ACE-Inhibition Benefit on Lung Function in Heart Failure is Modulated by ACE Insertion/Deletion Polymorphism

Purpose

The benefit of angiotensin converting enzyme (ACE) inhibition in chronic heart failure (HF) is partially due to its effects on pulmonary function and particularly on lung diffusion, the latter being counteracted by acetylsalicylic acid (ASA). Tissue ACE activity is largely determined by an insertion/deletion (I/D) polymorphism resulting in three possible genotypes (DD, ID and II). It is not clear if ACE inhibitor therapy could exert different effects in these genotypes. The aim of the study was to understand whether I/D polymorphism interferes with ACE inhibitor’s protection of the lungs in HF during acute fluid overload.

Methods

100 HF patients (left ventricular ejection fraction ≤40 %) in stable clinical conditions, treated with enalapril but without ASA performed pulmonary function tests including lung diffusion (DLco) and its subcomponents, membrane diffusion (Dm) and capillary volume (Vcap), and a cardiopulmonary exercise test before and immediately after rapid infusion of 500 cc saline.

Results

ACE I/D genotype prevalence was: DD = 28, ID =55 and II = 17 cases. No significant differences in major pulmonary function and exercise parameters were observed before saline infusion among ACE genotypes. After fluid challenge, DD patients presented a higher DLco and Dm reduction than ID and II (DLco ?2.3 ± 1.3 vs. -0.8 ± 1.9 and ?0.6 ± 1 mL/mmHg/min, p < 0.0001 and p < 0.01; Dm ?7 ± 5 vs. -3.2 ± 7.4 and ?1.3 ± 5 mL/mmHg/min, p < 0.05, respectively) and a higher increase in VE/VCO₂ slope than II (1.8 ± 1.9 vs. -0.8 ± 2.3, p = 0.01).

Conclusions

ACE DD genotype is associated with higher vulnerability of the alveolar-capillary membrane to acute fluid overload in HF patients treated with ACE inhibitors.

     

Pulmonary function testing and chest tomography in patients with acromegaly

Background

Despite the gradual improvement in treatment procedures and cure rates of acromegaly, a steady increase in the mortality rate due to respiratory disease has been documented in recent decades. In this study, our objectives were to describe the abnormalities in lung structure and function that occur in acromegalic patients and to correlate these changes with hormonal levels.

Methods

This cross-sectional study included 20 acromegalic patients and 20 age-and height-matched control subjects, all non-smokers. All subjects underwent spirometry, whole body plethysmography, carbon monoxide diffusing capacity, and respiratory muscle strength. Acromegalic patients also performed high-resolution computed tomography (HRCT).

Results

Most patients were female (65%), with a mean age of 52.5?±?13 years. Acromegalic patients showed lower values of maximum expiratory pressure (55.9?±?17.1 vs. 103.7?±?19.2%; p < 0.001) and maximum inspiratory pressure (71.4?±?27.8 vs. 85.3?±?24.1%; p = 0.005) compared to control subjects. The values of forced vital capacity (107.1?±?15.9 vs. 98.9?±?21.4%; p = 0.028), total lung capacity – TLC (107.3?±?12.9 vs. 93.7?±?7.60%; p = 0.002), residual volume (114.1?±?22.7 vs. 90.0?±?14.6%; p < 0.001), and airways’ resistance (3.82 vs. 2.31 cmH₂O/L/s; p = 0.039) were greater in acromegalic patients than in control subjects. The difference between the TLC measured by plethysmography and the V_A (alveolar volume) measured during the DL_CO maneuver was higher in acromegalic patients than in control subjects (0.69?±?0.46 vs. 0.19?±?0.61 L; p = 0.021). The main findings in HRCT in acromegalic patients were air trapping, airway calcification and bronchiectasis, which were observed in 60%, 40% and 35% of cases, respectively. There was no significant correlation between the levels of growth hormone and insulin-like growth factor I, the lung function and the air trapping.

Conclusions

Acromegalic patients show changes consistent with the involvement of the small airways and ventilation inhomogeneity, both in terms of lung function and structure. However, air trapping cannot be explained either by hormone levels or changes in lung function.

