Lack of association between angiotensin II type 1 receptor gene polymorphism and hypertension in Japanese.

Angiotensin II type 1 (AT1) receptor mediates the vasoconstriction and growth-promoting effect of angiotensin II in humans. It has been reported that a polymorphism of the AT1 receptor gene (an A/C transversion at position 1166; A1166C) may be associated with essential hypertension (HT). However, several conflicting results have also been reported. Therefore, we conducted an association study between A1166C variants of the AT1 receptor gene and hypertension in the Japanese population. We genotyped this variant in 3,918 subjects (1,492 hypertensive subjects and 2,426 normotensive subjects) recruited from the Suita study. In subjects not receiving antihypertensive medication, the influence of the genotype on blood pressure values adjusted for clinical covariates was analyzed. The genotype distribution did not differ between hypertensive and normotensive subjects in either men (frequency of the C allele: 8.1% vs. 7.8%, p=0.74) or women (8.1% vs. 7.7%, p=0.60). There were no significant differences in systolic blood pressure, diastolic blood pressure, or pulse pressure among the three genotypes in either men or women who had not received hypertensive medication. Our data suggest that the A1166C polymorphism of AT1 receptor is unlikely to influence blood pressure status in the Japanese population.     

Lack of association between thyrotropin receptor gene polymorphisms and subclinical hypothyroidism in children

Subclinical hypothyroidism is defined as a serum TSH level above the statistically set reference range, associated to normal free thyroid hormone concentrations. Genetic and environmental factors contribute to the inter- and intra-individual biological variations of TSH levels, sometimes leading to uncertainty of treatment in the clinical practice, especially when moderate elevations above the upper limit of the reference range are considered (5< TSH <10 mIU/l). In this view, the study of association between subclinical hypothyroidism and possible molecular effectors, such as polymorphisms in the TSH receptor (TSHR) gene, could be interesting. In this paper, we analyzed the TSHR gene polymorphisms in 103 hyperthyrotropinemic infants. A control group of 120 newborns of the same ethnic background was used to evaluate the frequencies of each polymorphism in the population. We found a statistically significant difference in the allelic frequency of the P52T polymorphism, being that the T variant was more represented in the control group (p=0.03). However, no significant results have been obtained in the analysis of the association between genotypes and serum TSH levels. In conclusion, we analyzed 7 polymorphic variants of TSHR gene in subclinical hypothyroidism. The only significant result refers to the allelic frequency of A in the P52T polymorphism, which is statistically reduced when compared with that of a control group.     

Lack of association between interleukin 23 receptor gene polymorphisms and rheumatoid arthritis susceptibility

The recent discovery of interleukin 23 (IL-23), its receptor, and the underlying signal transduction pathway has improved our understanding of cellular immunity. Several studies suggest that IL-23 is an essential promoter of chronic joint inflammation. In this report, we assess the possible association of interleukin 23 receptor (IL23R) polymorphisms and haplotypes with rheumatoid arthritis (RA). The study was conducted on 1,204 RA patients and 979 healthy controls. Seven polymorphisms were selected from previous IBD reports. The seven SNPs (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032 and rs1495965) were genotyped using the TaqMan assay. Comparison of RA and control subjects revealed no statistically significant differences in the distribution of the IL23R genotypes and haplotypes. Our results clearly indicate that IL23R gene polymorphisms do not play a significant role in susceptibility to RA in the Korean population. Accordingly, we conclude that IL23R gene polymorphisms cannot be applied as an effective genetic marker for RA susceptibility.     

