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1.  Height and Bone Mineral Density Are Associated with Naevus Count Supporting the Importance of Growth in Melanoma Susceptibility 
PLoS ONE  2015;10(1):e0116863.
Naevus count is the strongest risk factor for melanoma. Body Mass Index (BMI) has been linked to melanoma risk. In this study, we investigate the link between naevus count and height, weight and bone mineral density (BMD) in the TwinsUK cohort (N = 2119). In addition we adjusted for leucocyte telomere length (LTL) as LTL is linked to both BMD and naevus count. Naevus count was positively associated with height (p = 0.001) but not with weight (p = 0.187) despite adjusting for age and twin relatedness. This suggests that the previously reported melanoma association with BMI may be explained by height alone. Further adjustment for LTL did not affect the significance of the association between height and naevus count so LTL does not fully explain these results. BMD was associated with naevus count at the spine (coeff 18.9, p = 0.01), hip (coeff = 18.9, p = 0.03) and forearm (coeff = 32.7, p = 0.06) despite adjusting for age, twin relatedness, weight, height and LTL. This large study in healthy individuals shows that growth via height, probably in early life, and bone mass are risk factors for melanoma via increased naevus count. The link between these two phenotypes may possibly be explained by telomere biology, differentiation genes from the neural crests but also other yet unknown factors which may influence both bones and melanocytes biology.
doi:10.1371/journal.pone.0116863
PMCID: PMC4303431  PMID: 25612317
2.  Superior Mesenteric Artery Syndrome in a Patient with Cerebral Palsy 
Case Reports in Medicine  2014;2014:538289.
Superior mesenteric artery syndrome involves compression of the third part of the duodenum due to narrowing of the area between the aorta and the superior mesenteric artery (SMA). We will describe the case of a 34-year-old with cerebral palsy who presented with abdominal pain, nausea, vomiting, and weight loss and was diagnosed with SMA syndrome via CT-imaging. With failure of conservative measures, our patient underwent a duodenojejunostomy after which improvement in her weight as well as relief of her abdominal symptoms was noted. Given the rarity of this syndrome, physicians need to keep a high index of suspicion in order to prevent the damaging consequences.
doi:10.1155/2014/538289
PMCID: PMC4098610  PMID: 25053950
3.  Mapping cis- and trans-regulatory effects across multiple tissues in twins 
Nature genetics  2012;44(10):1084-1089.
Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many eQTL studies typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis-effect on expression cannot be accounted for by common cis-variants, a finding which exposes the contribution of low frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene and identify several replicating trans-variants which act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.
doi:10.1038/ng.2394
PMCID: PMC3784328  PMID: 22941192
4.  Methadone Induced Sensorineural Hearing Loss 
Case Reports in Medicine  2013;2013:242730.
Background. Sudden sensorineural hearing loss (SSHL) caused by opiate abuse or overuse has been well documented in the medical literature. Most documented case reports have involved either heroin or hydrocodone/acetaminophen. Recently, case reposts of methadone induced SSHL have been published. Case Report. We present the case of a 31-year-old man who developed SSHL after a methadone overdose induced stupor. He was subsequently restarted on methadone at his regular dose. On follow-up audiometry exams, he displayed persistent moderately severe sensorineural hearing loss bilaterally. Discussion. This case is notable because unlike all but one previously reported case, the patient—who was restated on methadone—did not make a complete recovery. Conclusion. Methadone overuse in rare cases causes SSHL.
doi:10.1155/2013/242730
PMCID: PMC3745859  PMID: 23983704
5.  Gene expression changes with age in skin, adipose tissue, blood and brain 
Genome Biology  2013;14(7):R75.
Background
Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age.
Results
Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues.
Conclusions
Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.
doi:10.1186/gb-2013-14-7-r75
PMCID: PMC4054017  PMID: 23889843
Aging; gene expression; skin; adipose; brain; microarrays
6.  Effects of proton pump inhibitors and electrolyte disturbances on arrhythmias 
Several case reports have been written regarding the relationship between the use of proton pump inhibitors (PPI) and hypomagnesemia. Some of these reported cases have electrocardiogram abnormalities where electrolytes deficiencies were the contributing factor for these events. This study investigates the correlation between different arrhythmias and the use of PPI and hypomagnesaemia incidence. Four-hundred and twenty-one patients admitted to the critical care unit with unstable angina, non-ST elevation myocardial infarction, and ST-elevation myocardial infarction were included in this study. One-hundred and eighty-four patients (43.8%) received PPI and 237 patients (51.16%) did not, magnesium levels were low (<1.8 mg/dL) in 95 patients (22.5%), and 167 patients (39.6%) developed arrhythmias. The P-values for the regression coefficient association for the use of PPI and the level of magnesium were P = 1.31e−29 and P = 8e−102, respectively. The P-values indicate that there is a statistically significant association between the PPI use, magnesium levels, and the occurrence of cardiovascular events, with a strong correlation factor of 0.817. Patients receiving PPIs should be followed closely for magnesium deficiency, especially if they experience acute cardiovascular events, because this may contribute to worsening arrhythmias and further complications.