     

Carotid artery protrusion and dehiscence in patients with acromegaly

Purpose

Acromegaly is a systemic disease which causes multiple bony alterations. Some authors reported that acromegalic patients have risk factors for an intraoperative vascular injury due to the specific anatomical features of their sphenoid sinus. The objective of our study was to analyze the anatomic characteristics of sphenoid sinus in acromegalic patients compared with controls, by evaluation of computed tomography (CT) findings.

Methods

We examined 45 acromegalic (acromegaly group) and 45 non-acromegalic patients (control group) with pituitary adenomas who were matched for sex, age, height, tumor size, and cavernous sinus invasion (Knosp grade). Preoperative CT of the pituitary region including the sphenoid sinus was used to evaluate the following anatomic characteristics: type of sphenoid sinus (sellar or pre-sellar/conchal); intrasphenoid septa (non/single or multiple); carotid artery protrusion; carotid artery dehiscence; intercarotid distance.

Results

Sixteen acromegalic patients (35.5 %) and 6 controls (13.3 %) had carotid artery protrusion. Additionally, 10 acromegalic patients (22.2 %) and 3 controls (6.6 %) had carotid artery dehiscence. Carotid artery protrusion and dehiscence were more frequent in the acromegaly group than in control group (p = 0.013 and 0.035, respectively). Other anatomic characteristics (type of sphenoid sinus, intrasphenoid septa, and intracarotid distance) showed no significant differences between acromegaly and control groups.

Conclusions

Our study suggests that carotid artery protrusion and dehiscence occur more frequently among acromegalic patients, compared with non-acromegalic patients. It is important for surgeons to be aware of these anatomic variations to avoid vital complications, such as carotid injuries, during surgery.

     

Progression of kidney disease in type 2 diabetes – beyond blood pressure control: an observational study

Background

Essential hypertension is a common, polygenic, complex disorder resulting from interaction of several genes with each other and with environmental factors such as obesity, dietary salt intake, and alcohol consumption. Since the underlying genetic pathways remain elusive, currently most studies focus on the genes coding for proteins that regulate blood pressure as their physiological role makes them prime suspects. The present study examines how polymorphisms of the insertion/deletion (I/D) ACE and M235T AGT genes account for presence and severity of hypertension, and embeds the data in a meta-analysis of relevant studies.

Methods

The I/D polymorphisms of the ACE and M235T polymorphisms of the AGT genes were determined by RFLP (restriction fragment length polymorphism) and restriction analysis in 638 hypertensive patients and 720 normotensive local blood donors in Weisswasser, Germany. Severity of hypertension was estimated by the number of antihypertensive drugs used.

Results

No difference was observed in the allele frequencies and genotype distributions of ACE gene polymorphisms between the two groups, whereas AGT TT homozygotes were more frequent in controls (4.6% vs. 2.7%, P =.08). This became significant (p = 0.035) in women only. AGT TT genotype was associated with a 48% decrease in the risk of having hypertension (odds ratio: 0.52; 95% CI, 0.28 to 0.96), and this risk decreased more significantly in women (odds ratio: 0.28; 95% CI, 0.1 to 0.78). The meta-analysis showed a pooled odds ratio for hypertension of 1.21 (TT vs. MM, 95% CI: 1.11 to 1.32) in Caucasians. No correlation was found between severity of hypertension and a specific genotype.

Conclusion

The ACE I/D polymorphism does not contribute to the presence and severity of essential hypertension, while the AGT M235T TT genotype confers a significantly decreased risk for the development of hypertension in the population studied here. This contrasts to the findings of meta-analyses, whereby the T allele is associated with increased risk for hypertension.     

Association of adiponectin gene polymorphisms and additional gene-gene interaction with nonalcoholic fatty liver disease in the Chinese Han population

Purpose

To investigate the association between the single nucleotide polymorphisms (SNPs) of the adiponectin gene and nonalcoholic fatty liver disease (NAFLD) as well as the impact of the interaction of multiple SNPs on NAFLD risk, based on a Chinese population study.