Lack of association between polymorphisms of thrombogenic genes and disease susceptibility in rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with increased mortality due to cardiovascular disease (CVD). Abnormalities in coagulation have been linked with CVD in general and RA population. The aim of our study is to determine whether particular single nucleotide polymorphisms thought to be involved in the regulation of coagulation are over-represented in patients with RA compared to controls. We compared the frequency of atherothrombotic polymorphisms (Factor V Leiden, fibrinogen G455A, prothrombin G20210A and plasminogen activator inhibitor 4G5G) in 322 RA patients [231 females, mean age 61.5 ± 12, median disease duration 10 years (IQR = 14)] with 441 local controls. No significant differences were observed in genotype or allele frequencies either between RA and controls or between the disease subgroups studied. Whereas these polymorphisms may be of importance at the level of individual patients, they are unlikely to be clinically important on a population basis.     

Lack of an association between polymorphisms of the T-cell receptor alpha-chain and ulcerative colitis

It was recently reported that, using a T-cell receptor alpha-chain complementary deoxyribonucleic acid probe (pGA5) and the restriction enzyme Eco RV, a 10-kilobase restriction fragment length polymorphism was detected significantly more frequently in patients with ulcerative colitis than in patients with Crohn's disease and controls. This finding had great potential importance, as no gene marker had previously been found to be strongly associated with inflammatory bowel disease. Therefore, an attempt to confirm it in an independent laboratory and patient population has been made in this study. Thirty patients with ulcerative colitis, 30 with Crohn's disease, and 30 healthy control subjects were studied using the Eco RV restriction enzyme and the same T-cell receptor alpha-chain complementary deoxyribonucleic acid probe as was used in the prior report. No 10-kilobase fragment or any other polymorphism using this probe-enzyme combination was found in any of the individuals studied. Polymorphisms were observed with the restriction enzyme Bgl II, but their frequencies did not distinguish between cases and controls. Therefore, there is as yet no evidence for an association between polymorphisms of Eco RV-digested genomic DNA probed with the pGA5 T-cell receptor alpha-chain complementary deoxyribonucleic acid and the predisposition to inflammatory bowel disease.     

Genomic association analysis identifies multiple loci influencing antihypertensive response to an angiotensin II receptor blocker

To identify genes influencing blood pressure response to an angiotensin II receptor blocker, single nucleotide polymorphisms identified by genome-wide association analysis of the response to candesartan were validated by opposite direction associations with the response to a thiazide diuretic, hydrochlorothiazide. We sampled 198 white and 193 blacks with primary hypertension from opposite tertiles of the race-sex-specific distributions of age-adjusted diastolic blood pressure response to candesartan. There were 285 polymorphisms associated with the response to candesartan at P<10(-4) in whites. A total of 273 of the 285 polymorphisms, which were available for analysis in a separate sample of 196 whites, validated for opposite direction associations with the response to hydrochlorothiazide (Fisher χ(2) 1-sided P=0.02). Among the 273 polymorphisms, those in the chromosome 11q21 region were the most significantly associated with response to candesartan in whites (eg, rs11020821 near FUT4, P=8.98 × 10(-7)), had the strongest opposite direction associations with response to hydrochlorothiazide (eg, rs3758785 in GPR83, P=7.10 × 10(-3)), and had the same direction associations with response to candesartan in the 193 blacks (eg, rs16924603 near FUT4, P=1.52 × 10(-2)). Also notable among the 273 polymorphisms was rs11649420 on chromosome 16 in the amiloride-sensitive sodium channel subunit SCNN1G involved in mediating renal sodium reabsorption and maintaining blood pressure when the renin-angiotensin system is inhibited by candesartan. These results support the use of genomewide association analyses to identify novel genes predictive of opposite direction associations with blood pressure responses to inhibitors of the renin-angiotensin and renal sodium transport systems.     

