It is common to observe the clustering of chronic hepatitis B surface antigen (HBsAg) carriers in families. Intra-familial transmission of hepatitis B virus (HBV) could be the reason for the familial clustering of HBsAg carriers. Additionally, genetic and gender factors have been reported to be involved. We conducted a three-stage genome-wide association study to identify genetic factors associated with chronic HBV susceptibility. A total of 1,065 male controls and 1,623 male HBsAg carriers were included. The whole-genome genotyping was done on Illumina HumanHap550 beadchips in 304 healthy controls and HumanHap610 beadchips in 321 cases. We found that rs9277535 (HLA-DPB1, P = 4.87×10−14), rs9276370 (HLA-DQA2, P = 1.9×10−12), rs7756516 and rs7453920 (HLA-DQB2, P = 1.48×10−11 and P = 6.66×10−15 respectively) were significantly associated with persistent HBV infection. A novel SNP rs9366816 near HLA-DPA3 also showed significant association (P = 2.58×10−10). The “T-T-G-G-T” haplotype of the five SNPs further signified their association with the disease (P = 1.48×10−12; OR = 1.49). The “T-T” haplotype composed of rs7756516 and rs9276370 was more prevalent in severe disease subgroups and associated with non-sustained therapeutic response (P = 0.0262). The “G-C” haplotype was associated with sustained therapeutic response (P = 0.0132; OR = 2.49). We confirmed that HLA-DPB1, HLA-DQA2 and HLA-DQB2 loci were associated with persistent HBV infection in male Taiwan Han-Chinese. In addition, the HLA-DQA2 and -DQB2 complex was associated with clinical progression and therapeutic response.

IntroductionHyperglycemia and insulin resistance are commonplace in critical illness, especially in patients with sepsis. Recently, several hormones secreted by adipose tissue have been determined to be involved in overall insulin sensitivity in metabolic syndrome-related conditions, including adipocyte fatty-acid binding protein (A-FABP). However, little is known about their roles in critical illness. On the other hand, there is evidence that several adipose tissue gene expressions change in critically ill patients.MethodsA total of 120 patients (72 with sepsis, 48 without sepsis) were studied prospectively on admission to a medical ICU and compared with 45 healthy volunteers as controls. Various laboratory parameters and metabolic and inflammatory profiles were assessed within 48 hours after admission. Clinical data were collected from medical records.ResultsCompared with healthy controls, serum A-FABP concentrations were higher in all critically ill patients, and there was a trend of higher A-FABP in patients with sepsis. In multivariate correlation analysis in all critically ill patients, the serum A-FABP concentrations were independently related to serum creatinine, fasting plasma glucose, total cholesterol, TNF-alpha, albumin, and the Acute Physiology and Chronic Health Evaluation II scores. In survival analysis, higher A-FABP levels (> 40 ng/ml) were associated with an unfavorable overall survival outcome, especially in sepsis patients.ConclusionsCritically ill patients have higher serum A-FABP concentrations. Moreover, A-FABP may potentially serve as a prognostic biomarker in critically ill patients with sepsis.

Human height can be described as a classical and inherited trait model. Genome-wide association studies (GWAS) have revealed susceptible loci and provided insights into the polygenic nature of human height. Familial short stature (FSS) represents a suitable trait for investigating short stature genetics because disease associations with short stature have been ruled out in this case. In addition, FSS is caused only by genetically inherited factors. In this study, we explored the correlations of FSS risk with the genetic loci associated with human height in previous GWAS, alone and cumulatively. We systematically evaluated 34 known human height single nucleotide polymorphisms (SNPs) in relation to FSS in the additive model (p < 0.00005). A cumulative effect was observed: the odds ratios gradually increased with increasing genetic risk score quartiles (p < 0.001; Cochran-Armitage trend test). Six affected genes-ZBTB38, ZNF638, LCORL, CABLES1, CDK10, and TSEN15-are located in the nucleus and have been implicated in embryonic, organismal, and tissue development. In conclusion, our study suggests that 13 human height GWAS-identified SNPs are associated with FSS risk both alone and cumulatively.Human height can be described as a classical, inherited, and polygenic trait model. The ultimate phenotype represents the outcome of genetics and developmental biology, including the enlargement of bone length and the sizes of tissues and organ sizes. Undoubtedly, the developmental processes may be affected by environmental factors, including nutrition 1 , exercise 2 , diseases 3-5 , and infections 6, 7 . However, ~80% of the variance in height among individuals can also be explained by genetic variation [8][9][10] . Modern high-density genotyping platforms have now made it possible to identify candidate genes across the whole genome in relation to complex traits and diseases [11][12][13] .Genetic factors that contribute to the genetic architecture of human height are widely identified by means of genome-wide screening methods [14][15][16][17][18][19][20][21][22][23][24] . Human height-related susceptibility loci related to the protein tyrosine phosphatase family, insulin-like growth factor, and skeletal growth have been reported in Asian populations 18,19,21,22,25 . In addition, predisposing loci determining height have also been discovered in European populations in genes related to skeletal development, mitosis, fibroblast growth factors, the WNT/β-catenin pathway, chondroitin sulfate-related genes, mammalian target of rampamycin, osteoglycin, binding of hyaluronic acid, Hedgehog