Methods

A total of 612 subjects (411 male, 201 female) were selected, including 302 NAFLD patients and 310 controls. Three SNPs were selected for genotyping in the case-control study: rs266729, rs822393, and rs1501299. A logistic regression model was used to examine the interaction between the SNPs and NAFLD. The odds ratio (OR) and 95 % confidence interval (95 % CI) were calculated. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the interaction among SNPs.

Results

Logistic analysis showed a significant association between genotypes of variants in rs266729 and rs822393 and increased NAFLD risk. The carriers of the homozygous mutant of two SNP polymorphisms revealed increased NAFLD risk compared to those with wild-type homozygotes; ORs (95 % CI) were 1.31 (1.14–1.81) (p = 0.001) and 1.18 (1.05–1.71) (p = 0.005), respectively. There was a significant two-locus model (p = 0.0010) involving rs266729 and rs822393, indicating a potential gene-gene interaction between rs266729 and rs822393. Overall, the two-locus models had a cross-validation consistency of 10 and testing accuracy of 62.17 %. Subjects with the CG or GG and CT or TT genotype have the highest NAFLD risk compared to subjects with the CC-CC genotype; the OR (95 % CI) was 2.52 (1.31–3.82), p < 0.001, after covariate adjustment.

Conclusions

Our results support an important association of the rs266729 (?11377 G/C) and rs822393 (?4522 C/T) polymorphism with increased risk of NAFLD. The interaction analysis showed a combined effect of rs266729 and rs822393 on NAFLD.

     

Cross-sectional prevalence of pancreatic cystic lesions in patients with acromegaly,a single-center experience

Purpose

Acromegaly is a disease associated with an increased risk for several kinds of neoplasms including colon and thyroid cancer. Although the association between acromegaly and pancreatic neoplasms has not been elucidated, it has recently been reported that GNAS gene mutations were found in 58% of intraductal papillary mucinous neoplasms (IPMNs), which are representative pancreatic cystic lesions, suggesting a link between IPMNs and acromegaly. To assess the prevalence of pancreatic cystic lesions in patients with acromegaly, we performed a retrospective cross-sectional single institute study.

Methods

Thirty consecutive acromegalic patients (20 females and 10 males; mean age, 60.9?±?11.9 years) who underwent abdominal contrast-enhanced computed tomography or magnetic resonance imaging between 2007 and 2015 at Kobe University Hospital were recruited. We also analyzed the relationship between presence of pancreatic cystic lesions and somatic GNAS mutations in pituitary tumors.

Results

Seventeen of 30 (56.7%) patients studied had pancreatic cystic lesions. Nine of 17 patients (52.9%) were diagnosed with IPMNs based on imaging findings. These results suggest that the prevalence of IPMNs may be higher in acromegalic patients in acromegalic patients than historically observed in control patients (up to 13.5%). In patients with pancreatic cystic lesions, the mean patient age was higher and the duration of disease was longer than in those without pancreatic cystic lesions (67.0?±?2.3 vs. 53.0?±?2.7 years, p?<?0.001, 15.5?±?2.4 vs. 7.3?±?2.8 years, p?=?0.04). There were no differences in serum growth hormone levels or insulin-like growth factor standard deviation scores between these two groups (21.3?±?6.4 vs. 23.0?±?7.4 ng/ml, p?=?0.86, 6.6?±?0.5 vs. 8.0?±?0.6, p?=?0.70). Neither the presence of somatic GNAS mutation in a pituitary tumor nor low signal intensity of the tumor in T2 weighted magnetic resonance imaging was associated with the presence of pancreatic cystic lesions.

Conclusions

These data demonstrate that old or long-suffering patients with acromegaly have a higher prevalence of pancreatic cystic lesions. Moreover, the prevalence of pancreatic cystic lesions may be increased in acromegalic patients.

     

IL-6 and MCP-1 genetic polymorphisms are predictive of decreased platelet counts caused by chemoradiotherapy in esophageal cancer

Background

A reliable marker of the sensitivity of esophageal cancer to chemoradiotherapy (CRT) as well as a personal biomarker predictive of adverse events during treatment has long been sought. The purpose of the present study was to test whether there is an association between interleukin-6 (IL-6) and/or monocyte chemoattractant protein-1 (MCP-1) polymorphisms and CRT-induced bone-marrow suppression––i.e., reductions in white blood cell and/or platelet counts.

