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Foot-based teleoperation can provide the user with hands-free control of a robotic assistive arm without interrupting the ongoing task in various potential industrial and medical applications. In this paper, a foot interface (FI) was adapted to control a robotic camera holder in laparoscopic surgery, where surgeons are in direct contact with patients, and their hands are occupied. A novel four degrees of freedom FI with intuitive two-level rate-based control and vibrotactile feedback is proposed. A comparative study was conducted between the proposed FI and a conventional FI with binary switches on a planar surface. The experiment includes a follow-the-command test and a peg-and-holes test. Results showed that our FI was less mentally tiring with shorter task completion time and fewer visual checks. A suitably designed FI is a good candidate for controlling a robotic assistive arm in surgical applications.

The effect of prematurity on normal developmental programs of white and gray matter as evaluated with magnetic resonance imaging indicates global changes in white and gray matter with functional implications. We have previously identified an association between lipids and diffusion tensor imaging features in preterm infants, both through a candidate gene approach and a data-driven statistical genetics method. Here we apply a penalized linear regression model, the graph-guided group lasso (GGGL), that can utilize prior knowledge and select single nucleotide polymorphisms (SNPs) within functionally related genes associated with the trait. GGGL incorporates prior information from SNP-gene mapping as well as from the gene functional interaction network to guide variable selection.

Preterm birth places newborn infants in an adverse environment that leads to brain injury linked to neuroinflammation. To characterise this pathology, we present a translational bioinformatics investigation, with integration of human and mouse molecular and neuroimaging datasets to provide a deeper understanding of the role of microglia in preterm white matter damage. We examined preterm neuroinflammation in a mouse model of encephalopathy of prematurity induced by IL1B exposure, carrying out a gene network analysis of the cell-specific transcriptomic response to injury, which we extended to analysis of protein-protein interactions, transcription factors, and human brain gene expression, including translation to preterm infants by means of imaging-genetics approaches in the brain. We identified the endogenous synthesis of DLG4 (PSD95) protein by microglia in mouse and human, modulated by inflammation and development. Systemic genetic variation in DLG4 was associated with structural features in the preterm infant brain, suggesting that genetic variation in DLG4 may also impact white matter development and inter-individual susceptibility to injury.Preterm birth accounts for 11% of all births 1, and is the leading global cause of deaths under 5 years of age 2. Over 30% of survivors experience motor and/or cognitive problems from birth 3, 4, which last into adulthood 5. These problems include a 3-8 fold increased risk of symptoms and disorders associated with anxiety, inattention and social and communication problems compared to term-born infants 6. Prematurity is associated with a 4-12 fold increase in the prevalence of Autism Spectrum Disorders (ASD) compared to the general population 7, as well as a risk ratio of 7.4 for bipolar affective disorder among infants born below 32 weeks of gestation 8.The characteristic brain injury observed in contemporary cohorts of preterm born infants includes changes to the grey and white matter tissues, that specifically include oligodendrocyte maturation arrest, hypomyelination and cortical changes visualised as decreases in fractional anisotropy 9–13. Exposure of the fetus and postnatal infant to systemic inflammation is an important contributing factor to brain injury in preterm born infants 12, 14, 15, and the persistence of inflammation is associated with poorer neurological outcome 16. Sources of systemic inflammation include maternal/fetal infections such as chorioamnionitis (which it is estimated affects a large number of women at a sub-clinical level), with the effect of systemic inflammation in the brain being mediated predominantly by the microglial response 17.Microglia are unique yolk-sac derived resident phagocytes of the brain 18, 19, found preferentially within the developing white matter as a matter of normal developmental migration 12. Microglial products associated with white matter injury include pro-inflammatory cytokines, such as interleukin-1β (IL1B) and tumour necrosis factor α (TNF-α)20, which can lead to a sub-clinical inflammatory situation associated with unfavourable outcomes 21. In addition to being key effector cells in brain inflammation, they are critical for normal brain development in processes such as axonal growth and synapse formation 22, 23. The role of microglia in neuroinflammation is dynamic and complex, reflected in their mutable phenotypes including both pro-inflammatory and restorative functions 24. Despite their important neurobiological role, the time course and nature of the microglial responses in preterm birth are currently largely unknown, and the interplay of inflammatory and developmental processes is also unclear. We, and others, believe that a better understanding of the molecular mechanisms underlying microglial function could harness their beneficial effects and mitigate the brain injury of prematurity and other states of brain inflammation25, 26A clinically relevant experimental mouse model of IL1B-induced systemic inflammation has been developed to study the changes occurring in the preterm human brain 27, 28. This model recapitulates the hallmarks of encephalopathy of prematurity including oligodendrocyte maturation delay with consequent dysmyelination, associated magnetic resonance imaging (MRI) phenotypes and behavioural deficits. Here, we take advantage of this model system to characterise the molecular underpinnings of the microglial response to IL1B-driven systemic inflammation and investigate its role in concurrent development.In preterm infants MRI is used extensively to provide in-vivo correlates of white and grey matter pathology, allowing clinical assessment and prognostication. Diffusion MRI (d-MRI) measures the displacement of water molecules in the brain, and provides insight into the underlying tissue structure. Various d-MRI measures of white matter have been associated with developmental outcome in children born preterm 29–32, with up to 60% of inter-individual variability in structural and functional features attributable to genetic factors 33, 34. White matter abnormalities are linked to associated grey matter changes at both the imaging and cellular level 10, 35, 36, with functional and structural consequences lasting into adulthood 37, 38. Tract Based Statistics (TBSS) allows quantitative whole-brain white matter analysis of d-MRI data at the voxel level while avoiding problems due to contamination by signals arising from grey matter 39. This permits voxel-wise statistical testing and inferences to be made about group differences or associations with greater statistical power. TBSS has been shown to be an effective tool for studying white matter development and injury in the preterm brain 40, providing a macroscopic in vivo quantitative measure of white matter integrity that is associated with cognitive, fine motor, and gross motor outcome 11, 41, 42.In this work we take a translational systems biology approach to investigate the role of microglia in preterm neuroinflammation and brain injury. We integrate microglial cell-type specific data from a mouse model of perinatal neuroinflammatory brain injury with experimental ex vivo and in vitro validation, translation to the human brain across the lifespan including analysis of human microglia, and assessment of the impact of genetic variation on structure of the preterm brain. We add to the understanding of the neurobiology of prematurity by: a) revealing the endogenous expression of DLG4 (PSD95) by microglia in early development, which is modulated by developmental stage and inflammation; and b) finding an association between systemic genetic variability in DLG4 and white matter structure in the preterm neonatal brain.