doi:10.2147/IJGM.S46932
PMCID: PMC3700779  PMID: 23847429
electrolyte disturbances; medications side effects; cardiac arrhythmias
7.  An Unusual Presentation of Gaucher Disease in an Infant With Progressive Dyspnea 
The Ochsner Journal  2013;13(2):270-272.
Background
The most common lysosomal storage disorder, Gaucher disease, represents a collection of 3 clinical syndromes associated with disrupted glucocerebroside catabolism. Despite the common occurrence of dyspnea in advanced Gaucher, dyspnea is rarely reported as a presenting symptom of the disease.
Case Report
A 10-month-old male was referred to the Otolaryngology Clinic for evaluation of progressive dyspnea. Physical examination was significant for cervical adenopathy, inspiratory stridor, and developmental delay. A complete evaluation for failure to thrive and lymphadenopathy was performed, with subsequent lymph node biopsy and enzyme assay confirming the presence of Gaucher disease.
Conclusion
A high level of suspicion is required to make an early diagnosis of Gaucher disease, but it should be considered in patients presenting with failure to thrive, generalized lymphadenopathy, and respiratory or neurologic findings. Initiation of early treatment is paramount for the prevention of irreversible disease.
PMCID: PMC3684340  PMID: 23789017
Gaucher disease; lymphoproliferative diseases; lysosomal storage diseases; respiratory sounds
8.  A Highly Tunable Silicone-Based Magnetic Elastomer with Nanoscale Homogeneity 
Magnetic elastomers have been widely pursued for sensing and actuation applications. Silicone-based magnetic elastomers have a number of advantages over other materials such as hydrogels, but aggregation of magnetic nanoparticles within silicones is difficult to prevent. Aggregation inherently limits the minimum size of fabricated structures and leads to non-uniform response from structure to structure. We have developed a novel material which is a complex of a silicone polymer (polydimethylsiloxane-co-aminopropylmethylsiloxane) adsorbed onto the surface of magnetite (γ-Fe203) nanoparticles 7–10 nm in diameter. The material is homogenous at very small length scales (< 100 nm) and can be crosslinked to form a flexible, magnetic material which is ideally suited for the fabrication of micro- to nanoscale magnetic actuators. The loading fraction of magnetic nanoparticles in the composite can be varied smoothly from 0 – 50% wt. without loss of homogeneity, providing a simple mechanism for tuning actuator response. We evaluate the material properties of the composite across a range of nanoparticle loading, and demonstrate a magnetic-field-induced increase in compressive modulus as high as 300%. Furthermore, we implement a strategy for predicting the optimal nanoparticle loading for magnetic actuation applications, and show that our predictions correlate well with experimental findings.