Methods

The study participants were 103 Japanese patients treated with definitive or pre-operative CRT for squamous cell esophageal cancer at Akita University Hospital. The patients were divided into two groups, with or without adverse events during or up to 1 month after CRT.

Results

Patient backgrounds––i.e., white blood cell and platelet counts before CRT and doses of chemotherapy and irradiation––did not differ between groups. However, there was a significantly higher incidence of grade 2–4 platelet count reductions (<75,000/mm³) among patients carrying the IL-6 ?634C/G+G/G genotype than among those carrying the C/C genotype. Similarly, there was a significantly higher incidence of grade 2–4 platelet count reductions among patients carrying the MCP-1 ?2518G/G genotype than among those carrying the A/A+A/G genotype. Univariate and multivariate logistic regression models revealed that the IL-6 ?634C>G and MCP-1 ?2518A>G polymorphisms were significantly associated with grade 2–4 platelet count reductions following CRT.

Conclusion

These polymorphisms may thus be clinically relevant and should be taken into consideration when devising CRT regimens or treatment strategies for esophageal cancer.

     

Association between FTO gene polymorphisms and HDL cholesterol concentration may cause higher risk of cardiovascular disease in patients with acromegaly

Introduction

Cardiovascular diseases are main cause of morbidity and mortality in acromegaly. Polymorphisms of FTO gene are associated with obesity and increased risk of CVD (independently of BMI). Aim of this study was to investigate the allele frequencies of two FTO gene polymorphisms: rs9939609 and rs9930506 in patients with acromegaly and to examine the association of FTO gene polymorphisms with BMI and selected metabolic parameters.

Materials and methods

Identification of two single nucleotide polymorphisms of FTO gene was carried out in 51 patients with acromegaly using the minisequencing method.

Results

The risk-allele frequencies of rs9939609 and rs9930506 polymorphisms were 0.471 and 0.529, respectively and they were higher than in general European population. There is no association of FTO gene polymorphisms with BMI, glucose, total cholesterol, LDL cholesterol and triglyceride. The risk alleles were associated with decreased HDL cholesterol concentration. Homozygotes for the rs9939609-risk allele had 1.25-fold lower HDL cholesterol concentration than carriers of the TT genotype (p?=?0.0024). The estimated average decrease in HDL cholesterol concentration per risk allele for rs9930506 was 11.2%. Nevertheless, statistically significant differences were observed only between AG versus GG and AA versus GG genotypes. Homozygotes for the rs9930506-risk allele had 1.27-fold lower HDL cholesterol concentration than carriers of the AA genotype (p?=?0.007).

Conclusion

The risk-allele frequencies of studied polymorphisms in acromegaly were higher than in general European population. There is an association between FTO gene polymorphisms and HDL cholesterol concentration, suggesting FTO gene polymorphisms may be associated with higher CVD risk in patients with acromegaly.

     

Association Between Vitamin D Metabolism Gene Polymorphisms and Risk of Tunisian Adults’ Asthma

Introduction

Several studies have shown a strong correlation between the serum vitamin D level and asthma severity and deficits in lung function.

Objective

Study the relationship between vitamin D and the severity of asthma by targeting five SNPs of vitamin D metabolism gene pathway in a Tunisian adult asthmatics population.

Methods

Our case–control study includes 154 adult asthmatic patients and 154 healthy Tunisian subjects. We genotyped many variants in three human genes encoding key components of the vitamin D metabolism, CYP2R1, CYP27B1, GC. The GC gene rs4588 and rs7041 polymorphisms were analysed using the PCR-RFLP method, while rs10741657 and rs12794714 for CYP2R1 gene and rs10877012 of CYP27B1 gene were investigated using TaqMan PCR genotyping techniques.

Results

We found that the presence of at least one copy of the rs12794714 A, allele was associated with lower risk of developing asthma (OR 0.61). Further, the rs12794714 is a protector factor against asthma severity (OR 0.5). However, the presence of rs10877012 TG genotype is a risk factor related to asthma severity (OR 1.89). When we classified the population according to sex, our results showed that rs10877012 TT genotype was a risk factor for women subjects (OR 6.7). Moreover, the expression of TT genotype was associated with a higher risk of asthma in non-smoker patients (OR 7.13). We found a significant lower VD serum levels in asthmatics than controls but no impact of the polymorphisms on VD levels.