BACKGROUND: The role of heritable factors in determining the common neurologic deficits seen after preterm birth is unknown, but the characteristic phenotype of neurocognitive, neuroanatomical, and growth abnormalities allows principled selection of candidate genes to test the hypothesis that common genetic variation modulates the risk for brain injury. METHODS: We collected an MRI-linked genomic DNA library from 83 preterm infants and genotyped tag single nucleotide polymorphisms in 13 relevant candidate genes. We used tract-based spatial statistics and deformation-based morphometry to examine the risks conferred by carriage of particular alleles at tag single nucleotide polymorphisms in a restricted number of genes and related these to the preterm cerebral endophenotype. RESULTS: Carriage of the minor allele at rs2518824 in the armadillo repeat gene deleted in velocardiofacial syndrome ( ARVCF ) gene, which has been linked to neuronal migration and schizophrenia, and rs174576 in the fatty acid desaturase 2 gene, which encodes a rate-limiting enzyme for endogenous long chain polyunsaturated fatty acid synthesis and has been linked to intelligence, was associated with white matter abnormality measured in vivo using diffusion tensor imaging ( P = .0009 and P = .0019, respectively). CONCLUSIONS: These results suggest that genetic variants modulate white matter injury after preterm birth, and known susceptibilities to neurologic status in later life may be exposed by the stress of premature exposure to the extrauterine environment.

Genetic abnormalities of cholangiocarcinoma have been widely studied; however, epigenomic changes related to cholangiocarcinogenesis have been less well characterized. We have profiled the DNA methylomes of 28 primary cholangiocarcinoma and six matched adjacent normal tissues using Infinium's HumanMethylation27 BeadChips with the aim of identifying gene sets aberrantly and epigenetically regulated in this tumor type. Using a linear model for microarray data, we identified 1610 differentially methylated autosomal CpG sites, with 809 hypermethylated (representing 603 genes) and 801 hypomethylated (representing 712 genes) in cholangiocarcinoma versus adjacent normal tissues (false-discovery rate ≤ 0.05). Gene ontology and gene set enrichment analyses identified gene sets significantly associated with hypermethylation at linked CpG sites in cholangiocarcinoma including homeobox genes and target genes of PRC2, EED, SUZ12, and histone H3 trimethylation at lysine 27. We confirmed frequent hypermethylation at the homeobox genes HOXA9 and HOXD9 by bisulfite pyrosequencing in a larger cohort of cholangiocarcinoma (n = 102). Our findings indicate a key role for hypermethylation of multiple CpG sites at genes associated with a stem cell-like phenotype as a common molecular aberration in cholangiocarcinoma. These data have implications for cholangiocarcinogenesis, as well as possible novel treatment options using histone methyltransferase inhibitors. Cancer Prev Res; 6(12); 1348–55. ©2013 AACR.

Objective: Obesity is linked to both increased metabolic disturbances and increased adipose tissue macrophage infiltration. However, whether macrophage infiltration directly influences human metabolism is unclear. The aim of this study was to investigate if there are obesity-independent links between adipose tissue macrophages and metabolic disturbances. Design and Methods: Expression of macrophage markers in adipose tissue was analyzed by DNA microarrays in the SOS Sib Pair study and in patients with type 2 diabetes and a BMI-matched healthy control group. Results: The expression of macrophage markers in adipose tissue was increased in obesity and associated with several metabolic and anthropometric measurements. After adjustment for BMI, the expression remained associated with insulin sensitivity, serum levels of insulin, C-peptide, high density lipoprotein cholesterol (HDL-cholesterol) and triglycerides. In addition, the expression of most macrophage markers was significantly increased in patients with type 2 diabetes compared to the control group. Conclusion: Our study shows that infiltration of macrophages in human adipose tissue, estimated by the expression of macrophage markers, is increased in subjects with obesity and diabetes and associated with insulin sensitivity and serum lipid levels independent of BMI. This indicates that adipose tissue macrophages may contribute to the development of insulin resistance and dyslipidemia.

Context: Men and women differ in body fat distribution and adipose tissue metabolism as well as in obesity comorbidities and their response to obesity treatment. Objective: The objective of the study was a search for sex differences in adipose tissue function. Design and Setting: This was an exploratory study performed at a university hospital. Participants and Main Outcome Measures: Resting metabolic rate (RMR), body composition, and sc adipose tissue genome-wide expression were measured in the SOS Sib Pair study (n = 732). Results: The relative contribution of fat mass to RMR and the metabolic rate per kilogram adipose tissue was higher in women than in men (P value for sex by fat mass interaction = .0019). Women had increased expression of genes involved in mitochondrial function, here referred to as a mitochondrial gene signature. Analysis of liver, muscle, and blood showed that the pronounced mitochondrial gene signature in women was specific for adipose tissue. Brown adipocytes are dense in mitochondria, and the expression of the brown adipocyte marker uncoupling protein 1 was 5-fold higher in women compared with men in the SOS Sib Pair Study (P = 7.43 × 10−7), and this was confirmed in a cross-sectional, population-based study (n = 83, 6-fold higher in women, P = .00256). Conclusions: The increased expression of the brown adipocyte marker uncoupling protein 1 in women indicates that the higher relative contribution of the fat mass to RMR in women is in part explained by an increased number of brown adipocytes.

Variable number tandem repeats (VNTRs) constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them. Recent large-scale genome-wide copy number variant mapping and association efforts have highlighted the need for improved methodology for association studies using these complex polymorphisms. Here we describe the in-depth investigation of a complex region on chromosome 8p21.2 encompassing the dedicator of cytokinesis 5 (DOCK5) gene. The region includes two VNTRs of complex sequence composition which flank a common 3975 bp deletion, all three of which were genotyped by polymerase chain reaction and fragment analysis in a total of 2744 subjects. We have developed a novel VNTR association method named VNTRtest, suitable for association analysis of multi-allelic loci with binary and quantitative outcomes, and have used this approach to show significant association of the DOCK5 VNTRs with childhood and adult severe obesity (P(empirical)= 8.9 × 10(-8) and P= 3.1 × 10(-3), respectively) which we estimate explains ~0.8% of the phenotypic variance. We also identified an independent association between the 3975 base pair (bp) deletion and obesity, explaining a further 0.46% of the variance (P(combined)= 1.6 × 10(-3)). Evidence for association between DOCK5 transcript levels and the 3975 bp deletion (P= 0.027) and both VNTRs (P(empirical)= 0.015) was also identified in adipose tissue from a Swedish family sample, providing support for a functional effect of the DOCK5 deletion and VNTRs. These findings highlight the potential role of DOCK5 in human obesity and illustrate a novel approach for analysis of the contribution of VNTRs to disease susceptibility through association studies.

