Characterization of the B Cell Receptor Repertoire in the Intestinal Mucosa and of Tumor-Infiltrating Lymphocytes in Colorectal Adenoma and Carcinoma.

The B cells inhabited in mucosa play a vital role in mediating homeostasis with autoantigens and external Ags. Tumor-infiltrating lymphocytes are potential prognostic markers and therapeutic agents for cancer. However, the spatial heterogeneity of the B cell repertoire in intestinal mucosa and the tumor-infiltrating lymphocytes in colorectal cancer (CRC) remain poorly understood. In this study, we developed an unbiased method to amplify the IgH repertoire, as well as a bioinformatic pipeline to process these high-throughput sequencing data. With biopsies from seven intestinal mucosal segments, we uncovered their strong spatial homogeneity among the large intestine, where the clone overlap rate was up to 62.21%. The heterogeneity between terminal ileum and large intestine was also observed, including discrepant isotype distribution and low clone overlap rate. With tumor and adjacent normal mucosal tissues from CRC and colorectal advanced adenoma (AD) patients, we observed a similar IgH profile between tumor and adjacent normal mucosal tissues in AD, as well as a slight difference in CRC. Interestingly, we found distinct repertoire properties in the CRC tumor from AD and normal mucosa. Finally, we identified 1445 public clones for the normal mucosa, and 22 public clones for the CRC tumor with characteristic features. These data may be of potential use in clinical prognosis, diagnosis, and treatment of CRC.

Clinical and Metabolic Characterization of Lean Caucasian Subjects With Non-alcoholic Fatty Liver.

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity; however, 5-8% of lean subjects also have evidence of NAFLD. We aimed to investigate clinical, genetic, metabolic and lifestyle characteristics in lean Caucasian subjects with NAFLD. METHODS: Data from 187 subjects allocated to one of the three groups according to body mass index (BMI) and hepatic steatosis on ultrasound were obtained: lean healthy (BMI≤25 kg/m2, no steatosis, N=71), lean NAFLD (BMI≤25 kg/m2, steatosis, N=55), obese NAFLD (BMI≥30 kg/m2, steatosis; N=61). All subjects received a detailed clinical and laboratory examination including oral glucose tolerance test. The serum metabolome was assessed using the Metabolomics AbsoluteIDQ p180 kit (BIOCRATES Life Sciences). Genotyping for single-nucleotide polymorphisms (SNPs) associated with NAFLD was performed. RESULTS: Lean NAFLD subjects had fasting insulin concentrations similar to lean healthy subjects but had markedly impaired glucose tolerance. Lean NAFLD subjects had a higher rate of the mutant PNPLA3 CG/GG variant compared to lean controls (P=0.007). Serum adiponectin concentrations were decreased in both NAFLD groups compared to controls (P<0.001 for both groups) The metabolomics study revealed a potential role for various lysophosphatidylcholines (lyso-PC C18:0, lyso-PC C17:0) and phosphatidylcholines (PCaa C36:3; false discovery rate (FDR)-corrected P-value<0.001) as well as lysine, tyrosine, and valine (FDR<0.001). CONCLUSIONS: Lean subjects with evidence of NAFLD have clinically relevant impaired glucose tolerance, low adiponectin concentrations and a distinct metabolite profile with an increased rate of PNPLA3 risk allele carriage.

Evaluation of genome-wide loci of iron metabolism in hereditary hemochromatosis identifies PCSK7 as a host risk factor of liver cirrhosis.

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10(-5)) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10(-5), ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.

Natural course of subjects with elevated liver tests and normal liver histology.