Conclusions

We found that rs12794714 and rs10877012 SNPs were associated with asthma risk.

     

Biochemical efficacy of long-acting lanreotide depot/Autogel in patients with acromegaly naïve to somatostatin-receptor ligands: analysis of three multicenter clinical trials

Purpose

In clinical research involving acromegalic patients naïve to somatostatin-receptor ligands (SRLs), 19 and 31% of those receiving the SRLs octreotide LAR and pasireotide LAR, respectively, achieved GH?<?2.5 ng/mL?+?normalized IGF-1 concentrations. The proportions achieving control appeared higher in the post-surgery compared with the de-novo setting with pasireotide, but more similar with octreotide. Using pooled data from multicenter clinical trials, we examined the biochemical efficacy of lanreotide depot/Autogel in similar settings.

Methods

Inclusion criteria: Ipsen-sponsored, 48–52-week trials in SRL-naïve acromegalic populations receiving lanreotide depot (60–120 mg); patients were included if de novo (no prior acromegaly treatment) or post-surgery (no medical treatment; radiotherapy allowed unless within previous 3 years). Efficacy endpoints included normalized IGF-1 levels and GH?<?2.5 ng/mL?+?normalized IGF-1 at study end/last value available. Analyses: all patients (analysis #1) and subset with baseline GH?>?5 ng/mL (analysis #2).

Results

Three studies were included. Analysis #1: normalized IGF-1 was achieved by 42% (71/171) of patients overall (post-surgery, 46% [21/46]; de-novo, 40% [50/125]); GH?<?2.5 ng/mL?+?normalized IGF-1 was achieved by 35% (59/171) (39% [18/46] and 33% [41/125], respectively). Analysis #2: normalized IGF-1 levels, 39% (46/118) (post-surgery, 40% [10/25]; de-novo, 39% [36/93]); GH?<?2.5 ng/mL?+?normalized IGF-1, 31% (36/118) (28% [7/25] and 31% [29/93], respectively).

Conclusion

In these pooled analyses of SRL-naïve patients receiving lanreotide depot, 39–42% achieved IGF-1 control and 31–35% achieved GH and IGF-1 control. Control rates within post-surgery cohorts did not differ markedly from those in corresponding de-novo cohorts.

     

Association between NAD(P)H oxidase p22phox gene variants and acute myocardial infarction in a Han Chinese population

Background

We investigated the association between five selected single-nucleotide polymorphisms (rs12933505, rs3180279, rs3794264, rs4673, rs1049255) in the NAD(P)H p22phox gene and acute myocardial infarction (AMI) as well as severity of coronary artery stenosis in a Han Chinese population.

Patients and methods

A total of 168 patients with AMI and 138 healthy controls were recruited. The TaqMan allelic discrimination assay was used to genotype five single-nucleotide polymorphisms.

Results

The frequency of the rs1049255 G allele was significantly lower in patients with AMI than in controls (p?=?0.022). Compared with subjects with an AA genotype, subjects with a GG or AG genotype had a lower risk of AMI [multivariate-adjusted odds ratio (OR), 0.53; 95?% CI, 0.29–0.95; p?=?0.031). Subjects with the GG and AG genotypes of rs1049255 showed a decreased susceptibility for triple-vessel disease (TVD) as compared with controls (multivariate-adjusted OR, 0.43; 95?% CI, 0.19–0.98; p?=?0.042). Multiple logistic regression analysis revealed that the rs1049255G variant was an independent protective factor for AMI/TVD.

Conclusion

The results suggest there is an association between the p22phox rs1049255 polymorphism with the prevalence of AMI and the severity of coronary artery stenosis in the Han Chinese population.