Multiple DNA methylation changes in the cancer methylome are associated with the acquisition of drug resistance; however it remains uncertain how many represent critical DNA methylation drivers of chemoresistance. Using isogenic, cisplatin-sensitive/resistant ovarian cancer cell lines and inducing resensitizaton with demethylating agents, we aimed to identify consistent methylation and expression changes associated with chemoresistance. Using genome-wide DNA methylation profiling across 27 578 CpG sites, we identified loci at 4092 genes becoming hypermethylated in chemoresistant A2780/cp70 compared with the parental-sensitive A2780 cell line. Hypermethylation at gene promoter regions is often associated with transcriptional silencing; however, expression of only 245 of these hypermethylated genes becomes downregulated in A2780/cp70 as measured by microarray expression profiling. Treatment of A2780/cp70 with the demethylating agent 2-deoxy-5'-azacytidine induces resensitization to cisplatin and re-expression of 41 of the downregulated genes. A total of 13/41 genes were consistently hypermethylated in further independent cisplatin-resistant A2780 cell derivatives. CpG sites at 9 of the 13 genes (ARHGDIB, ARMCX2, COL1A, FLNA, FLNC, MEST, MLH1, NTS and PSMB9) acquired methylation in ovarian tumours at relapse following chemotherapy or chemoresistant cell lines derived at the time of patient relapse. Furthermore, 5/13 genes (ARMCX2, COL1A1, MDK, MEST and MLH1) acquired methylation in drug-resistant ovarian cancer-sustaining (side population) cells. MLH1 has a direct role in conferring cisplatin sensitivity when reintroduced into cells in vitro. This combined genomics approach has identified further potential key drivers of chemoresistance whose expression is silenced by DNA methylation that should be further evaluated as clinical biomarkers of drug resistance. Oncogene (2012) 31, 4567-4576; doi:10.1038/onc.2011.611; published online 16 January 2012

The selenoprotein S (SELS) is a putative receptor for serum amyloid A, and recent studies have suggested that SELS may be a link between type 2 diabetes mellitus and inflammation. Genetic studies of SELS polymorphisms have revealed associations with circulating levels of inflammatory markers and hard end points of cardiovascular disease. In this study, we analyzed SELS expression in subcutaneous adipose tissue and SELS genotype in relation to metabolic risk factors. DNA microarray expression analysis was used to study the expression of SELS in lean and obese siblings from the Swedish Obese Subjects Sib Pair Study. TaqMan genotyping was used to analyze 3 polymorphisms, previously found to be associated with circulating levels of inflammatory markers, in the INTERGENE case-control study of myocardial infarction and unstable angina pectoris. Possible associations between SELS genotype and/or expression with anthropometry and measures of metabolic status were investigated. Real-time polymerase chain reaction was used to analyze the SELS expression in isolated human adipocytes incubated with insulin. In lean subjects, we found correlations between SELS gene expression in subcutaneous adipose tissue and measures of obesity (waist, P = .045; sagittal diameter, P = .031) and blood pressure (diastolic, P = .016; systolic P = .015); and in obese subjects, we found correlations with measures of obesity (body mass index, P = .03; sagittal diameter, P = .008) and glycemic control (homeostasis model assessment of insulin resistance, P = .011; insulin, P = .009) after adjusting for age and sex. The 5227GG genotype was associated with serum levels of insulin (P = .006) and homeostasis model assessment of insulin resistance (P = .007). The expression of SELS increased after insulin stimulation in isolated human adipocytes (P = .008). In this study, we found an association between both SELS gene expression in adipose tissue and SELS genotype with measures of glycemic control. In vitro studies demonstrated that the SELS gene is regulated by insulin in human subcutaneous adipocytes. This study further supports a role for SELS in the development of metabolic disease, especially in the context of insulin resistance.

Leptin is emerging as a key regulator of bone remodeling. In a population-based study of 1306 postmenopausal Danish women, nonsynonymous LEPR SNPs were associated with risk of adiposity, BMD, and vertebral fracture. Smoking exacerbates this LEPR-associated fracture risk. Introduction: Nonsynonymous single nucleotide polymorphisms (SNPs) in the human LEPR gene have been associated with adiposity in a number of studies, but there have been no large-scale studies of their implica- tions for BMD and osteoporotic fracture risk in postmenopausal women. Materials and Methods: We carried out a population-based study of 1430 women. Three well-known non- synonymous leptin receptor (LEPR) SNPs (Lys109Arg, Gln223Arg, and Lys656Asn) were genotyped for qualitative and quantitative association analysis. Phenotype characteristics of main interest were DXA mea- sures of body fat and lean tissue mass, BMD, and radiographic vertebral fractures. Results: Gln223Arg associated with risk of vertebral fracture (overall OR 1.76; OR in smokers 2.31; p 0.0004), in addition to BMD of the femoral neck and total hip (p 0.036 and 0.008, respectively). Heterozygote carriers showed lower BMD at both sites. Gln223Arg was also associated with adiposity (p 0.001 for total fat mass). For adiposity, the at-risk allele was G (resulting in an arginine at position 223). Conclusions: Variation in LEPR seemed to contribute to the variation in BMD and fracture risk in Danish postmenopausal women; the heterozygous genotype was associated with increased risk of manifest osteopo- rosis. Further studies are needed to replicate these data and to clarify the mechanisms involved. J Bone Miner Res 2007;22:544-550. Published online on January 22, 2007; doi: 10.1359/JBMR.070114

