Effect of metabolic genetic variants on long-term disease comorbidity in patients with type 2 diabetes.

Underlying genetic determinants contribute to developing type 2 diabetes (T2D) future diseases. The present study aimed to identify which genetic variants are associated with the incident of the major T2D co-morbid disease. First, we conducted a discovery study by investigating the genetic associations of comorbid diseases within the framework of the Utrecht Cardiovascular Pharmacogenetic studies by turning information of > 25 years follow-up data of 1237 subjects whom were genotyped and included in the discovery study. We performed Cox proportional-hazards regression to examine associations between genetic variants and comorbid diseases including cardiovascular diseases (CVD), chronic eye disease, cancer, neurologic diseases and chronic kidney disease. Secondly, we replicated our findings in two independent cohorts consisting of 1041 subjects. Finally, we performed a meta-analysis by combining the discovery and two replication cohorts. We ascertained 390 (39.7%) incident cases of CVD, 182 (16.2%) of chronic eye disease, 155 (13.8%) of cancer, 31 (2.7%) of neurologic disease and 13 (1.1%) of chronic kidney disease during a median follow-up of 10.2 years. In the discovery study, we identified a total of 39 Single Nucleotide Polymorphisms (SNPs) associated with comorbid diseases. The replication study, confirmed that rs1870849 and rs8051326 may play a role in the incidence of chronic eye disease in T2D patients. Half of patients developed at least one comorbid disease, with CVD occurring most often and earliest followed by chronic eye disease. Further research is needed to confirm the associations of two associated SNPs with chronic eye disease in T2D.

Transethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals not only shared but also ethnicity-specific disease associations.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such as delineation could not be made because of tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a transethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40 691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analyzed the physicochemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we not only identified consistent associations (regarding effects directions/magnitudes) across different ethnicities but also identified population-specific signals (regarding differences in allele frequencies). We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.

Construction and benchmarking of a multi-ethnic reference panel for the imputation of HLA class I and II alleles.

Genotype imputation of the human leukocyte antigen (HLA) region is a cost-effective means to infer classical HLA alleles from inexpensive and dense SNP array data. In the research setting, imputation helps avoid costs for wet lab-based HLA typing and thus renders association analyses of the HLA in large cohorts feasible. Yet, most HLA imputation reference panels target Caucasian ethnicities and multi-ethnic panels are scarce. We compiled a high-quality multi-ethnic reference panel based on genotypes measured with Illumina's Immunochip genotyping array and HLA types established using a high-resolution next generation sequencing approach. Our reference panel includes more than 1,300 samples from Germany, Malta, China, India, Iran, Japan and Korea and samples of African American ancestry for all classical HLA class I and II alleles including HLA-DRB3/4/5. Applying extensive cross-validation, we benchmarked the imputation using the HLA imputation tool HIBAG, our multi-ethnic reference and an independent, previously published data set compiled of subpopulations of the 1000 Genomes project. We achieved average imputation accuracies higher than 0.924 for the commonly studied HLA-A, -B, -C, -DQB1 and -DRB1 genes across all ethnicities. We investigated allele-specific imputation challenges in regard to geographic origin of the samples using sensitivity and specificity measurements as well as allele frequencies and identified HLA alleles that are challenging to impute for each of the populations separately. In conclusion, our new multi-ethnic reference data set allows for high resolution HLA imputation of genotypes at all classical HLA class I and II genes including the HLA-DRB3/4/5 loci based on diverse ancestry populations.

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.

Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

The trend of national and sub-national burden of gastrointestinal and liver diseases in Iran 1990 to 2013; study protocol.