doi:10.1016/j.jmmm.2011.08.045
PMCID: PMC3241051  PMID: 22184482
magnetic polymer; PDMS; composite materials; magnetic nanoparticles; actuators; microelectromechanical systems
9.  META-ANALYSIS OF GENOME-WIDE ASSOCIATION STUDIES IDENTIFIES THREE NEW RISK LOCI FOR ATOPIC DERMATITIS 
Paternoster, Lavinia | Standl, Marie | Chen, Chih-Mei | Ramasamy, Adaikalavan | Bønnelykke, Klaus | Duijts, Liesbeth | Ferreira, Manuel A | Alves, Alexessander Couto | Thyssen, Jacob P | Albrecht, Eva | Baurecht, Hansjörg | Feenstra, Bjarke | Sleiman, Patrick MA | Hysi, Pirro | Warrington, Nicole M | Curjuric, Ivan | Myhre, Ronny | Curtin, John A | Groen-Blokhuis, Maria M | Kerkhof, Marjan | Sääf, Annika | Franke, Andre | Ellinghaus, David | Fölster-Holst, Regina | Dermitzakis, Emmanouil | Montgomery, Stephen B | Prokisch, Holger | Heim, Katharina | Hartikainen, Anna-Liisa | Pouta, Anneli | Pekkanen, Juha | Blakemore, Alexandra IF | Buxton, Jessica L | Kaakinen, Marika | Duffy, David L | Madden, Pamela A | Heath, Andrew C | Montgomery, Grant W | Thompson, Philip J | Matheson, Melanie C | Le Souëf, Peter | Pourcain, Beate St | Smith, George Davey | Henderson, John | Kemp, John P | Timpson, Nicholas J | Deloukas, Panos | Ring, Susan M | Wichmann, H-Erich | Müller-Nurasyid, Martina | Novak, Natalija | Klopp, Norman | Rodríguez, Elke | McArdle, Wendy | Linneberg, Allan | Menné, Torkil | Nohr, Ellen A | Hofman, Albert | Uitterlinden, André G | van Duijn, Cornélia M | Rivadeneira, Fernando | de Jongste, Johan C | van der Valk, Ralf JP | Wjst, Matthias | Jogi, Rain | Geller, Frank | Boyd, Heather A | Murray, Jeffrey C | Kim, Cecilia | Mentch, Frank | March, Michael | Mangino, Massimo | Spector, Tim D | Bataille, Veronique | Pennell, Craig E | Holt, Patrick G | Sly, Peter | Tiesler, Carla MT | Thiering, Elisabeth | Illig, Thomas | Imboden, Medea | Nystad, Wenche | Simpson, Angela | Hottenga, Jouke-Jan | Postma, Dirkje | Koppelman, Gerard H | Smit, Henriette A | Söderhäll, Cilla | Chawes, Bo | Kreiner-Møller, Eskil | Bisgaard, Hans | Melén, Erik | Boomsma, Dorret I | Custovic, Adnan | Jacobsson, Bo | Probst-Hensch, Nicole M | Palmer, Lyle J | Glass, Daniel | Hakonarson, Hakon | Melbye, Mads | Jarvis, Deborah L | Jaddoe, Vincent WV | Gieger, Christian | Strachan, David P | Martin, Nicholas G | Jarvelin, Marjo-Riitta | Heinrich, Joachim | Evans, David M | Weidinger, Stephan
Nature genetics  2011;44(2):187-192.
Atopic dermatitis (AD) is a common chronic skin disease with high heritability. Apart from filaggrin (FLG), the genes influencing AD are largely unknown. We conducted a genome-wide association meta-analysis of 5,606 cases and 20,565 controls from 16 population-based cohorts and followed up the ten most strongly associated novel markers in a further 5,419 cases and 19,833 controls from 14 studies. Three SNPs met genome-wide significance in the discovery and replication cohorts combined: rs479844 upstream of OVOL1 (OR=0.88, p=1.1×10−13) and rs2164983 near ACTL9 (OR=1.16, p=7.1×10−9), genes which have been implicated in epidermal proliferation and differentiation, as well as rs2897442 in KIF3A within the cytokine cluster on 5q31.1 (OR=1.11, p=3.8×10−8). We also replicated the FLG locus and two recently identified association signals at 11q13.5 (rs7927894, p=0.008) and 20q13.3 (rs6010620, p=0.002). Our results underline the importance of both epidermal barrier function and immune dysregulation in AD pathogenesis.
doi:10.1038/ng.1017
PMCID: PMC3272375  PMID: 22197932
10.  Six Novel Susceptibility Loci for Early-Onset Androgenetic Alopecia and Their Unexpected Association with Common Diseases 
PLoS Genetics  2012;8(5):e1002746.
Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10−9–1.01×10−12). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06–1.55, p = 8.9×10−3). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10−88]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions.
Author Summary
While most genome-wide association studies (GWAS) focus on the identification of susceptibility loci for a specific disease, this hypothesis-free approach also enables the identification of unexpected associations between different diseases by taking advantage of the previously published GWAS associations. Androgenetic Alopecia (AGA, also known as male pattern baldness) is the most common type of hair loss in humans. Parkinson's disease is reported to occur more commonly in men than in women; however, there are no studies investigating the link between AGA and Parkinson's disease. Here, we show that a specific genetic locus, chromosome 17q21.31, which is associated with Parkinson's disease, is also a susceptibility locus for early-onset AGA. We further investigate the association between early-onset AGA and Parkinson's disease, irrespective of genotype, directly in a large-scale web-based study. We find that men with early-onset AGA have 28% higher risk of developing Parkinson's disease. The early-onset AGA locus on chromosome 17q21.31 has also been linked to decreased fertility previously. Future studies of this locus may implicate novel biological pathways affecting these three conditions.
doi:10.1371/journal.pgen.1002746
PMCID: PMC3364959  PMID: 22693459
11.  Extent, Causes, and Consequences of Small RNA Expression Variation in Human Adipose Tissue 
PLoS Genetics  2012;8(5):e1002704.
Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population.
Author Summary
Genetic information is transmitted to the cell only through RNA molecules. A special class of RNAs is comprised of the small (up to 30 nucleotide) ones, known to be potent regulators of various cellular processes. At the same time, they have not been as widely studied as messenger RNAs—we do not know how much variation in their sequence and expression level occurs naturally in human populations or how this variability influences other traits. We measured small RNA levels and genetic variability in fat tissue from 131 individuals by high-throughput sequencing. We could associate the expression levels with genetic background of the individuals, as well as changes in metabolic traits. Surprisingly, we found no large scale influence of small RNA variation on mRNA levels, their main regulatory target. Overall, our study is the first to give a quantitative picture of the naturally occurring variation in these important regulatory molecules in human fat tissue.
doi:10.1371/journal.pgen.1002704
PMCID: PMC3349731  PMID: 22589741
12.  Epigenome-Wide Scans Identify Differentially Methylated Regions for Age and Age-Related Phenotypes in a Healthy Ageing Population 
PLoS Genetics  2012;8(4):e1002629.
Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype–phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.
Author Summary
Epigenetic patterns vary during healthy ageing and development. Age-related DNA methylation changes have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To understand the biological mechanisms involved in potential longevity and rate of healthy ageing, we performed genome-wide association of epigenetic and genetic variation with both chronological age and age-related phenotypes. We identified hundreds of DNA methylation variants significantly associated with age and replicated these in an independent sample of young adult twins. Only a small proportion of these variants were also associated with age-related phenotypes. Therefore, the majority of age-related epigenetic changes do not contribute to rate of healthy ageing at later stages in life. Our results suggest that age-related changes in methylation occur throughout an individual's lifespan and that a proportion of these may be initiated from an early age. Intriguingly, a fraction of the age differentially methylated regions also associated with genetic variants in our sample, suggesting that DNA methylation may be a candidate mechanism of mediating not only environmental but also genetic effects on age-related phenotypes.
doi:10.1371/journal.pgen.1002629
PMCID: PMC3330116  PMID: 22532803
13.  Allergic Fungal Rhinosinusitis: A Review 
The Ochsner Journal  2011;11(3):271-275.
Background
Allergic fungal rhinosinusitis (AFRS) is a relatively new and incompletely understood clinical entity with characteristic clinical, radiographic, and histopathologic findings. AFRS is often misdiagnosed. Recognition and understanding of this unique disease will lead to efficient diagnosis and treatment of this curable process.
Methods
The following is a review, conducted via a PubMed English language search, of the current diagnosis, pathogenesis, and treatment of AFRS.
Results
AFRS is an immune-modulated disease entity. The Bent and Kuhn diagnostic criteria are the standard for diagnosis of this disease that occurs because of an incompletely understood allergic mechanism. Multimodality treatment relies heavily on surgical therapy along with corticosteroid use and immunotherapy.
Conclusions
AFRS is a unique disease process that differs from other forms of sinusitis and as such requires that physicians understand its diagnosis and management to provide care for patients with this condition.
PMCID: PMC3179194  PMID: 21960761
Allergic fungal sinusitis; allergic mucin; Aspergillus; Bent and Kuhn; Bipolaris; dematiaceous fungi; rhinosinusitis; sinusitis; type I and III hypersensitivity
14.  Eight Common Genetic Variants Associated with Serum DHEAS Levels Suggest a Key Role in Ageing Mechanisms 
PLoS Genetics  2011;7(4):e1002025.
Dehydroepiandrosterone sulphate (DHEAS) is the most abundant circulating steroid secreted by adrenal glands—yet its function is unknown. Its serum concentration declines significantly with increasing age, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. We conducted a meta-analysis of genome-wide association data with 14,846 individuals and identified eight independent common SNPs associated with serum DHEAS concentrations. Genes at or near the identified loci include ZKSCAN5 (rs11761528; p = 3.15×10−36), SULT2A1 (rs2637125; p = 2.61×10−19), ARPC1A (rs740160; p = 1.56×10−16), TRIM4 (rs17277546; p = 4.50×10−11), BMF (rs7181230; p = 5.44×10−11), HHEX (rs2497306; p = 4.64×10−9), BCL2L11 (rs6738028; p = 1.72×10−8), and CYP2C9 (rs2185570; p = 2.29×10−8). These genes are associated with type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins. Several SNPs were associated with changes in gene expression levels, and the related genes are connected to biological pathways linking DHEAS with ageing. This study provides much needed insight into the function of DHEAS.