     

Familial aggregation of albuminuria and arterial hypertension in an Aboriginal Australian community and the contribution of variants in <Emphasis Type="Italic">ACE</Emphasis> and <Emphasis Type="Italic">TP53</Emphasis>

Background

Aboriginal Australians are at high risk of cardiovascular, metabolic and renal diseases, resulting in a marked reduction in life expectancy when compared to the rest of the Australian population. This is partly due to recognized environmental and lifestyle risk factors, but a contribution of genetic susceptibility is also likely.

Methods

Using results from a comprehensive survey of one community (N?=?1350 examined individuals), we have tested for familial aggregation of plasma glucose, arterial blood pressure, albuminuria (measured as urinary albumin to creatinine ratio, UACR) and estimated glomerular filtration rate (eGFR), and quantified the contribution of variation at four candidate genes (ACE; TP53; ENOS3; MTHFR).

Results

In the subsample of 357 individuals with complete genotype and phenotype data we showed that both UACR (h²?=?64%) and blood pressure (sBP h²?=?29%, dBP, h²?=?11%) were significantly heritable. The ACE insertion-deletion (P?=?0.0009) and TP53 codon72 polymorphisms (P?=?0.003) together contributed approximately 15% of the total heritability of UACR, with an effect of ACE genotype on BP also clearly evident.

Conclusions

While the effects of the ACE insertion-deletion on risk of renal disease (especially in the setting of diabetes) are well recognized, this is only the second study to implicate p53 genotype as a risk factor for albuminuria - the other being an earlier study we performed in a different Aboriginal community (McDonald et al., J Am Soc Nephrol 13: 677-83, 2002). We conclude that there are significant genetic contributions to the high prevalence of chronic diseases observed in this population.

     

CCL4 is the only predictor for non-responder in GT-1 CHC patients with favorable IL28B genotype when treated with PegIFN/RBV

Background

Chemokines/cytokines play important roles in the pathogenesis of chronic hepatitis C (CHC). However, their clinical characteristics and implications in treatment responses to pegylated interferon plus ribavirin treatment (PegIFN/RBV) have not been fully illustrated yet. In this study, we intended to investigate the possible predictability of serum chemokines/cytokines on the treatment response in Taiwanese of CHC, genotype-1 (GT-1).

Methods

60 Patients with GT-1 CHC infection who had been treated with PegIFN/RBV were enrolled, including 27 (45%) with sustained virological response (SVR), 11 (18%) with relapse after 48 weeks of treatment and 22 (37%) non-response (NR). Clinical parameters, seven chemokines/cytokines, CCL3, CCL4, CXCL9, CXCL10, CXCL11, IL-10 and IFN-γ, and genotypes of rs12979860, the single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) were analyzed for their relationship to treatment response.

Results

Baseline serum levels of CXCL10, CXCL11, CCL3 and CCL4 were significantly higher in NR group while comparing with non-NR group. (CXCL10: p =?0.001; CXCL11: p <?0.001; CCL3: p =?0.006; CCL4: p =?0.005). However, only rs12979860 CC genotype was the independent factors for NR in GT-1 CHC infection (OR, 8.985; p =?0.008). In addition, baseline serum level of CCL4 was found to be the only independent factor for NR in GT-1 CHC patients with favorable IL28B genotype (OR, 1.134; p =?0.039).

Conclusions

IL28B genotype is the predictor for NR in GT-1 CHC patients treated with PegIFN/RBV, while baseline serum level of CCL4 is the only predictor for NR in GT-1 CHC patients with favorable IL28B genotype.

     

A Comparison of Health Plan- and Provider-Delivered Chronic Care Management Models on Patient Clinical Outcomes

BACKGROUND

The real world implementation of chronic care management model varies greatly. One aspect of this variation is the delivery mode. Two contrasting strategies include provider-delivered care management (PDCM) and health plan-delivered care management (HPDCM).

OBJECTIVE

We aimed to compare the effectiveness of PDCM vs. HPDCM on improving clinical outcomes for patients with chronic diseases.

DESIGN

We used a quasi-experimental two-group pre-post design using the difference-in-differences method.

PATIENTS

Commercially insured patients, with any of the five chronic diseases—congestive heart failure, chronic obstructive pulmonary disease, coronary heart disease, diabetes, or asthma, who were outreached to and engaged in either PDCM or HPDCM were included in the study.

