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Dapsone hypersensitivity syndrome is a rare yet severe adverse drug reaction caused by dapsone, a principal drug in multidrug therapy for leprosy. HLA-B*13:01 has been identified as a strong risk factor of dapsone hypersensitivity syndrome; however, its low positive predictive value indicated that additional genetic variants may be involved in the disease development. To discover contributing genetic variants within HLA loci in addition to HLA-B*13:01, we performed a high-coverage next-generation sequencing (NGS)–based HLA typing analysis in 103 dapsone-hypersensitive and 857 dapsone-tolerant HLA-B*13:01 –positive leprosy patients in a Chinese population. Five amino acid variants in high linkage disequilibrium of HLA-DRB1 were significantly associated with dapsone hypersensitivity syndrome (positions 133, 142, –17, 11, and 13). DRB1*16:02 and DRB1*15:01 tagged by these risk-conferring amino acid residues were associated at a nominal significance level. This study identifies five amino acid variants within HLA-DRB1 that are in high linkage disequilibrium and significantly associated with dapsone hypersensitivity syndrome in a Chinese population.

The nuclear transcription factor-κB (NF-κB) plays a pivotal role in controlling both innate and adaptive immunity and regulates the expressions of many immunological mediators. Abundant evidences have showed the importance of NF-κB pathway in the host immune responses against Mycobacterium leprae in the development of leprosy. However, no particular association study between leprosy and NF-κB pathway-related gene polymorphisms was reported. Here, we performed a large-scale and two-stage candidate association study to investigate the association between 94 NF-κB pathway-related genes and leprosy. Our results showed that rs58744688 was significantly associated with leprosy (P = 7.57 × 10-7 , OR = 1.12) by combining the previous genomewide association data sets and four independent validation sample series, consisting of a total of 4631 leprosy cases and 6413 healthy controls. This founding implicated that MAP3K14 and FMNL1 were susceptibility genes for leprosy, which suggested the involvement of macrophage targeting and NF-κB pathway in the development of leprosy.

Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD ( P = 1.71 × 10 –9 , odds ratio [OR] = 4.35) and rs149308743 in CARD9 ( P = 2.09 × 10 –8 , OR = 4.75); three low-frequency variants: rs76418789 in IL23R ( P = 1.03 × 10 –10 , OR = 1.36), rs146466242 in FLG ( P = 3.39 × 10 –12 , OR = 1.45), and rs55882956 in TYK2 ( P = 1.04 × 10 –6 , OR = 1.30); and two common variants: rs780668 in SLC29A3 ( P = 2.17 × 10 –9 , OR = 1.14) and rs181206 in IL27 ( P = 1.08 × 10 –7 , OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases.

Leprosy, a chronic infectious disease, results from the uncultivable pathogen Mycobacterium leprae (M. leprae), and usually progresses to peripheral neuropathy and permanent progressive deformity if not treated. Previously published genetic studies have identified 18 gene/loci significantly associated with leprosy at the genome-wide significant level. However as a complex disease, only a small proportion of leprosy risk could be explained by those gene/loci. To further identify more susceptibility gene/loci, we hereby performed a three-stage GWAS comprising 8,156 leprosy patients and 15,610 controls of Chinese ancestry. Four novel loci were identified including rs6807915 on 3p25.2 (P=1.94 × 10−8, OR=0.89), rs4720118 on 7p14.3 (P=3.85 × 10−10, OR=1.16), rs55894533 on 8p23.1 (P=5.07 × 10−11, OR=1.15) and rs10100465 on 8q24.11 (P=2.85 × 10−11, OR=0.85). Altogether, these findings have provided new insight and significantly expanded our understanding of the genetic basis of leprosy., Previous studies have shown genetic associations between leprosy and 18 different genes/loci. Here, Wang and colleagues perform genome-wide association study in Han Chinese leprosy patients and describe four novel loci to be associated to the disease.