BACKGROUND & AIMS: Liver biopsy (LB) is performed if non-invasive work-up of liver disease is inconclusive. The examination of liver tissue occasionally reveals normal histology. Long-term follow-up of such patients has not been performed. METHODS: We identified a total 70 subjects from our LB database with elevated liver tests and normal liver histology after a mean of 90.5 ± 52.3 (range 15-216) months and conducted reassessment of medical history, physical examination, laboratory testing, ultrasound, transient elastography and LB if indicated. RESULTS: At follow-up examination, 15 (7 females (f)/8 males (m); 21.4%) subjects had normal liver tests and no further evidence of liver disease. A subset of 37 (29 f/8 m; 52.9%) subjects had persistently elevated liver tests without evidence indicating progressive liver disease but the cause thereof remained unexplained also at the follow-up visit. Three (0 f/3 m; 4.3%) subjects had consumed excessive alcohol with indicators of alcoholic liver disease. Eleven subjects (4 f/7 m; 15.7%) had developed steatosis on ultrasound examination along with weight gain and/or biochemical features of the metabolic syndrome. In addition, three (2 f/1 m) patients developed autoimmune hepatitis, one female presented with primary biliary cirrhosis. One male was diagnosed with cholangiocellular carcinoma 3 months after the initial evaluation. CONCLUSION: The clinical course of most patients was benign, but in approximately 20% of the subjects a liver disease developed. Particular attention should be given to autoimmune liver diseases in subjects with positive autoantibodies. In addition, lifestyle factors such as weight gain and alcohol consumption were associated with the manifestation of liver diseases.

Hepatic steatosis in Wilson disease--Role of copper and PNPLA3 mutations.

BACKGROUND & AIMS: The earliest characteristic alterations of the liver pathology in Wilson disease (WD) include steatosis, which is sometimes indistinguishable from non-alcoholic fatty liver disease (NAFLD). Steatosis in WD may reflect copper-induced mitochondrial dysfunction. A genetic polymorphism in rs738409, in the patatin-like phospholipase domain-containing 3 gene (PNPLA3), is strongly associated with appearance of in NAFLD. This study evaluated the role of PNPLA3 and hepatic copper content for development of steatosis in patients with WD. METHODS: Liver biopsies obtained at diagnosis and the PNPLA3 genotype were analyzed in 98 Caucasian patients with WD (male: 52 [53.1%]; mean age: 27.6 years [CI 95%: 24.8-30.4, range: 5.8-61.5]). Steatosis was graded as percentage of lipid containing hepatocytes by an expert hepatopathologist unaware of the results of genetic testing. RESULTS: Moderate/severe steatosis (>33% of hepatocytes) was observed in 28 patients (pediatric: n=13/26 [50.0%], adult: n=15/72 [20.8%]; p=0.01). Forty-six patients (46.9%; pediatric: n=7, adult: n=39; p=0.022) had cirrhosis. Multivariate logistic regression identified PNPLA3 G allele (OR: 2.469, CI 95%: 1.203-5.068; p=0.014) and pediatric age (OR: 4.348; 1.577-11.905; p=0.004) as independent variables associated with moderate/severe steatosis. In contrast, hepatic copper content did not impact on moderate/severe steatosis (OR: 1.000, CI 95%: 1.000-1.001; p=0.297). CONCLUSIONS: Steatosis is common in WD and the PNPLA3 G allele contributes to its pathogenesis. The role of hepatic copper concentration and ATP7B mutations in steatosis development deserve further investigations.

HFE-related hemochromatosis: an update for the rheumatologist.

Hereditary hemochromatosis is a frequent disease in Caucasian populations. It leads to progressive iron overload in a variety of organs. The most common cause is the C282Y homozygous mutation in the HFE gene. The classical triad of skin hyperpigmentation, diabetes, and liver cirrhosis is nowadays rare but musculoskeletal symptoms are common in HFE-related hemochromatosis. Typically the second and third metacarpophalangeal joints, and the wrist, hip, and ankle joints are affected. Clinical symptoms include osteoarthritis-like symptoms, pseudogout attacks, and synovitis sometimes resembling rheumatoid arthritis. Radiographs show degenerative changes with joint space narrowing, osteophytes, and subchondral cysts. Chondrocalcinosis in the wrist and knee joints is seen in up to 50 % of patients. Although most other organ manifestations regress during phlebotomy, musculoskeletal symptoms often persist or even become worse. Importantly, patients are at an increased risk of severe large-joint arthritis necessitating joint replacement surgery. Therefore, future research should focus on the pathogenesis and treatment options for HH arthropathy.

VCAM-1 serum levels are associated with arthropathy in hereditary haemochromatosis.