AIMTo explore factors associated with persistent hepatitis B virus (HBV) infection in a cohort of hepatocellular carcinoma (HCC)-affected families and then investigate factors that correlate with individual viral load among hepatitis B surface antigen (HBsAg)-positive relatives.METHODSWe evaluated non-genetic factors associated with HBV replication in relatives of patients with HCC. Relatives of 355 HCC cases were interviewed using a structured questionnaire. Demographics, relationship to index case, HBsAg status of mothers and index cases were evaluated for association with the HBV persistent infection or viral load by generalized estimating equation analysis.RESULTSAmong 729 relatives enrolled, parent generation (P = 0.0076), index generation (P = 0.0044), mothers positive for HBsAg (P = 0.0007), and HBsAg-positive index cases (P = 5.98 × 10-8) were associated with persistent HBV infection. Factors associated with HBV viral load were evaluated among 303 HBsAg-positive relatives. Parent generation (P = 0.0359) and sex (P = 0.0007) were independent factors associated with HBV viral load. The intra-family HBV viral load was evaluated in families clustered with HBsAg-positive siblings. An intra-family trend of similar HBV viral load was found for 27 of 46 (58.7%) families. Male offspring of HBsAg-positive mothers (P = 0.024) and older siblings were associated with high viral load.CONCLUSIONSex and generation play important roles on HBV viral load. Maternal birth age and nutritional changes could be the reasons of viral load difference between generations.

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Context Human height is an inheritable, polygenic trait under complex and multilocus genetic regulation. Familial short stature (FSS; also called genetic short stature) is the most common type of short stature and is insufficiently known. Objective To investigate the FSS genetic profile and develop a polygenic risk predisposition score for FSS risk prediction. Design and Setting The FSS participant group of Han Chinese ancestry was diagnosed by pediatric endocrinologists in Taiwan. Patients and Interventions The genetic profiles of 1163 participants with FSS were identified by using a bootstrapping subsampling and genome-wide association studies (GWAS) method. Main Outcome Measures Genetic profile, polygenic risk predisposition score for risk prediction. Results Ten novel genetic single nucleotide polymorphisms (SNPs) and 9 reported GWAS human height-related SNPs were identified for FSS risk. These 10 novel SNPs served as a polygenic risk predisposition score for FSS risk prediction (area under the curve: 0.940 in the testing group). This FSS polygenic risk predisposition score was also associated with the height reduction regression tendency in the general population. Conclusion A polygenic risk predisposition score composed of 10 genetic SNPs is useful for FSS risk prediction and the height reduction tendency. Thus, it might contribute to FSS risk in the Han Chinese population from Taiwan.

Haplotype-based approaches may have greater power than single-locus analyses when the SNPs are in strong linkage disequilibrium with the risk locus. To overcome potential complexities owing to large numbers of haplotypes in genetic studies, we evaluated two data mining approaches, multifactor dimensionality reduction (MDR) and classification and regression tree (CART), with the concept of haplotypes considering their haplotype uncertainty to detect haplotype-haplotype (HH) interactions. In evaluation of performance for detecting HH interactions, MDR had higher power than CART, but MDR gave a slightly higher type I error. Additionally, we performed an HH interaction analysis with a publicly available dataset of Parkinson's disease and confirmed previous findings that the RET proto-oncogene is associated with the disease. In this study, we showed that using HH interaction analysis is possible to assist researchers in gaining more insight into identifying genetic risk factors for complex diseases.

BackgroundGenome-wide association studies have been successful in identifying common genetic variants for human diseases. However, much of the heritable variation associated with diseases such as Parkinson’s disease remains unknown suggesting that many more risk loci are yet to be identified. Rare variants have become important in disease association studies for explaining missing heritability. Methods for detecting this type of association require prior knowledge on candidate genes and combining variants within the region. These methods may suffer from power loss in situations with many neutral variants or causal variants with opposite effects.ResultsWe propose a method capable of scanning genetic variants to identify the region most likely harbouring disease gene with rare and/or common causal variants. Our method assigns a score at each individual variant based on our scoring system. It uses aggregate scores to identify the region with disease association. We evaluate performance by simulation based on 1000 Genomes sequencing data and compare with three commonly used methods. We use a Parkinson’s disease case–control dataset as a model to demonstrate the application of our method.Our method has better power than CMC and WSS and similar power to SKAT-O with well-controlled type I error under simulation based on 1000 Genomes sequencing data. In real data analysis, we confirm the association of α-synuclein gene (SNCA) with Parkinson’s disease (p = 0.005). We further identify association with hyaluronan synthase 2 (HAS2, p = 0.028) and kringle containing transmembrane protein 1 (KREMEN1, p = 0.006). KREMEN1 is associated with Wnt signalling pathway which has been shown to play an important role for neurodegeneration in Parkinson’s disease.ConclusionsOur method is time efficient and less sensitive to inclusion of neutral variants and direction effect of causal variants. It can narrow down a genomic region or a chromosome to a disease associated region. Using Parkinson’s disease as a model, our method not only confirms association for a known gene but also identifies two genes previously found by other studies. In spite of many existing methods, we conclude that our method serves as an efficient alternative for exploring genomic data containing both rare and common variants.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-014-0088-9) contains supplementary material, which is available to authorized users.