Objective: The main purpose of this study was to investigate associations of single-nucleotide polymorphisms (SNPs) in the adipocyte C1q and collagen domain-containing (ACDC) gene and its regulator, the nuclear peroxisome proliferator-activated receptor (PPAR)-γ gene, with body fat mass and its topographical distribution in postmenopausal women. Research Methods and Procedures: Participants were 1501 healthy women, 60 to 85 years old, who were genotyped for four SNPs in the ACDC gene (−11391G/A, −11377C/G, +45T/G, +276G/T) and the Pro12Ala SNP in the PPAR-γ gene. Total body fat mass and the central to peripheral fat mass ratio (CFM/PFM ratio) were measured using DXA. Adiponectin and homeostasis model assessment of insulin resistance were measured in 287 subjects. Results: The −11377C/G SNP was associated with adiponectin (p < 0.001) and the CFM/PFM ratio (p = 0.005); the G allele being associated with low adiponectin and high CFM/PFM ratio. Similar associations of adiponectin (p = 0.0001) and the CFM/PFM ratio (p = 0.002) characterized the 1_2 (G_G) promoter haplotype (11391G/A_−11377C/G). Genotype variation of SNP Pro12Ala was associated with total body fat mass (p = 0.04); women with GG being the most obese (p = 0.01). The Ala/Ala (GG) genotype of Pro12Ala SNP interacted with the CC genotype of SNP-11377C/G in the determination of BMI (p = 0.001), when analyzed using a codominant model. Discussion: Polymorphisms in the ACDC gene are associated with body fat distribution, whereas the Pro12Ala polymorphism in PPAR-γ is associated with overall adiposity, apparently in interaction with an ACDC promoter SNP.

Interleukin-1 (IL1) is a potent endogenous pyrogen and inducer of the acute phase response, and these innate immune responses are an important part of the human host's initial reaction to infection by the malaria parasite. In addition, several single-nucleotide polymorphisms (SNPs) in this region have previously been demonstrated to be associated with susceptibility to infectious disease. Therefore, a possible association with malaria susceptibility was investigated. A total of 13 polymorphic markers were used in a two-stage screening strategy to genotype a Gambian case-control study group by either restriction endonuclease digestion or the Sequenom MassARRAY assay. This involved an initial screen of 188 severe cases and 188 mild controls, and if there was a significant association with a malaria phenotype (P T (P=0.035 for mild malaria versus controls) and interleukin-1 beta +3953 C --> T (P=0.030 for mild malaria versus severe malaria). Haplotypes constructed using the SNPHAP programme were not associated with any of the malaria phenotypes investigated. In summary, if IL1 variants are involved in malaria susceptibility in the Gambia at all, then the effects are small.

Malaria continues to claim the lives of more children worldwide than any other infectious disease, and improved understanding of disease immunology is a priority for the development of new therapeutic and vaccination strategies. FcgammaRIIa (CD32) contains a polymorphic variant (H/R131) that has been associated with variability in susceptibility to both bacterial diseases and Plasmodium falciparum parasitemia. We investigated the role of this polymorphism in West Africans with mild and severe malarial disease. The HH131 genotype was significantly associated with susceptibility to severe malaria (P = 0.03, odds ratio = 1.40, 95% confidence interval = 1.02-1.91). In contrast to studies of parasitemia, the presence of the R131 allele, rather than the RR131 genotype, appeared to be the important factor in protection from disease. This is the first evidence for an association between CD32 polymorphism and severe malaria and provides an example of balancing selective pressures from different infectious diseases operating at the same genetic locus.

The chromosome 21q22.11 cytokine receptor cluster contains four genes that encode subunits of the receptors for the cytokines interleukin-10 and interferon-alpha, -beta and -gamma that may have a role in malaria pathogenesis. A total of 15 polymorphic markers located within these genes were initially genotyped in 190 controls and 190 severe malaria cases from The Gambia. Two interferon-alpha receptor-1 (IFNAR1) gene SNPs (17470 and L168 V) showed evidence for an association with severe malaria phenotypes and were typed in a larger series of samples comprising 538 severe malaria cases, 338 mild malaria cases and 562 controls. Both the 17470-G/G and L168V-G/G genotypes were associated with protection against severe malaria, in general, and cerebral malaria, in particular (P=0.004 and 0.003, respectively). IFNAR1 diplotypes were then constructed for these two markers using the PHASE software package. The (17470-G L168V-G/17470-G L168V-G) diplotype was found to be associated with a reduced risk of cerebral malaria and the (17470-C L168V-C/17470-G L168V-G) diplotype with an increased risk of cerebral malaria (overall 3 x 2 chi(2)=12.8, d.f.=2, P=0.002 and 3 x 2 chi(2)=15.2, d.f.=2, P=0.0005, respectively). These data suggest a role for the type I interferon pathway in resistance to cerebral malaria.

Summary: A program package to enable genome-wide association of copy number variants (CNVs) with quantitative phenotypes in families of arbitrary size and complexity. Intensity signals that act as proxies for the number of copies are modeled in a variance component framework and association with traits is assessed through formal likelihood testing. Availability and implementation: The Java package is made available at www.imperial.ac.uk/medicine/people/m.falchi/. Contact: m.falchi@imperial.ac.uk

Previous segregation analysis of a sample of 234 randomly selected Australian families showed evidence for a recessive major gene controlling serum immunoglobulin E (IgE) levels independently of the specific response to allergens (SRA). Since linkage has been recently reported between serum IgE levels and the 5q candidate region spanning the interleukin-4 (IL-4) gene, we investigated whether the recessive major gene detected by segregation analysis was linked to the IL-4 region and whether polymorphisms within the IL-4 gene were associated with IgE levels. Both sib-pair method and combined segregation and linkage analysis using the regressive models were applied to our data. Whereas there was no evidence of linkage of total IgE levels to the IL-4 region, an indication of linkage (P values ranging between 0.01 and 0.03) was found between IgE levels adjusted for SRA and two IL-4 polymorphisms: one dinucleotide repeat in intron 2 of the IL-4 gene and a single nucleotide (-590 C to T) polymorphism in the IL-4 promoter. However, the putative IL-4 linked gene did not appear to be in linkage disequilibrium with either of these two polymorphisms. A contribution of the IL-4 promoter polymorphism, presumed to be a potential functional variant influencing IgE variation, was also excluded.