Author Summary
Dehydroepiandrosterone sulphate (DHEAS), mainly secreted by the adrenal gland, is the most abundant circulating steroid in humans. It shows a significant physiological decline after the age of 25 and diminishes about 95% by the age of 85 years, which has led to speculation that a relative DHEAS deficiency may contribute to the development of common age-related diseases or diminished longevity. Twin- and family-based studies have shown that there is a substantial genetic effect with heritability estimate of 60%, but no specific genes regulating serum DHEAS concentration have been identified to date. Here we take advantage of recent technical and methodological advances to examine the effects of common genetic variants on serum DHEAS concentrations. By examining 14,846 Caucasian individuals, we show that eight common genetic variants are associated with serum DHEAS concentrations. Genes at or near these genetic variants include BCL2L11, ARPC1A, ZKSCAN5, TRIM4, HHEX, CYP2C9, BMF, and SULT2A1. These genes have various associations with steroid hormone metabolism—co-morbidities of ageing including type 2 diabetes, lymphoma, actin filament assembly, drug and xenobiotic metabolism, and zinc finger proteins—suggesting a wider functional role for DHEAS than previously thought.
doi:10.1371/journal.pgen.1002025
PMCID: PMC3077384  PMID: 21533175
15.  The Architecture of Gene Regulatory Variation across Multiple Human Tissues: The MuTHER Study 
PLoS Genetics  2011;7(2):e1002003.
While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis—MCTA) permits immediate replication of eQTLs using co-twins (93%–98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%–20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.
Author Summary
Regulation of gene expression is a fundamental cellular process determining a large proportion of the phenotypic variance. Previous studies have identified genetic loci influencing gene expression levels (eQTLs), but the complexity of their tissue-specific properties has not yet been well-characterized. In this study, we perform cis-eQTL analysis in a unique matched co-twin design for three human tissues derived simultaneously from the same set of individuals. The study design allows validation of the substantial discoveries we make in each tissue. We explore in depth the tissue-dependent features of regulatory variants and estimate the proportions of shared and specific effects. We use continuous measures of eQTL sharing to circumvent the statistical power limitations of comparing direct overlap of eQTLs in multiple tissues. In this framework, we demonstrate that 30% of eQTLs are shared among tissues, while 29% are exclusively tissue-specific. Furthermore, we show that the fold change in expression between eQTL genotypic classes differs between tissues. Even among shared eQTLs, we report a substantial proportion (10%–20%) of significant tissue differences in magnitude of these effects. The complexities we highlight here are essential for understanding the impact of regulatory variants on complex traits.
doi:10.1371/journal.pgen.1002003
PMCID: PMC3033383  PMID: 21304890
16.  No Correlation Between Childhood Maltreatment and Telomere Length 
Biological Psychiatry  2010;68(6):e21-e22.
doi:10.1016/j.biopsych.2010.02.026
PMCID: PMC2930212  PMID: 20678755
17.  Pigmentation and Vitamin D Metabolism in Caucasians: Low Vitamin D Serum Levels in Fair Skin Types in the UK 
PLoS ONE  2009;4(8):e6477.
Background
Vitamin D may play a protective role in many diseases. Public health messages are advocating sun avoidance to reduce skin cancer risk but the potential deleterious effects of these recommendations for vitamin D metabolism have been poorly investigated.
Methodology/Principal Findings
We investigated the association between 25-hydroxy-vitamin D (25(OH)D), skin type and ultraviolet exposure in 1414 Caucasian females in the UK. Mean age of the cohort was 47 years (18–79) and mean 25(OH)D levels were 77 nmol/L (6–289). 25(OH)D levels were strongly associated with season of sampling with higher levels in the spring and summer months (p<0.0001). Light skin types (skin type 1 and 2) have lower levels of 25(OH)D (mean 71 nmol/L) compared to darker skin types (skin type 3 and 4) (mean 82 nmol/L) after adjusting for multiple confounders (p<0.0001). The trend for increasing risk of low vitamin D with fairer skin types was highly significant despite adjustment for all confounders (p = 0.001).