OBJECTIVES: The aim of this study was to assess the role of vascular adhesion molecule 1 (VCAM-1) in patients with hereditary haemochromatosis (HH) with or without arthropathy. METHODS: Sera from a large cross-sectional cohort of unselected HH patients (n=147) were obtained and compared to an age-matched and sex-matched control group. Serum levels of VCAM-1 were measured by ELISA and were correlated with clinical measures. RESULTS: VCAM-1 serum levels were elevated in HH patients as compared to matched controls (mean 913±456 vs 654±451 ng/ml, p<0.0001). Within the HH patient group, VCAM-1 levels were much higher in patients with arthropathy and joint replacement surgery. VCAM-1 levels correlated well with radiographic measures of HH arthropathy (r=0.36, p<0.0001). Multivariate regression analysis confirmed a highly significant association of VCAM-1 serum levels and the presence of HH arthropathy, independent from diabetes, body mass index and age. CONCLUSIONS: VCAM-1 serum levels emerge as a biomarker for haemochromatosis arthropathy.

Idiopathic hand osteoarthritis vs haemochromatosis arthropathy--a clinical, functional and radiographic study.

OBJECTIVE: Haemochromatosis arthropathy is a secondary OA and the most frequent and earliest clinical presentation of hereditary haemochromatosis (HH). The aim of this study was to perform a direct clinical, functional and radiographic comparison with idiopathic hand OA (HOA) to unravel important differences between these clinical entities. METHODS: In total, 299 patients (141 with HH arthropathy of the hands and 158 patients with idiopathic HOA) were recruited. Structured clinical assessment including hand function tests, as well as hand radiographs with scoring according to Kellgren-Lawrence, were carried out in all patients. RESULTS: HH arthropathy and HOA differed significantly: patients with HH arthropathy were younger and predominantly male as compared with HOA. In males but not females, HH arthropathy led to an earlier start of symptoms than in HOA. Patients with HOA had more tender joints and worse hand function than patients with HH arthropathy, although subjective measures of joint pain and function were similar. MCP and wrist joint involvement was more frequent and severe in HH arthropathy, while HOA patients more frequently had degenerative changes in the first CMC as well as PIP and DIP joints. CONCLUSION: HH arthropathy and idiopathic HOA differ significantly in terms of epidemiology, localization, severity of symptoms and radiographic changes.

Association of the IL28B genotype with insulin resistance in patients with chronic hepatitis C.

BACKGROUND & AIMS: Insulin resistance, fibrosis and steatosis are established predictors of response to peg-interferon/ribavirin therapy in chronic hepatitis C (CHC). Several host genetic polymorphisms (IL28B, PNPLA3) modify treatment-outcome, the degree of steatosis or fibrosis. The aim of our study was to evaluate the role of these polymorphisms on insulin resistance (IR) in treatment-naïve patients with chronic hepatitis C. METHODS: Two hundred and two non-diabetic CHC patients (GT1: 181, GT4: 21; m = 126, f = 76) undergoing liver biopsy in two tertiary academic centers were studied. The SNPs rs12979860 (IL28B) and rs738409 (PNPLA3) were investigated by RT-PCR. HOMA-IR, BMI, stage of fibrosis, extent of steatosis, and genetic data were analyzed. RESULTS: Insulin resistance (HOMA-IR ≥ 3.0) was associated with rs12979860 genotype, presence of advanced fibrosis, and higher BMI. HOMA-IR in CC and in TC/TT was 2.08 ± 1.61 (mean ± SD) and 2.94 ± 2.89 (p=0.041), respectively. HOMA-IR was higher in advanced than in mild fibrosis (F3-4: 3.92 ± 3.15; F0-2: 2.38 ± 2.38; p=0.004). The percentage of steatotic hepatocytes was higher in patients with advanced fibrosis (21.3 ± 21.5 vs. 9.1 ± 14.2; p<0.001), HOMA-IR ≥ 3.0 (17.7 ± 17.8 vs. 8.8 ± 15.4%; p<0.001), and BMI > 25.0 kg/m(2) (14.7 ± 17.0 vs. 9.1 ± 16.1; p<0.001). The rs738409 GG genotype was associated with advanced fibrosis and steatosis, but not with HOMA-IR. Multivariable logistic regression identified advanced fibrosis (OR: 2.820, 95% CI: 1.344-5.917; p = 0.006) and the IL28B genotype non-CC (OR: 3.000, 1.348-6.676; p = 0.007) as independent risk factors for insulin resistance. CONCLUSIONS: Insulin resistance is more common in carriers of the T allele of SNP rs12979860 than in CC homozygotes and may partly explain the poor outcome of peginterferon/ribavirin therapy in these patients.