IgE dysregulation is a major pathogenic feature of atopic dermatitis and other IgE-mediated allergic diseases such as asthma and rhinitis. Allergen complexed to IgE binds to the high affinity receptor for IgE (Fc epsilon RI) on the surface of epidermal Langerhans cells, mast cells and basophils, triggering the release of inflammatory mediators. The beta subunit of Fc epsilon RI has been localized to human chromosome 11q12-13, and variants within this gene have been shown to associate with asthma and measures of atopy. We have tested several polymorphisms within Fc epsilon RI-beta for association to atopic dermatitis in a panel of 60 families (panel A), recruited through a proband with atopic dermatitis. The findings were tested in a second panel of families (panel B). Significant sharing of maternal alleles was seen for atopic dermatitis and allele 2 of RsaI intron 2 (RsaIvin2*2) (P = 0.0022) and allele 1 of RsaI exon 7 (RsaIvex7*1) (P = 0.0036) Fc epsilon RI-beta gene polymorphisms. These findings were replicated in Panel B, confirming the association of Fc epsilon RI-beta RsaI polymorphisms with atopic dermatitis. The combined significance of the association of atopic dermatitis to RsaI polymorphisms was P = 0.0002 (RsaIvin2*2) and P = 0.00034 (RsaIvex7*1). The polymorphisms also showed association with asthma: P = 0.0068 (RsaIvin2*2) and P = 0.018 (RsaIvex7*1). Polymorphisms within the Fc epsilon RI-beta gene are strongly associated with atopic dermatitis.

Although family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS.To systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations.A systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies.We identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49-0.83) with moderate heterogeneity (I(2)=27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes.Few putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses.Combining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations.

Kari Tikkinen*, Hamilton, Canada; Rufus Cartwright, London, United Kingdom; Anna Kirby, San Diego, CA; Altaf Mangera, Sheffield, United Kingdom; Gans Thiagamoorthy, London, United Kingdom; Prabhakar Rajan, Glasgow, United Kingdom; Jori Pesonen, Tampere, Finland; Tom Palmer, Bristol, United Kingdom; Chris Ambrose, Vik Khullar, Andrew Walley, Marjo-Riitta Jarvelin, Phillip Bennett, London, United Kingdom; Chris Chapple, Sheffield, United Kingdom

Anna Kirby*, San Diego, CA; Rufus Cartwright, London, United Kingdom; Kari Tikkinen, Hamilton, Canada; Tom Palmer, Bristol, United Kingdom; Gans Thiagamoorthy, London, United Kingdom; Prabhakar Rajan, Glasgow, United Kingdom; Jori Pesonen, Tampere, Finland; Andrew Walley, London, United Kingdom; Altaf Mangera, Sheffield, United Kingdom; Georgios Grigoriadis, Chris Ambrose, Marjo-Riitta Jarvelin, Phillip Bennett, London, United Kingdom; Chris Chapple, Sheffield, United Kingdom; Vik Khullar, London, United Kingdom

Background We have previously identified an association between lipids and features of diffusion tensor imaging in preterm infants, highlighting the KEGG peroxisome proliferator-activated receptor pathway (PPAR) as the most highly ranked in association with a white matter phenotype. Here we applied a penalised linear regression model—the graph-guided group lasso (GGGL)—to select single nucleotide polymorphisms within functionally related genes associated with the imaging trait. The GGGL model utilises network-based prior knowledge to improve the selection of variables of interest. Methods Images acquired with a 3T MR scanner were collected along with saliva for 72 preterm infants (mean gestational age 28 weeks [+4 days], mean postmenstrual age at scan 40 weeks [+3 days]). Salivary DNA was extracted and genotyped with HumanOmniExpress-12 arrays (Illumina, San Diego, CA, USA). Fractional anisotropy maps were constructed from diffusion tensor imaging, and tract-based spatial statistics were used to obtain a group white matter skeleton varying with degree of prematurity, adjusting for age at scan. GGGL was applied to the genes in the PPAR pathway. Findings The GGGL method selected five of the 69 genes in the PPAR pathway, and these were functionally related in terms of Gene Ontology Biological Process and linearly correlated with white matter fractional anisotropy ( AQP7, ME1, PLIN1, SLC27A1 , and ACAA1 ). Analysis of transcriptional regulation with the PASTAA algorithm indicated that ACAA1, AQP7, ME1 , and SLC27A1 were jointly regulated by the EGR4 transcription factor (adjusted p=7·7×10 −4 ). Interpretation Our GGGL analysis of genes in the PPAR pathway identified five highly ranked genes involved in neuronal growth, myelinogenesis, and nervous system response to inflammation, and jointly transcriptionally regulated. Since preterm infants are at increased risk of mental illness and cardiovascular morbidity in later life, this work uses an integrative data-driven strategy to propose a unifying mechanism for these systemic effects, suggesting a promising avenue for intervention. Funding Medical Research Council, National Institute for Health Research Biomedical Research Centre.

Serous borderline tumors (SBOTs) are a challenging group of ovarian tumors positioned between benign and malignant disease. We have profiled the DNA methylomes of 12 low-grade serous carcinomas (LGSCs), 19 SBOTs, and 16 benign serous tumors (BSTs) across 27,578 CpG sites to further characterize the epigenomic relationship between these subtypes of ovarian tumors. Unsupervised hierarchical clustering of DNA methylation levels showed that LGSCs differ distinctly from BSTs, but not from SBOTs. Gene ontology analysis of genes showing differential methylation at linked CpG sites between LGSCs and BSTs revealed significant enrichment of gene groups associated with cell adhesion, cell-cell signaling, and the extracellular region, consistent with a more invasive phenotype of LGSCs compared with BSTs. Consensus clustering highlighted differences between SBOT methylomes and returned subgroups with malignant- or benign-like methylation profiles. Furthermore, a two-loci DNA methylation signature can distinguish between these SBOT subgroups with benign- and malignant-like methylation characteristics. Our findings indicate striking similarities between SBOT and LGSC methylomes, supporting a common origin and the view that LGSC may arise from SBOT. A subgroup of SBOTs can be classified into tumors with a benign- or a malignant-like methylation profile that may help in identifying tumors more likely to progress into LGSCs.

