Pancreatitis is a relatively serious disease caused by the self-digestion of trypsin in the pancreas. The generation of diseases is closely related to gene and phenotype information. Generally, gene-phenotype relations are mainly obtained through clinical experiments, but the cost is huge. With the amount of published biomedical literature increasing exponentially, it carries a wealth of disease-related gene and phenotype information. This study provided an effective way to obtain disease-related gene and phenotype information. To our best knowledge, this work first attempted to explore relationships between genotype and phenotype about the pancreatitis from the computational perspective. It mined 6152 genes and 76,753 pairs of genotype and phenotype extracted from the biomedical literature about pancreatitis using text mining. Based on the above 76,753 pairs, the study proposed an improved normalized point-wise mutual information (REL-NPMI) model to optimize gene-phenotype relations related to pancreatitis, and obtained 12,562 gene-phenotype pairs which may be related to pancreatitis. The extracted top 20 results were validated and evaluated. The experimental results show that the method is promising for exploring pancreatitis\' molecular mechanism, thus it provides a computational way for studying pancreatitis\' disease pathogenesis. Data resources and the Pancreatitis Gene-Phenotype Association Database are available at http://114.116.4.45:8081/and resources are also available at https://github.com/polipoptbe8023/REL-NPMI.git.

BACKGROUND: Hypertriglyceridemia (HTG) is a leading cause of acute pancreatitis. HTG can be caused by either primary (genetic) or secondary etiological factors, and there is increasing appreciation of the interplay between the two kinds of factors in causing severe HTG.
OBJECTIVE: The main aim of this study was to identify the genetic basis of hypertriglyceridemia-induced acute pancreatitis (HTG-AP) in a Chinese family with three affected members (the proband, his mother and older sister).
METHODS: The entire coding and flanking sequences of LPL, APOC2, APOA5, GPIHBP1 and LMF1 genes were analyzed by Sanger sequencing. The newly identified LPL nonsense variant was subjected to functional analysis by means of transfection into HEK-293 T cells followed by Western blot and activity assays. Previously reported pathogenic LPL nonsense variants were collated and compared with respect to genotype and phenotype relationship.
RESULTS: We identified a novel nonsense variant, p.Gln118* (c.351C > T), in the LPL gene, which co-segregated with HTG-AP in the Chinese family. We provided in vitro evidence that this variant resulted in a complete functional loss of the affected LPL allele. We highlighted a role of alcohol abuse in modifying the clinical expression of the disease in the proband. Additionally, our survey of 12 previously reported pathogenic LPL nonsense variants (in 20 carriers) revealed that neither serum triglyceride levels nor occurrence of HTG-AP was distinguishable among the three carrier groups, namely, simple homozygotes, compound heterozygotes and simple heterozygotes.
CONCLUSIONS: Our findings, taken together, generated new insights into the complex etiology and expression of HTG-AP.

The rare autosomal dominant disorder acute intermittent porphyria (AIP) is caused by the deficient activity of hydroxymethylbilane synthase (HMBS). The symptoms of AIP are acute neurovisceral attacks which are induced by the dysfunction of heme biosynthesis. To better interpret the underlying mechanism of clinical phenotypes, we collected 117 HMBS gene mutations from reported individuals with AIP and evaluated the mutations\' impacts on the corresponding protein structure and function. We found that several mutations with most severe clinical symptoms are located at dipyromethane cofactor (DPM) binding domain of HMBS. Mutations on these residues likely significantly influence the catalytic reaction. To infer new pathogenic mutations, we evaluated the pathogenicity for all the possible missense mutations of HMBS gene with different bioinformatic prediction algorithms, and identified 34 mutations with serious pathogenicity and low allele frequency. In addition, we found that gene PPARA may also play an important role in the mechanisms of AIP attacks. Our analysis about the distribution frequencies of the 23 variations revealed different distribution patterns among eight ethnic populations, which could help to explain the genetic basis that may contribute to population disparities in AIP prevalence. Our systematic analysis provides a better understanding for this disease and helps for the diagnosis and treatment of AIP.

It has long been known that canonical 5\' splice site (5\'SS) GT>GC variants may be compatible with normal splicing. However, to date, the actual scale of canonical 5\'SSs capable of generating wild-type transcripts in the case of GT>GC substitutions remains unknown. Herein, combining data derived from a meta-analysis of 45 human disease-causing 5\'SS GT>GC variants and a cell culture-based full-length gene splicing assay of 103 5\'SS GT>GC substitutions, we estimate that ~15-18% of canonical GT 5\'SSs retain their capacity to generate between 1% and 84% normal transcripts when GT is substituted by GC. We further demonstrate that the canonical 5\'SSs in which substitution of GT by GC-generated normal transcripts exhibit stronger complementarity to the 5\' end of U1 snRNA than those sites whose substitutions of GT by GC did not lead to the generation of normal transcripts. We also observed a correlation between the generation of wild-type transcripts and a milder than expected clinical phenotype but found that none of the available splicing prediction tools were capable of reliably distinguishing 5\'SS GT>GC variants that generated wild-type transcripts from those that did not. Our findings imply that 5\'SS GT>GC variants in human disease genes may not invariably be pathogenic.