MAIN MEASURES

Outreached patients were those who received an attempted or actual contact for enrollment in care management; and engaged patients were those who had one or more care management sessions/encounters with a care manager. Effectiveness measures included blood pressure, low density lipoprotein (LDL), weight loss, and hemoglobin A1c (for diabetic patients only). Primary endpoints were evaluated in the first year of follow-up.

KEY RESULTS

A total of 4,000 patients were clustered in 165 practices (31 in PDCM and 134 in HPDCM). The PDCM approach demonstrated a statistically significant improvement in the proportion of outreached patients whose LDL was under control: the proportion of patients with LDL?<?100 mg/dL increased by 3 % for the PDCM group (95 % CI: 1 % to 6 %) and 1 % for the HPDCM group (95 % CI: ?2 % to 5 %). However, the 2 % difference in these improvements was not statistically significant (95 % CI: ?2 % to 6 %). The HPDCM approach showed 3 % [95 % CI: 2 % to 6 %] improvement in overall diabetes care among outreached patients and significant reduction in obesity rates compared to PDCM (4 %, 95 % CI: 0.3 % to 8 %).

CONCLUSIONS

Both care management delivery modes may be viable options for improving care for patients with chronic diseases. In this commercially insured population, neither PDCM nor HPDCM resulted in substantial improvement in patients’ clinical indicators in the first year. Different care management strategies within the provider-delivered programs need further investigation.

     

Association study of the miRNA-binding site polymorphisms of <Emphasis Type="Italic">CDKN2A/B</Emphasis> genes with gestational diabetes mellitus susceptibility

Aims

Gestational diabetes mellitus (GDM) is a complex disease induced by a combination of genetic factors and environmental exposures. Growing evidence suggests that common single nucleotide polymorphisms within miRNA-binding sites (miR-binding SNPs) contribute to the development of various diseases. However, the roles of miR-binding SNPs in GDM have not been fully elucidated. The CDKN2A/B genes have been identified as two of the strongest genetic determinants for diabetes risk. The aim of the study was to first investigate the associations between miR-binding SNPs of CDKN2A/B, GDM susceptibility, and quantitative metabolism traits.

Methods

Three miR-binding SNPs of CDKN2A/B gene (rs1063192, rs3217992, and rs3088440) were selected and genotyped using TaqMan allelic discrimination assays in 839 cases of GDM and 900 controls.

Results

The CC genotype of CDKN2B rs1063192, which is located in the hsa-miR-323b-5p binding site, was significantly associated with GDM [OR 1.418 (1.143, 1.908); p = 0.003]. The C allele of rs1063192 occurred with significantly higher frequency in GDM [OR 1.22 (1.03, 1.44); p = 0.021]. The rs1063192 genotype CC exhibited increased glucose levels at 1 h and 3 h, as well as higher insulin levels at 3 h during an OGTT compared with the control TT genotype (p < 0.05). We also found that the rs1063192 CC genotype was associated with lower total cholesterol and LDL cholesterol levels (p < 0.05).

Conclusions

The CC genotype of CDKN2B rs1063192 in the hsa-miR-323b-5p binding site increased the risk of GDM in pregnant Chinese Han women. Importantly, our study provides evidence that miR-binding SNPs are a novel source of GDM susceptibility loci.

     

PNPLA3 Gene Polymorphisms in HCV/HIV-Coinfected Individuals

Background and Aims

The patatin-like phospholipase domain-containing 3 (PNPLA3) gene has been associated with the development of alcoholic and nonalcoholic steatohepatitis. Using a newly developed and validated assay for PNPLA3, we explored the prevalence of gene polymorphisms in a cohort of HCV/HIV-coinfected individuals to determine whether there was an association with insulin resistance or hepatic fibrosis.

Methods

A high-resolution melting point (HRM) assay was developed and validated. The assay was used to evaluate samples obtained in the context of a clinical trial performed at ACTG sites across the USA in HIV-infected patients. Clinical features and treatment outcomes were assessed in relation to the PNPLA3 genotype.