Adipocytes secrete many proteins that regulate metabolic functions. The gene inter-α (globulin) inhibitor H5 (ITIH-5) encodes a secreted protein and is known to be expressed abundantly in the placenta. However, using gene expression profiles data we observed high expression of ITIH-5 in adipose tissue. The aim of this study was to test the hypothesis that ITIH-5 is strongly expressed in human adipocytes and adipose tissue, and is related to obesity and clinical metabolic variables. ITIH-5 adipose tissue mRNA expression was analyzed with DNA microarray and real-time PCR, and its association with clinical variables was examined. ITIH-5 protein expression was analyzed using western blot. ITIH-5 mRNA expression was abundant in human adipose tissue, adipocytes, and placenta, and higher in subcutaneous (sc) compared to omental adipose tissue (P < 0.0001). ITIH-5 mRNA and protein expression in sc adipose tissue were higher in obese compared to lean subjects (P < 0.0001 and P < 0.001, respectively). ITIH-5 mRNA expression was reduced after diet-induced weight loss (P < 0.0001). ITIH-5 mRNA expression was associated with anthropometry and clinical metabolic variables. In conclusion, ITIH-5 is highly expressed in sc adipose tissue, increased in obesity, down regulated after weight loss, and associated with measures of body size and metabolism. Together, this indicates that ITIH-5 merits further investigation as a regulator of human metabolism.

Recent studies have reported associations of sirtuin 1 (SIRT1) single nucleotide polymorphisms (SNPs) to both obesity and BMI. This study was designed to investigate association between SIRT1 SNPs, SIRT1 gene expression and obesity. Case-control analyses were performed using 1,533 obese subjects (896 adults, BMI40 kg/m(2) and 637 children, BMI97th percentile for age and sex) and 1,237 nonobese controls, all French Caucasians. Two SNPs (in high linkage disequilibrium (LD), r(2) = 0.96) were significantly associated with adult obesity, rs33957861 (P value = 0.003, odds ratio (OR) = 0.75, confidence interval (CI) = 0.61-0.92) and rs11599176 (P value: 0.006, OR = 0.74, CI = 0.61-0.90). Expression of SIRT1 mRNA was measured in BMI-discordant siblings from 154 Swedish families. Transcript expression was significantly correlated to BMI in the lean siblings (r(2) = 0.13, P value = 3.36 × 10(-7)) and lower SIRT1 expression was associated with obesity (P value = 1.56 × 10(-35)). There was also an association between four SNPs (rs11599176, rs12413112, rs33957861, and rs35689145) and BMI (P values: 4 × 10(-4), 6 × 10(-4), 4 × 10(-4), and 2 × 10(-3)) with the rare allele associated with a lower BMI. However, no SNP was associated with SIRT1 transcript expression level. In summary, both SNPs and SIRT1 gene expression are associated with severe obesity.

Obesity has been present in the human population at a low frequency for a very long time, most likely caused by rare monogenic or syndromic genetic disease. In the last few decades of the twentieth century and into the twenty-first, rates of obesity have greatly increased, initially in the USA, then in other Western industrialized countries until we now have a genuinely global epidemic. As evolution works on a far longer timescale than this, it has been concluded by many that genetics cannot possibly play a part in common obesity. However, many studies have demonstrated significant heritability for obesity-related traits, including body mass index (BMI), waist circumference (WC), waist–hip ratio (WHR), and eating behavior. One example would be twin studies of BMI, which have generated heritability estimates of 0.5–0.7 for this trait, commonly used to define clinical obesity. In this chapter we review the evidence for the crucial role of genetics in common clinical obesity within our obesogenic environment. We focus on the role of heritability in common obesity and provide an overview of both study designs and results for different obesity-related traits.

The last few years have seen major advances in common non-syndromic obesity research, much of it the result of genetic studies. This Review outlines the competing hypotheses about the mechanisms underlying the genetic and physiological basis of obesity, and then examines the recent explosion of genetic association studies that have yielded insights into obesity, both at the candidate gene level and the genome-wide level. With obesity genetics now entering the post-genome-wide association scan era, the obvious question is how to improve the results obtained so far using single nucleotide polymorphism markers and how to move successfully into the other areas of genomic variation that may be associated with common obesity.

Visfatin was recently reported as a novel adipokine encoded by the NAMPT (PBEF1) gene. This study was aimed at investigation of the possibility that single-nucleotide polymorphisms (SNPs) in the visfatin gene are associated with either obesity or type 2 diabetes (T2D). A set of eight "tag-SNPs" were selected and ABI SNPlex assays designed for genotyping purposes. A total of 1,709 severely obese subjects were typed (896 class III obese adults and 813 children) together with 2,367 T2D individuals and 2,850 controls. For quantitative trait analysis, an additional 2,362 subjects were typed for rs10487818 from a general population sample. One rare SNP, rs10487818, located in intron 4 of NAMPT was associated with severe obesity, with a minor allele frequency of 1.6% in controls, 0.4% in the class III obese adults and, remarkably, 0% in the severely obese children. A highly significant association was observed for the presence or absence of the rare allele, i.e., (A,A) vs. (A,T + T,T) genotypes, in children (P = 6 x 10(-9)) and in adults (P = 8 x 10(-5)). No other significant (P < 0.05) association was observed with obesity or T2D for this or any other SNP. No association with BMI or waist-to-hip ratio was observed in a general population sample (n = 5,212). This is one of the first rare SNPs shown to be protective against a common polygenic disease and provides further evidence that rare alleles of strong effect can contribute to complex diseases such as severe obesity.

We analyzed genome-wide association data from 1,380 Europeans with early-onset and morbid adult obesity and 1,416 age-matched normal-weight controls. Thirty-eight markers showing strong association were further evaluated in 14,186 European subjects. In addition to FTO and MC4R, we detected significant association of obesity with three new risk loci in NPC1 (endosomal/lysosomal Niemann-Pick C1 gene, P = 2.9 x 10(-7)), near MAF (encoding the transcription factor c-MAF, P = 3.8 x 10(-13)) and near PTER (phosphotriesterase-related gene, P = 2.1 x 10(-7)).