A role for low hepatic copper concentrations in nonalcoholic Fatty liver disease.

OBJECTIVES: Copper has a role in antioxidant defense, lipid peroxidation, and mitochondrial function, and copper deficiency has been linked to atherogenic dyslipidemia. We aimed to investigate the potential role of copper availability in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). METHODS: Patients with NAFLD (n=124) were compared to patients with chronic hepatitis C (n=50), hemochromatosis (n=35), alcoholic liver disease (n=13), autoimmune hepatitis (n=11), and control subjects (n=27). We determined liver and serum copper concentrations with correlation to clinical, histological, and biochemical parameters in humans. The effect of dietary copper restriction on liver histology and intermediary metabolism in rats was investigated. RESULTS: Hepatic copper concentrations in patients with NAFLD were lower than in control subjects (17.9+/-8.4 vs. 31.4+/-8.2 microg/g; P<0.001) and in patients with other liver diseases (P<0.05 for all liver diseases). In patients with NAFLD, lower liver copper was correlated with more pronounced hepatic steatosis (R=-0.248; P=0.010), fasting glucose (R=-0.245; P=0.008), and components of the metabolic syndrome (MetS; R=0.363; P<0.001). Patients with nonalcoholic steatohepatitis (NASH; n=31) had lower hepatic copper concentrations than those with simple steatosis (n=93; P=0.038). Restriction of dietary copper in rats induced hepatic steatosis and insulin resistance (IR). CONCLUSIONS: Reduced hepatic copper concentrations are found in human NAFLD and are associated with more pronounced hepatic steatosis, NASH, and components of the MetS. The development of hepatic steatosis and IR in response to dietary copper restriction in rats suggests that copper availability may be involved in the development of NAFLD.

Association between Cardiovascular Risk and Diabetes with Colorectal Neoplasia: A Site-Specific Analysis.

Several studies have shown site-specific differences in colorectal cancer (CRC) with respect to the risk factors. CRC was shown to be associated with cardiovascular risk (CVR) factors, but site-specific variations have not been investigated so far. This study aimed to assess the associations between the prevalence and subsite-specific differences of colorectal neoplasia and established CVR scores or known coronary artery disease (CAD) in a large asymptomatic European screening cohort (N = 2098). Participants underwent simultaneous screening colonoscopy and CVR evaluation, using the Framingham Risk Score and Heart Score. Lesions found in the colonoscopy were classified by location (proximal/distal colon or rectum). More neoplasias were found in the proximal versus the distal colon (p < 0.001). The Framingham Risk Score and Heart Score showed incremental risk for colorectal adenoma, across the tertiles in the proximal and the distal colon (p < 0.001). The prevalence of adenomas in the rectum was much lower, but also here, incremental risk could be shown for the Framingham Risk but not the Heart Risk Score tertiles. Prevalence of adenomas in the proximal colon was higher in subjects with type 2 diabetes (T2DM) (p = 0.006), but no association was found between adenomas and T2DM in the distal colon (p = 0.618) and the rectum (p = 0.071). Males had a higher CVR and more findings, in the screening colonoscopy, as compared to females, however, no site-specific differences were noted. Patients with known CAD and high CVR have an increased risk of colorectal neoplasia in both the proximal and distal colon. Patients with T2DM have a higher risk for neoplasia in the proximal colon.

HFE hemochromatosis screening in patients with severe hip osteoarthritis: A prospective cross-sectional study.