BACKGROUND: It is expected that gastrointestinal (GI) and liver diseases inflict considerable burden on health systems in Iran; therefore, highlighting the significance of GI disorders across the other most burdensome diseases requires comprehensive assessment and regular updates of the statistics of such diseases in Iran. OBJECTIVE: To assess in-depth sub-national estimates and trends for the incidence and prevalence of selected GI and liver diseases by age, gender and province over the period 1990 - 2013 in Iran. METHODS: This is a national and sub-national burden of disease study on 21 GI diseases using all available data sources, including cancer registry, death registration system data, hospital data, and all available published data. Analyses will be performed separately by gender, age groups, year, and province. We will conduct 21 separated systematic reviews of the literature for 21 diseases categories through searching online international electronic databases (i.e. the Medline database of the National Library of Medicine, Web of Science, and Scopus), Iranian search engines (i.e., IranMedex, Scientific Information Database (SID), and IRANDOC), and gray literature. We will search the medical literature published between January 1985 and December 2013. We generated two models, Spatio-temporal and Multilevel Autoregressive models, to estimate mean and uncertainty interval for the parameters of interest by gender, age, year, and province. The models will be informed by data of gender, age, year, and province. Markov Chain Monte Carlo (MCMC) methods will be used to perform Bayesian inference in both modeling framework. All programs will be written in R statistical packages (version 3.0.1). RESULTS: We will calculate and present 1990 to 2013 trends in terms of prevalence, years of life lost due to premature mortality (YLLs), years lived with disability (YLDs), and disability-adjusted life years DALYs for the 21 selected GI diseases by gender, and province. We will also quantify the uncertainty interval for the estimates of interest. CONCLUSION: Results of the present study will have implications for policy making; as they allow for understanding geographic distributions of the selected GI diseases, and identifying health disparities across provinces.

Epidemiological, Demographic, and Colonic Extension ofUlcerative Colitis in Iran: A Systematic Review.

BACKGROUND: Ulcerative colitis (UC), as the prototype of inflammatory bowel disease of the large bowel, is increasing in Iran and other developing countries. There are few studies that discuss the properties of this disease Iran. The result of this review may provide a general consensus about the epidemiological features of UC in Iran. METHODS: This was a qualitative, systematic review that investigated the incidence, prevalence, and demographic properties of UC in Iran. We evaluated all published studies in the PubMed database, IranMedex, Magiran, and Scientific Information Database (SID) that pertained to the epidemiology and demographic features of UC in Iran from January 1987 to January 2012. After searching with defined keywords and implementing the inclusion and exclusion criteria, 11 case series and 2 case-control studies fulfilled the criteria for inclusion. RESULTS: The estimated prevalence of UC is 15 per 105 persons, and the reported incidences were 3.04 and 3.25 per 105 persons in two Iranian provinces. The disease was more commonly observed in women and people in their fourth decade of life. Cigarette smoking conferred protection and familial association seemed to be similar to developed countries. UC did not appear to be more common among the higher socioeconomic class. In addition the proximal colon and rectum were less commonly involved. CONCLUSION: Although the data is limited, the prevalence and incidence of UC in Iran shows an increasing pattern similar to other countries in the region. There is no clear association with socioeconomic status. Milder forms of the disease are common in Iran. A comprehensive nationwide data bank is needed for a better definition of the disease characteristics.

Liver histology and HBV DNA levels in chronically HBV infected patients with persistently normal alanine aminotransferase.

BACKGROUND: Data on histological activity and HBV DNA levels in patients with chronic HBV infection and persistently normal alanine aminotransferase levels are sparse. We aimed to investigate the histological activity and HBV DNA levels in these patients. METHODS: There were 132 patients with HBeAg negative chronic HBV infection and persistently normal alanine aminotransferase levels that were included prospectively. Data were dichotomized according to the median levels. Associations of histology with HBV DNA and other variables were assessed. RESULTS: A total of 80 patients were male. The median age was 36 years. The median baseline HBV DNA was 2.9Log10 IU/mL. There were 50 cases (38%) with a total score > or = 5, 53 cases (40.2%) had grade > or = 4 and 40 cases (30.3%) had stage > or = 2. A baseline HBV DNA <2000 IU/mL was seen in 24 cases (48%) of those with total score > or = 5, 28 cases (53%) of those with grade > or = 4 and 9 cases (22.5%) with stage > or = 2. Multivariate analysis of baseline HBV DNA above the median level significantly predicted the total score, grade and stage with an adjusted odds ratio of 5.43, 3.47, and 4.23, respectively when compared to below median values. A second liver biopsy was performed in 61 patients. The median time interval between the two biopsies was 40 months. Total scores of 23 cases (38%) progressed by > or = 2 scores and the HBV DNA of 18 cases (22.5%) increased by > or = 1 Log10 IU when compared to baseline values. CONCLUSION: HBeAg negative chronic HBV infection with persistently normal alanine aminotransferase is not a silent disease. Active liver disease may be seen in such patients with viral loads less than 2000 IU/mL.