Results

The HRM methodology demonstrated 100% concordance with results obtained by Sanger sequencing. Among 241 participants tested, 66.0% had the wild-type allele (CC) and the remainder had the aberrant PNPLA3 gene polymorphism in the homozygotic (GG) or heterozygotic (CG) form. Race and ethnicity were associated with PNPLA3 genotype but fibrosis stage, Homeostatic Model Assessment of Insulin Resistance, and HCV treatment outcome were not.

Conclusion

The HRM method is an effective, rapid technique for characterizing PNPLA3 genotype. In those with HCV/HIV infection, nearly 40% carry gene polymorphisms associated with the development of NASH or ASH. Prospective studies should focus on this group to determine whether they represent a subset of HIV-infected persons at increased risk of fibrotic progression.

     

Preclinical markers of atherosclerosis in acromegaly: a systematic review and meta-analysis

Objective

Multiple studies investigated preclinical markers of peripheral vascular damage in acromegaly (ACRO) reporting discordant results. The aim of this study was to run a meta-analysis to examine whether intima media thickness (IMT), flow mediated dilation (FMD) and arterial pulse wave velocity (PWV) are affected in acromegalic patients and to assess the impact of effective treatment of growth hormone excess on these outcomes.

Study selection

Twenty-seven studies comparing ACRO vs control (CON) populations and active (ACT) vs inactive (INACT) ACRO were included in the meta-analysis.

Data synthesis

ACRO compared to CON have higher IMT (ES?=?0.83, 95% C.I. 0.35–1.30), p?=?0.001, impaired FMD (ES?=???1.59, 95% C.I. ??2.33 to ??0.85, p?<?0.0001) and higher PWV (ES?=?0.76 95% C.I. 0.37–1.16, p?=?0.0001). When patients with ACT vs INACT disease were considered IMT was higher (ES?=?0.43, 95% C.I. 0.02–0.84, p?=?0.041) and FMD was impaired (ES?=???0.66, 95% C.I. ??1.28 to 0.04, p?=?0.038) in ACT patients. Meta-regression analysis of studies comparing IMT in ACT vs INACT acromegalic patients showed a significant and inverse association between the effect size and the percent of hypertensive (p?=?0.025) and diabetic (p?=?0.041) patients.

Conclusions

IMT, FMD and arterial stiffness are impaired in acromegaly showing that these patients may be at increased risk of atherosclerosis. In patients with active disease these preclinical markers of atherosclerosis are worse compared to patients with inactive disease but the role of diabetes and hypertension is prevailing on growth hormone excess.

     

Efficacy and safety of sofosbuvir-based regimens in chronic hepatitis C patients on dialysis

Introduction

Patients with end-stage renal disease (ESRD) have poor treatment tolerance and outcome to interferon-based regimens. Sofosbuvir-based regimens have improved treatment success in chronic hepatitis C. There is limited data in ESRD patients as sofosbuvir is excreted by the kidney. Several small studies have shown good results.

Methods

Sixteen consecutive patients of ESRD (on dialysis) and chronic hepatitis C were treated with sofosbuvir-based regimens as they were prospective kidney transplantation recipients, at a tertiary care center in north India. Sofosbuvir was given 400 mg on alternate days. Data is shown as number, mean (SD), and median (range).

Results

Sixteen patients (12 males) aged 45±12 years received sofosbuvir-based treatment. These patients were on hemodialysis from 10 (2–48) months. Eleven of these patients had genotype 1, four had genotype 3, and one had genotype 4 infection; baseline RNA was 7 (5–8) log. The following treatment regimens were used: sofosbuvir, ribavirin, and low dose peginterferon (n = 8; 6 genotype 1 and one each had genotype 3 and 4); sofosbuvir and daclatasvir (n = 7); sofosbuvir, ribavirin, and daclatasvir (n = 1). Ten patients achieved end of treatment response and 8 (80%) of these achieved sustained virological response at 12 weeks (SVR12); six are on treatment. Two patients with genotype one (including one with cirrhosis) had relapse. Seven patients needed blood transfusion; interferon was stopped in one due to thrombocytopenia. Fatigue was present in 4 patients.

Conclusion

Sofosbuvir-based regimens can be used in ESRD patients on dialysis with good efficacy.