OBJECTIVE: Despite the high frequency of HFE gene mutations in Western Europe, widespread screening for HFE hemochromatosis is not recommended due to its variable phenotype. Joint pain and a premature osteoarthritis-like disease including the hip joints are the most frequent manifestation in patients with HFE hemochromatosis and iron overload. Therefore, screening of patients with severe osteoarthritis of the hip could identify patients with HFE hemochromatosis. METHODS: In this prospective cross-sectional study, 940 patients aged <70 years with end-stage osteoarthritis of the hip undergoing elective joint replacement surgery were screened for HFE hemochromatosis and compared to age- and sex-matched controls. RESULTS: No greater prevalence of C282Y homozygosity mutation or elevated serum ferritin or transferrin saturation levels was found in the study cohort with severe osteoarthritis of the hip than in controls from the general population. CONCLUSION: Our screening approach could not identify an increased prevalence of HFE gene mutations and iron overload in younger patients with severe osteoarthritis of the hip.

Genetic architecture of the APM1 gene and its influence on adiponectin plasma levels and parameters of the metabolic syndrome in 1,727 healthy Caucasians.

The associations of the adiponectin (APM1) gene with parameters of the metabolic syndrome are inconsistent. We performed a systematic investigation based on fine-mapped single nucleotide polymorphisms (SNPs) highlighting the genetic architecture and their role in modulating adiponectin plasma concentrations in a particularly healthy population of 1,727 Caucasians avoiding secondary effects from disease processes. Genotyping 53 SNPs (average spacing of 0.7 kb) in the APM1 gene region in 81 Caucasians revealed a two-block linkage disequilibrium (LD) structure and enabled comprehensive tag SNP selection. We found particularly strong associations with adiponectin concentrations for 11 of the 15 tag SNPs in the 1,727 subjects (five P values <0.0001). Haplotype analysis provided a thorough differentiation of adiponectin concentrations with 9 of 17 haplotypes showing significant associations (three P values <0.0001). No significant association was found for any SNP with the parameters of the metabolic syndrome. We observed a two-block LD structure of APM1 pointing toward at least two independent association signals, one including the promoter SNPs and a second spanning the relevant exons. Our data on a large number of healthy subjects suggest a clear modulation of adiponectin concentrations by variants of APM1, which are not merely a concomitant effect in the course of type 2 diabetes or coronary artery disease.

Low hepatic copper content and PNPLA3 polymorphism in non-alcoholic fatty liver disease in patients without metabolic syndrome.

INTRODUCTION: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is multifactorial including metabolic, genetic (e.g. PNPLA3 [patatin-like phospholipase domain-containing 3 gene]), viral factors and drugs. Besides, there is evidence for a role of copper deficiency. Aim of the study was to evaluate the role of hepatic copper content, PNPLA3 in NAFLD patients with and without metabolic syndrome (MetS). METHODS: One-hundred seventy-four NAFLD patients, who underwent liver biopsy for diagnostic work-up, were studied. Diagnosis of MetS was based on the WHO Clinical Criteria. Steatosis was semiquantified as percentage of fat containing hepatocytes and was graded according to Brunt. Histological features of non-alcoholic steatohepatitis (NASH) were assessed using the Bedossa classification. Hepatic copper content (in µg/g dry weight) was measured by flame atomic absorption spectroscopy. SNP rs738409 in PNPLA3 was investigated by RT-PCR. RESULTS: Mean hepatic copper content was 22.3 (19.6-25.1) µg/g. The mean percentage of histologically lipid containing hepatocytes was 42.2% (38.3-46.0) and correlated inversely with hepatic copper content (ρ=-0.358, P<0.001). By subgroup analysis this inverse correlation remained significant only in patients without MetS (OR: 0.959 [CI95%: 0.926-0.944], P=0.020). Presence of minor allele (G) of PNPLA3 was also associated with moderate/severe steatosis (≥33%) both in patients with (OR: 2.405 [CI95%: 1.220-4.744], P=0.011) and without MetS (OR: 2.481 [CI95%: 1.172-5.250], P=0.018), but was only associated with NASH (OR: 2.002 [CI95%: 1.062-3.772], P=0.032) and liver fibrosis (OR: 2.646 [CI95%: 1.299-5.389], P=0.007) in patients without MetS. CONCLUSION: Hepatic copper content and PNPLA3 mutations are associated with disease activity in NAFLD patients without MetS. Presence of MetS appears to mask the effects of hepatic copper and PNPLA3.

Ultrasound verified inflammation and structural damage in patients with hereditary haemochromatosis-related arthropathy.