Noninvasive markers of liver fibrosis and inflammation in chronic hepatitis B-virus related liver disease.

BACKGROUND/AIMS: Noninvasive markers for predicting significant fibrosis and inflammation have not yet been validated in an unselected group of chronic hepatitis B virus (HBV) carriers. The aim of this study was to create noninvasive models to predict significant fibrosis and inflammation in chronic HBV carriers. METHODS: A total of 276 (229 HBeAg negative, 47 HBeAg positive) unselected consecutive treatment naïve patients chronically infected with HBV who attended our center over a 36-month period underwent liver biopsy. HBeAg negative patients were randomly divided into two cohorts: training group (N = 130) and validation group (N = 99). HBeAg positive patients were analyzed as a whole without separation. Thirteen parameters were analyzed separately in HBeAg negative and HBeAg positive patients to predict significant fibrosis (Ishak stage >or=3) and inflammation (Ishak grade >or=7). RESULTS: In HBeAg negative patients significant liver fibrosis was best predicted using the variables HBV DNA levels, alkaline phosphatase, albumin, and platelet counts with an area under ROC curve (AUC) of 0.91 for the training group and 0.85 for the validation group. Using the low cutoff probability of 4.72, significant fibrosis could be excluded with negative predictive value of 99% in the entire cohort, and liver biopsy would have been avoided in 52% of patients. The best model for predicting significant inflammation included the variables age, HBV DNA levels, AST, and albumin with an AUC of 0.93 in the training and 0.82 in the validation group. In HBeAg positive patients no factor could predict accurately stages of liver fibrosis, but the best factor for predicting significant inflammation was AST with an AUC of 0.87. CONCLUSIONS: Significant hepatic fibrosis and necroinflammation can reliably be predicted using routinely checked tests and HBV DNA levels.

Surface area: a better predictor of disease severity than the height and volume of the barium column in patients with primary achalasia.

OBJECTIVE: Subjective assessment of primary achalasia is not accurate. We aimed to study the utility of surface area of barium retention in the objective assessment of these patients. METHODS: Subjective and objective esophageal functions of 99 patients with primary achalasia were evaluated initially and 43 of them were reevaluated 1 month after balloon dilation. RESULTS: Before dilation: Ninety-nine patients were enrolled. Forty-one of them were male. The mean age was 37.5+/-15.3 years. The mean score, resting lower esophageal sphincter pressure, height, surface and volume of barium retention at 5 min were 8.03+/-3.1, 59.1+/-20 mmHg, 9.9+/-4.9 cm, and 23.6+/-13.9 cm and 53.2+/-47.7 cm, respectively. Surface area at 5 min had best correlation and predictive value for resting lower esophageal sphincter pressure. After dilation: Forty-three of 99 patients were reevaluated after balloon dilation. The mean age was 36.8+/-13.6 years. Seventeen of them were male. Mean score, resting lower esophageal sphincter pressure, height, surface area and volume of barium retention at 5 min dropped significantly after dilation. Surface area at 5 min had best correlation and predictive value for lower esophageal sphincter pressure. CONCLUSIONS: Surface area of barium retention at 5 min is an accurate objective tool to assess patients with primary achalasia. It is cheap and easy to perform; therefore, it could be used more frequently in postdilation follow-up.