yield important insights into the general mechanisms by which some or most nephropathies progress to ESRD. In addition, CS can be discontinued and so is a potentially correctable risk factor for ESRD, a syndrome whose incidence continues to increase. Therefore, the mechanism(s) by which CS induces nephropathy progression is an important area of investigation.     

Prevalence of genetic renal disease in children

Background

Genetic etiology comprises a significant proportion of renal disease in childhood. Completion of the Human Genome Project and increased genetic testing has assisted with the increased recognition of a genetic basis to many renal disorders. Australia and New Zealand have a relatively stable but diverse population, with eight major pediatric nephrology referral centers, which allow ascertainment of disease frequency.

Methods

To determine prevalence, pediatric nephrologists at the eight centers in Australia and New Zealand were surveyed on their estimated number of patients with renal disease of genetic etiology over a 10-year period. Disease prevalence was calculated using combined national population data.

Results

The overall prevalence of genetic kidney disease in children in Australia and New Zealand is 70.6 children per million age-representative population. Congenital anomalies of the kidney and urinary tract (CAKUT) and steroid-resistant nephrotic syndrome (SRNS) are the most frequent, with a prevalence of 16.3 and 10.7, respectively, per million children.

Conclusion

We find a similar prevalence of genetic renal disorders in Australia and New Zealand to those reported in other countries. This is likely to be due to inclusion of children with all forms of renal disease rather than being limited to those with renal impairment.     

Linkage of plasma adiponectin levels to 3q27 explained by association with variation in the APM1 gene

We performed a genome-wide linkage scan of plasma adiponectin levels in 569 nondiabetic participants in the Amish Family Diabetes Study. The highest logarithm of odds (LOD) score (2.13; P = 0.0009) occurred on chromosome 3q27 between markers D3S1602 and D3S1580, which flank APM1/ACDC, the adiponectin gene. The APM1 +2019 A/- insertion/deletion polymorphism in the 3' untranslated region (single nucleotide polymorphism [SNP] +2019; deletion allele frequency 0.30 in Amish) showed strong association with adiponectin levels in a dosage-dependent manner in a direction consistent with that reported in previous studies, with deletion heterozygosity increasing adiponectin levels by 1.3 +/- 0.5 microg/ml and deletion homozygosity increasing levels by 3.0 +/- 0.8 microg/ml (P < 0.0001). Two other SNPs, rs2241766 and rs1501299, showed moderate association. In a subset of 523 subjects genotyped for both SNP +2019 and rs2241766, including the APM1 SNP +2019 genotype as a covariate reduced the linkage signal at 3q27 by 1.26 LOD units (from 2.22 to 0.96) and including both SNPs reduced the signal by 1.51 LOD units (to 0.71). These findings, combined with a two-point LOD score of 2.35 for SNP +2019, provide evidence that variation in APM1 is responsible for linkage of adiponectin levels to 3q27 in the Old Order Amish.     

Progress in gene targeting: using mutant mice to study renal function and disease

Genetic engineering in mice has provided much information about gene function in renal health and disease. This knowledge has largely come from conventional transgenic approaches. Recently, methods have been developed to control the cell type, timing and reversibility of target gene expression. Advances in identifying promoters conferring renal cell-specific gene regulation in vivo have greatly facilitated interpretation of gene targeting studies. Site-specific recombinases have permitted cell-specific knockout of genes; Cre is the preeminent recombinase, but recent progress with other recombinases, include Flp and PhiC31, will likely increase the usefulness of this class of enzymes. Temporally regulated gene expression, particularly using doxycycline- and tamoxifen-inducible systems, holds great promise for avoiding developmental effects of gene mutations as well as facilitating comparison of the same animal's phenotype before and after gene modification. RNA interference is undergoing tremendous growth and has great potential for achieving gene knockdown quickly and reversibly. To date, however, the utility of these systems in modifying renal function in transgenic mice remains unproven. Finally, new gene targeting tools are in development that may substantially simplify generation of transgenic animals. This review discusses the state-of-the-art in gene targeting in the kidney, reviewing function, indications and limitations of the molecular biologic tools.     

Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide (NO) synthase. Its concentration is elevated in patients with end-stage renal disease (ESRD), in part because it is excreted via the kidneys. In this study, the plasma concentrations of ADMA, symmetric dimethylarginine, and L-arginine were determined in relation to plasma nitrate levels (as an index of NO formation) for a group of 80 patients with ESRD. The effects of two treatment methods, i.e., hemodialysis (HD) and peritoneal dialysis (PD), and the role of the presence of atherosclerotic disease were evaluated. Forty-three patients receiving HD and 37 patients receiving PD were compared with healthy control subjects. Plasma L-arginine and dimethylarginine levels were determined by HPLC, using precolumn derivatization with o-phthaldialdehyde. Plasma nitrate levels were determined by gas chromatography-mass spectrometry. Predialysis ADMA concentrations in HD-treated patients were approximately sixfold higher than those in the control group (6.0+/-0.5 versus 1.0+/-0.1 micromol/L; P < 0.05). Plasma nitrate concentrations were significantly lower in HD-treated patients, which suggests that ADMA may inhibit NO synthase. In contrast, plasma ADMA levels and nitrate concentrations in PD-treated patients were similar to those in control subjects. Plasma L-arginine concentrations were not significantly decreased in patients with ESRD. ADMA concentrations were significantly decreased 5 h after HD, compared with baseline values. ADMA levels were significantly higher in HD-treated patients with manifest atherosclerotic disease than in HD-treated patients without atherosclerotic disease (7.31+/-0.70 versus 3.95+/-0.52 micromol/L; P < 0.05). This study confirms that ADMA is accumulated in ESRD. PD-treated patients exhibit significantly lower ADMA levels than do HD-treated patients. Accumulation of ADMA may be a risk factor for the development of endothelial dysfunction and cardiovascular disease in patients with ESRD.