The biological connections between psoriasis and diabetes have been suggested by epidemiological, immunological and genetic studies. To identify additional shared susceptibility loci and investigate shared pathogenesis between these two diseases, we genotyped 89 reported diabetes susceptibility loci in 4456 psoriasis cases and 6027 controls of Chinese population using the MassARRAY system from Sequenom. We discovered three significant associations at rs6679677 on 1p13.2 (P=6.15×10-5 , OR=5.07), rs16861329 on 3q27.3 (P=2.02×10-4 , OR=0.87) and rs849135 on 7p15.1 (P=6.59×10-9 , OR=1.78), which suggested PTPN22, ST6GAL1 and JAZF1 as novel susceptibility genes for psoriasis in Chinese population. Our findings implicated the involvement of T-cell receptor signalling pathway in the pathogenesis of psoriasis and further confirmed the shared genetic susceptibility between psoriasis and diabetes.

Genetic polymorphism within the 9q32 locus is linked with increased risk of several diseases, including Crohn’s disease (CD), primary biliary cholangitis (PBC) and leprosy. The most likely disease-causing gene within 9q32 is TNFSF15, which encodes the pro-inflammatory cytokine TNF super-family member 15, but it was unknown whether these disparate diseases were associated with the same genetic variance in 9q32, and how variance within this locus might contribute to pathology. Using genetic data from published studies on CD, PBC and leprosy we revealed that bearing a T allele at rs6478108/rs6478109 (r2 = 1) or rs4979462 was significantly associated with increased risk of CD and decreased risk of leprosy, while the T allele at rs4979462 was associated with significantly increased risk of PBC. In vitro analyses showed that the rs6478109 genotype significantly affected TNFSF15 expression in cells from whole blood of controls, while functional annotation using publicly-available data revealed the broad cell type/tissue-specific regulatory potential of variance at rs6478109 or rs4979462. In summary, we provide evidence that variance within TNFSF15 has the potential to affect cytokine expression across a range of tissues and thereby contribute to protection from infectious diseases such as leprosy, while increasing the risk of immune-mediated diseases including CD and PBC.

Twenty pigs were randomly divided into four groups of five pigs each (not transported – control, 1, 2 and 4 h of transportation). A significant increase of ALT, AST and CK in the blood serum and acute parenchyma cell lesions were observed and those were characterized by acute degenerations in the heart and liver. Hsp27 expression levels increased significantly in the heart after 2 h and in the liver after 4 h of transportation, accompanying with the hsp27 mRNA increasing significantly in the heart and liver after 1 h of transportation. αB-crystallin expression levels were fluctuant (not significantly) in the heart and liver during transporting, however, αB-crystallin mRNA increase notably in the heart after 1 h and decrease significantly in the liver at 1 and 2 h of transportation, respectively. In conclusion, the cellular damage to the heart and liver is highest after 1 h of transportation, Hsp27 and αB-crystallin play dissimilar roles and show tissue-specific response in different tissues during transportation.

The objective of this study was to examine the dynamics of changes in the expression of Hsp27, Hsp70, and Hsp90, along with the transcription of their corresponding mRNAs, in the hearts of transported pigs. The transported pigs were divided into three groups, with each group transported for 1, 2 or 4 h. Creatine kinase concentrations clearly increased during 1 h and 2 h of transportation, indicating that cardiac muscle cells were severely damaged at the beginning of transportation. The pattern of changes in Hsp27, Hsp70 and Hsp90 expression in the hearts of the transported pigs demonstrated that expression patterns vary for different Hsps, with a significant induction of Hsp27 expression after 2 h of transportation, no obvious changes in Hsp70 expression, and a significant reduction in Hsp90 expression after 1 h, 2 h and 4 h of transportation. The results also demonstrated that the expression patterns of Hsp27 and Hsp90 were almost coincident with their corresponding mRNA transcription levels, suggesting that different Hsps may differ in their abilities to protect heart tissue in pigs responding to transportation stress. CK and ELISA results showed that in the initial transportation stage the increased Hsp27 and Hsp70 protected cardiac muscle cells from transport stress, although cardiac muscle cells were severely damaged at the beginning of transportation. Hsp90 synthesis may be disturbed by the damaged cardiac muscle cells and cause persistently decreased Hsp90 levels.