RATIONALE: Increasing evidence supports a key role for the transcription factor nuclear factor (NF)-kappaB in the host response to pneumococcal infection. Control of NF-kappaB activity is achieved through interactions with the IkappaB family of inhibitors, encoded by the genes NFKBIA, NFKBIB, and NFKBIE. Rare NFKBIA mutations cause immunodeficiency with severe bacterial infection, raising the possibility that common IkappaB gene polymorphisms confer susceptibility to common bacterial disease. OBJECTIVES: To determine whether polymorphisms in NFKBIA, NFKBIB, and NFKBIE associate with susceptibility to invasive pneumococcal disease (IPD) and thoracic empyema. METHODS: We studied the frequencies of 62 single-nucleotide polymorphisms (SNPs) across NFKBIA, NFKBIB, and NFKBIE in individuals with IPD and control subjects (n=1,060). Significantly associated SNPs were then studied in a group of individuals with thoracic empyema and a second control group (n=632). MEASUREMENTS AND MAIN RESULTS: Two SNPs in the NFKBIA promoter region were associated with protection from IPD in both the initial study group and the pneumococcal empyema subgroup. Significant protection from IPD was observed for carriage of mutant alleles at these two loci on combining the groups (SNP rs3138053: Mantel-Haenszel 2x2 chi2=13.030, p=0.0003; odds ratio [OR], 0.60; 95% confidence interval [CI], 0.45-0.79; rs2233406: Mantel-Haenszel 2x2 chi2=18.927, p=0.00001; OR, 0.55; 95% CI, 0.42-0.72). An NFKBIE SNP associated with susceptibility to IPD but not pneumococcal empyema. None of the NFKBIB SNPs associated with IPD susceptibility. CONCLUSIONS: NFKBIA polymorphisms associate with susceptibility to IPD. Genetic variation in an inhibitor of NF-kappaB therefore not only causes a very rare immunodeficiency state but may also influence the development of common infectious disease.

Obesity has always existed in human populations, but until very recently was comparatively rare. The availability of abundant, energy-rich processed foods in the last few decades has, however, resulted in a sharp rise in the prevalence of obesity in westernized countries. Although it is the obesogenic environment that has resulted in this major healthcare problem, it is acting by revealing a sub-population with a pre-existing genetic predisposition to excess adiposity. There is substantial evidence for the heritability of obesity, and research in both rare and common forms of obesity has identified genes with significant roles in its aetiology. Application of this understanding to patient care has been slower. Until very recently, the health risks of obesity were thought to be well understood, with a straightforward correlation between increasing obesity and increasing risk of health problems such as type 2 diabetes, coronary heart disease, hypertension, arthritis and cancer. It is becoming clear, however, that the location of fat deposition, variation in the secretion of adipokines and other factors govern whether a particular obese person develops such complications. Prediction of the health risks of obesity for individual patients is not straightforward, but continuing advances in understanding of genetic factors influencing obesity risk and improved diagnostic technologies mean that the future for such prediction is looking increasingly bright.

AIMS/HYPOTHESIS: Genetic variants of genes for peptide YY (PYY), neuropeptide Y2 receptor (NPY2R) and pancreatic polypeptide (PPY) were investigated for association with severe obesity. SUBJECTS AND METHODS: The initial screening of the genes for variants was performed by sequencing in a group of severely obese subjects (n=161). Case-control analysis of the common variants was then carried out in 557 severely obese adults, 515 severely obese children and 1,163 non-obese/non-diabetic control subjects. Rare variants were genotyped in 700 obese children and the non-obese/non-diabetic control subjects (n=1,163). RESULTS: Significant association was found for a 5' variant (rs6857715) in the NPY2R gene with both severe adult obesity (p=0.002) and childhood obesity (p=0.02). This significant association was further supported by a pooled allelic analysis of all obese cases (adults and children, n=928) vs the control subjects (n=938) (p=0.0004, odds ratio=1.3, 95% CI 1.1-1.5). Quantitative trait analysis of BMI and WHR was performed and significant association was observed for SNP rs1047214 in NPY2R with an increase in WHR in the severely obese children (co-dominant model p=0.005, recessive model p=0.001). Association was also observed for an intron 3 variant (rs162430) in the PYY gene with childhood obesity (p=0.04). No significant associations were observed for PPY variants. Only one rare variant in the NPY2R gene (C-5641T) was not found in lean individuals and this was found to co-segregate with obesity in one family. CONCLUSIONS/INTERPRETATION: These results provide evidence of association for NPY2R and PYY gene variants with obesity and none for PPY variants. A rare variant of the NPY2R gene showed evidence of co-segregation with obesity and its contribution to obesity should be investigated further.

Obesity is an important cause of morbidity and mortality in developed countries, and is also becoming increasingly prevalent in the developing world. Although environmental factors are important, there is considerable evidence that genes also have a significant role in its pathogenesis. The identification of genes that are involved in monogenic, syndromic and polygenic obesity has greatly increased our knowledge of the mechanisms that underlie this condition. In the future, dissection of the complex genetic architecture of obesity will provide new avenues for treatment and prevention, and will increase our understanding of the regulation of energy balance in humans.

The influence of haptoglobin polymorphisms on severe malaria occurrence was assessed in 1183 individuals from The Gambia. No significant association was found between severe malaria and either haptoglobin genotypes or phenotypes. The advantages of using a deoxyribonucleic acid-based haptoglobin typing method are discussed.

Introduction The prevalence and diversity of fungal airway isolates is increasing in cystic fibrosis (CF). Amidst an extending spectrum of fungal complications, lack of standardised mycology methods and poor sensitivity of culture-dependent techniques renders interpretation of isolates challenging. Aims To evaluate the diagnostic utility of fungal cytology and microbiology stains in addition to prolonged sputum culture from adult CF patients in comparison to standard mycology techniques. Secondly, to develop a novel, next-generation sequencing assay targeting the ITS2 region of the fungal ribosomal-RNA gene to comprehensively profile the sputum fungal microbiota. Methods Sputum samples were investigated by a panel of three mycology techniques: prolonged fungal culture (each examined at: Day7, D14, D21, D28); Calcofluor White (CFW) stain; Grocott’s Methenamine Silver (GMS) stain. A cohort of samples was also subject to broad-spectrum fungal next-generation sequencing. Results 25 adult patients provided 45 sputum samples. Four fungal species were cultivatable: Candida species (26.6%); Aspergillus fumigatus (4.4%); Scedosporium apiospermum (15.5%) and Exophiala dermatitidis (11.1%). Prolonged culture significantly increased overall fungal prevalence by 22% compared to standard duration (D7) p = 0.008 ) . A significant increase of 11.1% in S. apiopspermum prevalence was observed p = 0.02 ) , whilst all E. dermatitidis isolates required prolonged culture. The sensitivity of GMS and CFW stains (85% and 93%) compared favourably to standard duration culture (29%). DNA extracted from a pilot group of these sputum samples (n = 14/45) was subject to PCR using barcode-indexed ITS2 primers designed for Illumina-MiSeq amplicon sequencing. Fungal taxa were detected in all samples, of which seven samples (50%) were negative after prolonged culture. Preliminary sequencing analysis of an extended sample cohort (n = 30) has detected 89 fungal taxa, from which only four species were cultured. Conclusions Prolonged fungal culture is associated with a significant increase in fungal prevalence. The increased sensitivity is restricted to less common filamentous fungi associated with increasing pathogenicity: S. apiospermum and E. dermatitidis. The predictive value of stains in identifying samples positive at prolonged culture, but negative at standard duration illustrates their clinical utility. Illumina-MiSeq ITS2-amplicon sequencing directly from sputum has identified a more diverse CF airways fungal microbiota. Preliminary analysis suggests that this is a highly sensitive tool for detecting fungi from sputum, including species which are refractory to standard and enhanced culture.