Conclusions/Significance
Contrary to previous studies across different ethnic backgrounds, this study within Caucasian UK females shows that fair skin types have lower levels of 25(OH)D compared to darker skin types with potential detrimental health effects. Public health campaigns advocating sun avoidance in fair skinned individuals may need to be revised in view of their risk of vitamin D deficiency.
doi:10.1371/journal.pone.0006477
PMCID: PMC2714459  PMID: 19649299
18.  Male-pattern baldness susceptibility locus at 20p11 
Nature genetics  2008;40(11):1282-1284.
We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 × 10−14 for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 × 10−15).
doi:10.1038/ng.255
PMCID: PMC2672151  PMID: 18849991
19.  Efflux Pump Overexpression in Multiple-Antibiotic-Resistant Mutants of Bacteroides fragilis 
Multidrug-resistant mutants of a wild-type Bacteroides fragilis strain (strain ADB77) and a quadruple resistance nodulation division family efflux pump deletion mutant (ADB77 ΔbmeB1 ΔbmeB3 ΔbmeB12 ΔbmeB15) were selected with antimicrobials. Ampicillin, doripenem, imipenem, levofloxacin, and metronidazole selected for mutants from both strains; cefoxitin selected for mutants from strain ADB77 only; and sodium dodecyl sulfate selected mutants from ADB77ΔbmeB1 ΔbmeB3 ΔbmeB12 ΔbmeB15 only. The mutants overexpressed one or more efflux pumps.
doi:10.1128/AAC.00141-06
PMCID: PMC1563565  PMID: 16940115
20.  In Vitro Activities of Doripenem and Comparator Agents against 364 Anaerobic Clinical Isolates 
Antimicrobial Agents and Chemotherapy  2005;49(10):4413-4417.
The in vitro activities of doripenem against 364 anaerobic isolates were measured and compared to those of ertapenem, imipenem, meropenem, ceftriaxone, and levofloxacin. All of the carbapenems were active against nearly all Bacteroides fragilis group isolates. Doripenem was either comparable to or slightly less active than imipenem and meropenem against most isolates but more active than the other penems against Clostridium difficile. Doripenem appears to have excellent activity against a broad range of anaerobes.
doi:10.1128/AAC.49.10.4413-4417.2005
PMCID: PMC1251538  PMID: 16189137
21.  Assessing satisfaction with desloratadine and fexofenadine in allergy patients who report dissatisfaction with loratadine 
BMC Family Practice  2003;4:10.
Background
The FDA recently moved loratadine (Claritin) from prescription only status to over-the-counter (OTC). In response to the availability of an OTC non-sedating antihistamine, many managed care organizations are reevaluating which if any prescription antihistamines should remain on formulary. From a managed care perspective, determining which of the remaining prescription antihistamines results in the greatest patient satisfaction with allergy treatment would be informative.
Methods
We report on a weighted cross sectional survey (n = 10,023) delivered online to a sample of allergy sufferers in the U.S. during the month of December 2002. Two segments were identified for analysis: patient who were dissatisfied with loratadine and converted to desloratadine (Clarinex; n = 61), and patients who were dissatisfied with loratadine and converted to fexofenadine (Allegra; n = 211). The two segments were compared along a series of measures that the literature suggests are related to treatment satisfaction.
Results
The survey found that two of the satisfaction measures differentiated desloratadine converters from fexofenadine converters (p < .05): mean sum of self-reported adverse events and nighttime awakening due to allergy symptoms. For the remainder of satisfaction measures though, patients who were dissatisfied with loratadine reported equal duration of coverage and satisfaction with desloratadine as fexofenadine. When severity of disease was controlled for in the analysis, a pattern emerged suggesting greater levels of satisfaction amongst loratadine dissatisfied patients who converted to desloratadine. Point estimates suggest a consistent pattern favoring desloratadine patient satisfaction, with statistically significant results reported for sum of adverse effects, nighttime awakening due to symptoms, symptom severity just prior to the next dose, and overall satisfaction (p < 0.05).
Conclusions
On average, patients who were dissatisfied with loratadine reported equal or better satisfaction with desloratadine as fexofenadine. Patients with severe allergic rhinitis reported greater satisfaction when converted from loratadine to desloratadine than fexofenadine for select satisfaction measures. These results suggest that if managed care intends to position prescription antihistamines as second line for OTC loratadine treatment dissatisfaction, desloratadine is a useful treatment alternative. These findings, while informative to formulary decision-makers, must be interpreted with caution. Only through head-to-head controlled clinical trials can differences in efficacy and safety be established.
doi:10.1186/1471-2296-4-10
PMCID: PMC194638  PMID: 12917016

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