The aim of the present study was to examine the effect of transport on the expression of hsp90 mRNA , and on the proteins HSF-1 and Hsp90, in pig tissues. The pigs were divided into four groups and transported for 0 (control), 1, 2 or 4 h, respectively. The concentrations of serum aspartate aminotransferase and alanine aminotransferase distinctly increased after transportation. The levels of Hsp90 protein and mRNA were coincident in the tissues of transported pigs. After 2 h of transport, Hsp90 levels decreased in the stomach, and greatly decreased in the heart and liver. HSF-1 levels continuously decreased in the heart, while they remained unchanged in the liver and stomach, during transport of the pigs. These results indicate that expression of Hsp90 and HSF-1 are sensitive to transport in a time- and tissue-dependent manner, suggesting that these proteins may play different roles in these tissues during transportation.

We investigated and described the kinetics of heat shock protein (Hsp) 110 expression and distribution in rat primary myocardial cells exposed to heat stress in vitro. After incubation at 37°C for 72 h, myocardial cells were heat stressed at 42°C for 0, 10, 20, 40, 60, 120, 240, 360, and 480 min. Significant increases in aspartate transaminase, lactate dehydrogenase, and creatine kinase enzymatic activities in the myocardial cell culture media were observed during heat stress, suggesting that the integrity of the myocardial cells was altered. Immunocytochemical analysis revealed that the expressed Hsp110 was constitutively localized in the cytoplasm and in the nuclei in small amounts characterized by a granular pattern. Nuclear Hsp110 levels increased significantly after 240 min of heat stress compared with levels in the control. The overall levels of Hsp110 expression increased significantly after 20 min. After 240 min, Hsp110 levels were approximately 1.2-fold higher than those in the control. Increasing levels of hsp110 messenger RNA detected using real-time quantitative polymerase chain reaction were observed after 20 min of heat stress, and the levels peaked with a 10-fold increase after 240 min of heat stress. These results indicate that the expression of Hsp110 in primary myocardial cells in vitro is sensitive to hyperthermic stress and that Hsp110 is involved in the potential acquisition of thermotolerance after heat stress. Therefore, Hsp110 might play a fundamental role in opposing and alleviating heat-induced damage caused by hyperthermic stress in primary myocardial cells.

The aim of this study was to assess changes of Hsp70 and HSF-1 protein and mRNA expression in stress-sensitive organs of pigs during transportation for various periods of time. Twenty pigs were randomly divided into four groups (0 h, 1 h, 2 h, and 4 h of transportation). A significant increased activity of AST and CK was observed after 1 h and 2 h of transportation. Histopathological changes in the heart, liver, and stomach indicated that these organs sustained different degrees of injury. Hsp70 protein expression in the heart and liver of transported pigs did not change significantly while it increased significantly (p < 0.05) in the stomach. Hsp70 mRNA levels decreased significantly (p < 0.05) in the heart after 4 h of transportation. However, mRNA expression increased significantly in the liver after 1 (p < 0.05) and 4 h (p < 0.01) of transportation, and increased significantly in the stomach of the transported pigs after 1, 4 (p < 0.01), and 2 h (p < 0.05). HSF-1 levels were reduced at 1 and 4 h (p < 0.05) only in the hearts of transported pigs. These results indicate that Hsp70 mediates distinct stress-related functions in different tissues during transportation.

Twenty pigs were randomly divided into four groups based on the amount of time spent in transport (zero, one, two or four hours). Pathological examination of all transported pigs showed that exfoliation of chief cells from the gastric surface occurred in pigs during transportation. These results imply that integrity of the gastric mucosa was compromised by damage occurring during the four-hour transportation, despite the fact that gastric ulcers were not present. Levels of Hsp90 expression in stomach tissues were significantly decreased (P