Lack of an association between interleukin-12 receptor beta1 polymorphisms and tuberculosis in Koreans

BACKGROUND: The fact that only 10% of people infected with Mycobacterium tuberculosis develop clinical tuberculosis (TB) suggests the presence of genetic factors in the pathogenesis of TB. To date, a number of single nucleotide polymorphisms (SNPs) in several candidate genes have been proposed as genetic risk factors of TB; however, reports are conflicting. OBJECTIVES: We investigated whether SNPs in the interleukin (IL)-12 receptor beta1 gene are associated with TB in Koreans. METHODS: One hundred and fifteen patients with bacteriologically or pathologically confirmed TB and 151 healthy anonymous blood donors were enrolled. The genotypes of 5 SNPs on IL-12 receptor beta1 gene, +705A/G (Q214R), +1158T/C (M365T), +1196G/C (G378R), +1637G/A (A525T) and +1664 C/T (P534S), were determined by PCR-RFLP. RESULTS: No difference was observed between TB patients and controls in terms of the genotype frequencies of the 5 SNPs of the IL-12 receptor beta1 gene or of their haplotypes. CONCLUSIONS: In view of the finding that these SNPs have been reported to be associated with TB in the Japanese and Moroccan populations, our results may reflect racial differences in genetic susceptibility to TB.     

Lack of association between common polymorphisms in genes of the renin-angiotensin system and mortality after myocardial infarction

The insertion/deletion (I/D) polymorphism in the ACE gene and the A1166C polymorphism in the AT1R gene have been associated with left ventricular remodelling and prognosis after acute myocardial infarction (AMI). We investigated whether these genetic variants associate with impaired left ventricular ejection fraction (LVEF) and increased risk for in-hospital mortality after AMI. Consecutive AMI patients were recruited on admission and were genotyped for the above-mentioned polymorphisms. The frequency of the studied genotypes did not differ significantly between deceased patients and those who survived. The LVEF did not differ among patients with or without the DD genotype (45 +/- 10 vs. 45 +/- 10%, p = 0.892) or the CC genotype (45 +/- 10 vs. 46 +/- 10%, p = 0.859). These data question the role of the studied genotypes in the pathogenesis of AMI and do not support the previously supported hypothesis that these genotypes influence prognosis after AMI.     

Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study

OBJECTIVES: The study investigated the potential role of eight candidate genes in the susceptibility to idiopathic dilated cardiomyopathy (IDC). BACKGROUND: Idiopathic dilated cardiomyopathy has a familial origin in 20% to 25% of cases, and several genetic loci have been identified in rare monogenic forms of the disease. These findings led to the hypothesis that genetic factors might also be involved in sporadic forms of the disease. In complex diseases that do not exhibit a clear pattern of familial aggregation, the candidate gene approach is a strategy widely used to identify susceptibility genes. All genes coding for proteins involved in biochemical or physiological abnormalities of cardiac function are potential candidates for IDC. METHODS: We studied 433 patients with IDC and 401 gender- and age-matched controls. Polymorphisms investigated were the I/D polymorphism of the angiotensin I-converting enzyme (ACE) gene, the T174M and M235T polymorphisms of the angiotensinogen (AGT) gene, the A-153G and A+39C polymorphisms of the angiotensin-II type 1 receptor (AGTR1) gene, the T-344C polymorphism of the aldosterone synthase (CYP11B2) gene, the G-308A polymorphism of the tumor necrosis factor-alpha (TNF) gene, the R25P polymorphism of the transforming growth factor beta1 (TGFB1) gene, the G+11/in23T polymorphism of the endothelial nitric oxide synthase (NOS3) gene and the C-1563T polymorphism of the brain natriuretic peptide (BNP) gene. RESULTS: None of the polymorphisms were significantly associated with the risk or the severity of the disease. CONCLUSIONS: We did not find evidence for an involvement of any of the 10 investigated polymorphisms in the susceptibility to IDC.     

Endothelin-1 augments pressor response to angiotensin II infusion in rats.