BACKGROUND: Chronic arthropathy occurs in approximately two thirds of patients with hereditary haemochromatosis (HH). The aim was to study inflammatory and structural lesions in patients with HH with (HH-A) and without arthropathy (HH-WA) using ultrasonography. METHODS: This was a cross-sectional study of 26 patients with HH-A, 24 with HH-WA and 37 with hand osteoarthritis (HOA). Clinical examination was performed in 68 joints, and we retrieved data on hand function, pain and global disease activity (all using a visual analogue scale (VAS)), morning stiffness and ferritin levels. Standard x-ray and ultrasound were conducted in 36 joints (hands, hips, knees and ankles), and we graded grey scale synovitis (GSS), power Doppler ultrasound (PD), osteophytes, erosions, tenosynovitis and cartilage damage semi-quantitatively in accordance with prior publications. RESULTS: Ultrasound revealed a high proportion of inflammatory changes in HH-A; GSS was found in 96.2% and PD signals in 80.8% of patients (median GSS score 9, PD score 2.5). The frequency of these findings was similar in HOA. Inflammation was also common in HH-WA, yielding GSS in 83.3% and PD signals in 50.0% of patients. Cartilage damage was most prominent in HH-A as compared to HH-WA and HOA (median scores 11.0, 2.5 and 2.0, respectively). The prevalence and extent of erosions and osteophytes were similar in all groups. None of the ultrasound scores was associated with pain or function; GSS, PD, osteophyte and cartilage scores correlated with x-ray-verified structural damage. CONCLUSION: A high prevalence of ultrasound-verified inflammation and cartilage damage was found in HH-A, and to a lesser extent in HH-WA. These findings were associated with x-ray-verified damage but not with clinical scores of pain and function.

Relations of vitamin D status, gender and type 2 diabetes in middle-aged Caucasians.

Vitamin D (Vit D) deficiency may be linked to the development of obesity-associated complications such as insulin resistance and type 2 diabetes. We therefore evaluated the relationship of Vit D serum concentrations with metabolic parameters and type 2 diabetes in middle-aged Caucasian men and women. One thousand six hundred and thirty-one Caucasians (832 males, 58.8 ± 9.7 years; 799 females, 59.7 ± 10.7 years) were evaluated in a cross-sectional study. Vit D status was assessed by measuring the serum concentration of 25-hydroxyvitamin D3 [25(OH)D3]. Type 2 diabetes prevalence was ascertained by medical history, fasting plasma glucose concentrations, oral glucose tolerance testing and/or glycosylated hemoglobin. Men displayed higher crude or seasonally adjusted 25(OH)D3 serum concentrations than women (24.64 ± 10.98 vs. 22.88 ± 11.6 ng/ml; P < 0.001). Strong associations between body mass index (BMI) and 25(OH)D3 were observed in both genders (P < 0.001). Seasonally adjusted levels of 25(OH)D3 revealed stronger associations with type 2 diabetes in women than men (P < 0.001). However, adjustment for BMI and other confounding variables revealed an independent inverse association of 25(OH)D3 with diabetes only in women (P < 0.001), whereas the association was abrogated in men. Using a 15 ng/ml 25(OH)D3 cutoff for binary comparison, adjusted odds ratios for having newly diagnosed or known type 2 diabetes more than doubled (2.95 [95 % CI 1.37-4.89] and 3.26 [1.59-6.68], respectively), in women below the cutoff. We conclude that in women, but not in men, low 25(OH)D3 serum levels are independently associated with type 2 diabetes. These findings suggest sex-specific effects of Vit D in the pathogenesis of type 2 diabetes.

Parathyroid Hormone is Related to Dysplasia and a Higher Rate of Distal Colorectal Adenoma in Women but Not Men.