Atopic dermatitis (AD) and asthma are characterized by IgE-mediated atopic (allergic) responses to common proteins (allergens), many of which are proteinases. Loci influencing atopy have been localized to a number of chromosomal regions1, including the chromosome 5q31 cytokine cluster2,3,4. Netherton disease is a rare recessive skin disorder in which atopy is a universal accompaniment5. The gene underlying Netherton disease (SPINK5)6 encodes a 15-domain serine proteinase inhibitor (LEKTI) which is expressed in epithelial and mucosal surfaces and in the thymus6,7. We have identified six coding polymorphisms in SPINK5 (Table 1) and found that a Glu420→Lys variant shows significant association with atopy and AD in two independent panels of families. Our results implicate a previously unrecognized pathway for the development of common allergic illnesses.

We have carried out a genome screen for atopic dermatitis (AD) and have identified linkage to AD on chromosomes 1q21, 17q25 and 20p. These regions correspond closely with known psoriasis loci, as does a previously identified AD locus on chromosome 3q21. The results indicate that AD is influenced by genes with general effects on dermal inflammation and immunity.

Asthma is strongly familial and so results partly from genetic factors. Defining these factors improves the understanding of the aetiology and pathophysiology of the disease. The involvement of particular genes may allow the prediction of distinct clinical courses and responses to therapy, and the early identification of children at genetic risk of asthma will then be possible. Although the estimate of risk may be relatively imprecise, the prevention of illness by environmental or other intervention in susceptible children is both feasible and desirable. Genetic discoveries will, in the long run, lead to new pharmacological treatments for asthma.

The cytokine cluster located on chromosome 5 has been shown by linkage studies to play a role in the genetic determination of circulating immunoglobulin E (IgE) levels in atopic subjects. In the study presented here, the reported chromosome 5 linkage has been investigated in two sets of subjects. The first consisted of a general population sample of 230 nuclear families (n = 1004) from Busselton, a small West Australian country town. The second group consisted of 124 unrelated atopic asthmatics and 59 unrelated non-atopic, non-asthmatic controls, all resident in the Oxfordshire Regional Health Authority area in the United Kingdom. A previously reported interleukin-4 (II-4) promoter polymorphism (-590 C-->T) was analysed in these populations by a newly designed method of specific PCR amplification and BsmFI restriction endonuclease digestion. In the Busselton population the polymorphism was shown to be weakly associated with specific IgE to house dust mite (Mann-Whitney-U test, p = 0.013) and to wheeze (MWU test, p = 0.029), but not with specific IgE to grass pollen, total serum IgE, bronchial hyperresponsiveness, eosinophil count, or asthma. In the Oxfordshire subjects there were no statistically significant associations with any measure of asthma or atopy. These data show that the -590 C-->T II-4 promoter polymorphism is only weakly associated with certain measures of asthma and atopy in some subjects. It was specifically not associated with serum IgE concentration or asthma in either of the two groups in this study.

Summary. Three novel point mutations were detected in the glucocerebrosidase gene of three unrelated Gaucher's disease patients by direct sequencing of PCR products. The first is a C to G change at position 4263 in the genomic sequence (exon 7) which results in a proline to arginine change at position 266 in the mature enzyme (P266R). The second is a G to C change at position 5276 in the genomic sequence (exon 8) which results in an aspartic acid to histidine change at position 315 (D315H), The third is a C to A change at position 5286 in the genomic sequence (exon 8) which results in an alanine to aspartic acid change at position 318 (A318D). The first mutation destroys an AvaII restriction endonuclease site, the second creates a BspM I site and the third creates a BamH I site.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10−8–1.2×10−43). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p, Author Summary Serum adiponectin levels are highly heritable and are inversely correlated with the risk of type 2 diabetes (T2D), coronary artery disease, stroke, and several metabolic traits. To identify common genetic variants associated with adiponectin levels and risk of T2D and metabolic traits, we conducted a meta-analysis of genome-wide association studies of 45,891 multi-ethnic individuals. In addition to confirming that variants at the ADIPOQ and CDH13 loci influence adiponectin levels, our analyses revealed that 10 new loci also affecting circulating adiponectin levels. We demonstrated that expression levels of several genes in these candidate regions are associated with serum adiponectin levels. Using a powerful novel method to assess the contribution of the identified variants with other traits using summary-level results from large-scale GWAS consortia, we provide evidence that the risk alleles for adiponectin are associated with deleterious changes in T2D risk and metabolic syndrome traits (triglycerides, HDL, post-prandial glucose, insulin, and waist-to-hip ratio), demonstrating that the identified loci, taken together, impact upon metabolic disease.

The CCR5-delta32 deletion polymorphism (CCR5-delta32) was investigated for linkage and association to asthma and atopy using two panels of nuclear families containing 1284 individuals. No statistically significant linkage to asthma/wheeze or atopy was observed in either of the two panels of families. Multiallelic transmission disequilibrium tests (TDT) of the combined data found no significant association for atopy (52 independent alleles transmitted, 51 non-transmitted) or asthma/wheeze (39 transmitted, 44 non-transmitted). Although functional evidence might suggest that CCR5 is a good candidate gene for atopic asthma, this study provides no genetic evidence from CCR5-delta32 polymorphism to support this hypothesis.

Twenty-six patients with Gaucher's disease diagnosed in the United Kingdom and two obligate carriers, all of non-Jewish origin, were screened for the two common disease causing mutations and two rarer mutations in the glucocerebrosidase gene. These mutations are referred to as N370S, L444P, Ins84G, and 1066 + 1G-->A, respectively. The results showed that out of 54 alleles screened, 26% were N370S, 35% were L444P, and the remaining 39% were rare or undefined. The results also showed a clear correlation between the presence of at least one N370S allele and mild disease.