To assess possible roles of endothelin in the regulation of blood pressure, we studied effects of a subpressor dose of endothelin-1 (3 micrograms/kg/day) on chronic blood pressure responses to infusion of angiotensin II and norepinephrine in rats. Rats were infused with angiotensin II at a subpressor dose (400 micrograms/kg/day i.p.) or with norepinephrine at a subpressor dose (360 micrograms/kg/day i.p.) for 6 days. Systolic blood pressure was significantly elevated during combined infusion of endothelin-1 and angiotensin II, whereas endothelin-1 alone or angiotensin II alone failed to induce any significant changes in systolic blood pressure compared with vehicle alone. This effect was sustained for the whole experimental period and was not associated with any significant changes in body weight, fluid intake, urine volume, or urinary electrolyte excretion. In contrast, combined infusion of endothelin-1 and norepinephrine failed to elevate systolic blood pressure, and no significant difference in systolic blood pressure was observed for the whole experimental period among the four groups of rats with endothelin-1 in combination with norepinephrine, endothelin-1 alone, norepinephrine alone, and vehicle alone. The present results indicate that angiotensin II and endothelin-1, but not norepinephrine and endothelin-1, work synergistically to raise the blood pressure and also suggest the possibility that endothelin-1 may modulate blood pressure control.     

Lack of association between connexin40 polymorphisms and coronary artery disease

BackgroundMacrocytosis, as a qualitative abnormality of erythrocytes, has not drawn attention as a prognostic indicator after PCI, while anemia, as a quantitative abnormality of erythrocytes, has been recognized as a predictor of adverse outcomes. The aim of this study was to perform prognostic risk stratification of patients after PCI based on the presence or absence of macrocytosis.MethodsThe clinical records of 941 consecutive patients who underwent PCI at a single institution were retrospectively reviewed. The prognostic implication of macrocytosis was evaluated by univariate and multivariate Cox's proportional hazard regression analysis.ResultsThere were 130 (13.8%) patients with macrocytosis. A significantly higher all-cause and cardiac mortality, as well as incidence of composite adverse events were observed in the Macrocytic group. Kaplan–Meier analysis also showed a significantly poorer overall survival in patients with macrocytosis. Even after exclusion of anemic patients, this tendency was still observed. Furthermore, macrocytosis was significantly and independently associated with adverse outcomes after PCI (aHR of cardiac death: 3.45, 95%CI: 1.22–9.80, P = 0.019). Interestingly, fewer patients with macrocytosis were prescribed statins compared with those without it (33.8% vs. 47.1%, P = 0.005).ConclusionsThe results of the study indicate that measuring mean corpuscular volume (MCV) as a qualitative index of erythrocytes might be helpful for a prognostic risk stratification of patients subjected to PCI.     

Lack of association of angiotensin II type 1 receptor gene polymorphism with diabetic nephropathy in insulin-dependent diabetes mellitus

Several observations suggest that inherited factors are influential in the development of nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). Genetic components of the renin angiotensin system are possible candidate genes. The aim of this study was to determine the role of the hypertension associated angiotensin II type 1 receptor (AT1R) gene A¹¹⁶⁶C polymorphism in susceptibility to nephropathy in IDDM. We examined 264 Caucasoid patients with IDDM and overt nephropathy (as defined by persistent proteinuria in the absence of other causes, hypertension and retinopathy), 136 IDDM patients with long duration of diabetes and no nephropathy (LDNN group), 200 recently diagnosed IDDM patients (Sporadic Diabetic group), and 212 non-diabetic subjects. The AT1R gene polymorphism was assessed using the polymerase chain reaction and restriction isotyping. Genotype frequencies did not differ significantly between the sporadic diabetic group and the nephropathy group (p = 0.245), nor between the long duration non-nephropathy group and the nephropathy group (p = 0.250). Allele frequencies were not significantly different between the three groups (p = 0.753). We conclude that there is no significant association between the hypertension associated AT1R gene polymorphism and diabetic nephropathy in patients with IDDM in the UK. © 1997 John Wiley & Sons, Ltd.     