Molecular and clinical observations provide evidence for a potential role of parathyroid hormone (PTH) in colorectal cancer development. We therefore aimed to assess the association of PTH with regard to colorectal cancer precursor lesions. A cohort of 1432 participants, 777 men, 58.4 ± 9.6 years and 701 women, 59.1 ± 10.6 years, undergoing screening colonoscopy were allocated to PTH serum concentrations either above or below 55 ng/L. The number, localization, size, and histology of the polypoid lesions detected during screening colonoscopy were recorded according to PTH serum concentrations. Serum PTH concentrations were not different between men and women. Women with PTH serum concentrations above the cut-off had significantly more adenomas (13/40; 32.5%) of the distal colon compared to women below the cut-off (91/659; 13.8%; P = 0.001). Additionally, the rate of dysplasia in adenomas of the distal colon was higher in women with high compared to low PTH concentrations (P = 0.001). These findings remained robust after adjustments for serum vitamin D, age, plasma creatinine, BMI, diabetes, and liver steatosis. No associations were observed between serum PTH concentrations and colorectal lesions in men. These data suggest that elevated PTH serum concentrations might have a role in colorectal cancer development as indicated by higher rates of adenomas, specifically with dysplasia, in women. The role of PTH in colon carcinogenesis and its sex specificity deserve further study.

Gut microbiome development along the colorectal adenoma-carcinoma sequence.

Colorectal cancer, a commonly diagnosed cancer in the elderly, often develops slowly from benign polyps called adenoma. The gut microbiota is believed to be directly involved in colorectal carcinogenesis. The identity and functional capacity of the adenoma- or carcinoma-related gut microbe(s), however, have not been surveyed in a comprehensive manner. Here we perform a metagenome-wide association study (MGWAS) on stools from advanced adenoma and carcinoma patients and from healthy subjects, revealing microbial genes, strains and functions enriched in each group. An analysis of potential risk factors indicates that high intake of red meat relative to fruits and vegetables appears to associate with outgrowth of bacteria that might contribute to a more hostile gut environment. These findings suggest that faecal microbiome-based strategies may be useful for early diagnosis and treatment of colorectal adenoma or carcinoma.

Associations of a human G protein beta3 subunit dimorphism with insulin resistance and carotid atherosclerosis.

BACKGROUND AND PURPOSE: The C825T dimorphism of the gene encoding the human G protein beta3 subunit (GNB3) is associated with hypertension and obesity. Although these findings suggest an association with insulin resistance and atherosclerosis, this hypothesis has yet been tested only partially. METHODS: To investigate this hypothesis, the C825T dimorphism was determined in a population of 932 middle-aged white subjects of middle European (Austrian) origin. Insulin sensitivity was measured with the short insulin tolerance test; intima-media thickness of the carotid artery and morphological plaque burden were measured by ultrasound. RESULTS: Insulin sensitivity was found to be significantly lower in carriers of the T allele (3.55+/-1.27 versus 3.92+/-1.30%/min, P=0.012) in the group of male subjects with abdominal body fat distribution (waist-to-hip ratio >0.9). No effect was observed in women or men with a waist-to-hip ratio <0.9. Advanced carotid artery plaques were more frequent (odds ratio, 1.606; 95% confidence interval, 1.002 to 2.575; P=0.04) in carriers of the T allele regardless of sex. No effect was observed with regard to carotid artery intima-media thickness. CONCLUSIONS: In summary, our results demonstrate that the GNB3 825T allele is associated with reduced insulin sensitivity in men with abdominal fat distribution and with more advanced carotid atherosclerosis in middle-aged white men and women.

Glucose acts as a regulator of serum iron by increasing serum hepcidin concentrations.

Mutual clinical and molecular interactions between iron and glucose metabolism have been reported. We aimed to investigate a potential effect of glucose on iron homeostasis. We found that serum iron concentrations gradually decreased over 180 min after the administration of 75 g of glucose from 109.8 ± 45.4 mg/L to 94.4 ± 40.4 mg/L (P<.001; N=40) but remained unchanged in control subjects receiving tap water (N=21). Serum hepcidin, the key iron regulatory hormone which is mainly derived from hepatocytes but also expressed in pancreatic ß-cells, increased within 120 min after glucose ingestion from 19.7 ± 9.9 nmol/L to 31.4 ± 21.0 nmol/L (P<.001). In cell culture, glucose induced the secretion of hepcidin and insulin into the supernatant of INS-1E cultures, but did not change the amount of hepcidin detectable in the hepatocyte cell culture HepG2. We additionally confirmed the expression of hepcidin in a human islet cell preparation. These results suggest that glucose acts as a regulator of serum iron concentrations, most likely by triggering the release of hepcidin from ß-cells.