Lack of association between androgen receptor polymorphisms and bone mineral density or physical function in older men

Individuals whose androgen receptors have short polyglutamine tracts (resulting from CAG repeats) may have greater receptor signaling activity of the androgen receptor. We evaluated the association between bone mineral density (BMD) and CAG repeats in 91 older men with normal (control) and low femoral neck (EN) BMD (OP) or a history of femoral fracture (FX). Bioavailable testosterone (BioT) and physical performance, including composite score (EPESE) and physical activity (PASE), were also measured. Comparing FX, OP, and control subjects, we observed BMD Tscores of -2.16 +/- 1.08, -2.26 +/- 0.74, and -0.20 +/- 0.40 (p < 0.001); CAG repeat lengths of 21.9 +/- 2.7, 22.5 +/- 2.4, and 22.3 +/- 2.9 (p = 0.63); BioT levels of 2.29 +/- 1.25, 2.19 +/- 1.11, and 3.99 +/- 1.25 nmol/L (p < 0.001); EPESE scores of 8.0 +/- 3.0, 9.7 +/- 2.0, and 11.3 +/- 0.9 (p < 0.001); and PASE scores of 91 +/- 66, 122 +/- 66, and 200 +/- 55 (p < 0.001), respectively. There were no significant correlations between CAG repeats and BioT or physical performance. Men with osteoporosis or fracture had lower BioT, physical performance, and physical activity than controls. This study found no association between CA G repeats and FN BMD in older men with normal or low BMD or FX.     

Association between angiotensin II type 1 receptor polymorphisms and the occurrence of nonalcoholic fatty liver disease

Background: Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver injury in many countries. Genetic factors are important for the development of NAFLD, as well as environmental factors. Recently an angiotensin II type 1 receptor (AGTR1) has been recognized as important in the aetiology of fibrosis in the liver. Objective: In this study we investigated the association between angiotensin II type 1 receptor gene polymorphism (ATGR1) and NAFLD. Methods: One hundred and sixty‐seven NAFLD patients [106 with nonalcoholic steatohepatitis (NASH) and 61 with simple steatosis] with a positive diagnosis by liver biopsy and 435 healthy control subjects were recruited in this study. Results: We investigated 12 single nucleotide polymorphisms (SNPs) of the ATGR1 gene, among which rs3772622 showed the lowest P‐value of allele frequency model (P=0.0000012) with an odds ratio (95% confidence interval) of 1.95 (1.49–2.55). Five SNPs (rs3772622, rs3772633, rs2276736, rs3772630 and rs3772627) were significantly associated with NAFLD, even when the most conservative Bonferroni's correction was applied. Linkage disequilibrium analysis revealed that SNP rs3772622 and another four SNPs (rs3772633, rs2276736, rs3772630 and rs3772627) were in the same block. We investigated the association between rs3772622 genotypes and the fibrosis index. The results of the analysis revealed an additive increase of the fibrosis index in the patients with the A allele of rs3772622. Conclusions: This is the first report to demonstrate the genetic variations in ATGR1 that may influence the risk of NAFLD and liver fibrosis in NAFLD.     

Plasma aldosterone response to upright posture and angiotensin II infusion in aldosterone-producing adenoma.

Nineteen patients with primary aldosteronism due to surgically confirmed aldosterone-producing adenoma (APA) were examined to evaluate the response of aldosterone to upright posture and angiotensin II infusion. Upright posture reportedly decreases the plasma aldosterone concentration (PAC) in APA but raises it in idiopathic hyperaldosteronism. However, our findings showed the opposite result, in that the upright posture did not change or raised PAC in 15 of 19 cases (79%). Angiotensin II was infused i.v. at doses from 0.5-2 ng/min.kg body weight in six patients in whom the upright posture raised PAC, but did not raise PAC in all cases. This result supports the assumption that APA is functionally insensitive to angiotensin II. A concomitant rise of ACTH, pretreatment with calcium channel blockade, and other modulating factors may be involved in this PAC rise. Whatever the reason, such a high frequency of patients with increased PAC in APA raises some question about the clinical value of the upright posture test. We believe, then, there is reason to check any interpretation concerning increased PAC in the case of the upright posture test in distinguishing between APA and idiopathic hyperaldosteronism.