Justine A. Ellis

Androgenetic alopecia: pathogenesis and potential for therapy.

Androgenetic alopecia occurs in men and women, and is characterised by the loss of hair from the scalp in a defined pattern. Determining factors appear to be genetic predisposition coupled with the presence of sufficient circulating androgens. The prevalence of this condition is high (up to 50% of white males are affected by 50 years of age) and, although there are no serious direct health consequences, the loss of scalp hair can be distressing. Knowledge of the pathogenesis of androgenetic alopecia has increased markedly in recent years. Pre-programmed follicles on the scalp undergo a transformation from long growth (anagen) and short rest (telogen) cycles, to long rest and short growth cycles. This process is coupled with progressive miniaturisation of the follicle. These changes are androgen dependent, and require the inheritance of several genes. To date, only one of these genes, which encodes the androgen receptor (AR), has been identified. Of the many treatments available for androgenetic alopecia, only two (finasteride and minoxidil) have been scientifically shown to be useful in the treatment of hair loss. However, these therapies are variable in their effectiveness. Discovery of the involvement of the AR gene, and the identification of other genes contributing to the condition, might lead to the development of new and more effective therapies that target the condition at a more fundamental level.

Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37–1.73]; combined P=2.58 · 10−13). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25–1.44; P=1.032 · 10−14). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16–3.66) for systolic and 1.40 (95% CI: 0.25–2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

Genetic linkage of β and γ subunits of epithelial sodium channel to systolic blood pressure

Summary Background Mutations in the genes on chromosome 16p12 that encode the β and γ subunits of the epithelial sodium channel ( SCNNIB and SCNNIG , respectively) have been linked with rare sodium-dependent forms of low and high blood pressure. Other DNA variants in or around these genes may contribute to variation in blood pressure and the risk of coronary heart disease and stroke. Methods We studied 286 white families from the general population in Victoria, Australia. Each family comprised both parents and two natural children. All participants were genotyped at chromosome 16p12 by use of four highly polymorphic microsatellite markers. Quantitative phenotype measurements were correlated with genotype in identity-by-descent sibling-pair linkage analyses. Findings We found significant linkage between systolic blood pressure and chromosome 16p12 after parametric analyses (p=0·0003) and non-parametric analyses (p=0·001). The mean difference in systolic blood pressure between siblings identical-by-descent at these loci was half as large (7·1 mm Hg) as the difference between siblings non-identical at these loci (14·0 mm Hg, p=0·001). No linkage between chromosome 16p12 and diastolic blood pressure or body-mass index was observed. Interpretation Chromosome 16p12 and the SCNNIB and SCNNIG genes are implicated in the physiological variation of systolic blood pressure. Our findings are important in explaining individual cardiovascular risk within the general population.

Variation in Associations between Allelic Variants of the Vitamin D Receptor Gene and Onset of Type 1 Diabetes Mellitus by Ambient Winter Ultraviolet Radiation Levels: A Meta-Regression Analysis

Vitamin D receptor (VDR) gene polymorphisms may be associated with risk of developing type 1 diabetes mellitus (T1DM), but reports have been conflicting. The authors reexamined population-based case-control studies on selected VDR polymorphisms and T1DM to investigate whether variation in reported associations could be partly explained by differences in ambient winter ultraviolet radiation (UVR) levels. A meta-analysis of 16 studies from 19 regions (midwinter UVR range, 1.0-133.8 mW/m(2)) was conducted. The association between winter UVR and the log odds ratio was examined by meta-regression. For FokI and BsmI, the log odds ratio for the association between the F and B alleles and T1DM increased as regional winter UVR increased (p = 0.039 and p = 0.036, respectively). The association between the TaqI T allele and T1DM was reduced with increasing winter UVR (p = 0.040). Low winter regional UVR was associated with a higher proportion of controls carrying BsmI and ApaI uppercase alleles and a lower proportion of controls carrying TaqI uppercase alleles. These findings strengthen the case that VDR variants are involved in the etiology of T1DM. They suggest that environmental UVR may influence the association between VDR genotype and T1DM risk. Further work on VDR polymorphisms and T1DM should concomitantly examine the roles of past UVR exposure and vitamin D status.

Association of the Human Y Chromosome With High Blood Pressure in the General Population

Genetic variation in the Y chromosome has significant effects on male blood pressure in experimental animals, but the effects in humans are unknown. We examined the relationship between blood pressure and a polymorphic Hin dIII restriction site in the nonrecombining region of the Y chromosome in 409 randomly selected men from the general population. Carefully standardized measures of systolic and diastolic blood pressures were made. The Hin dIII restriction site was significantly more common (43.2%) in men in the lowest decile of the diastolic blood pressure distribution than men in the highest decile (15.9%, P =0.007). No significant difference in genotype frequency was observed between the lowest and highest deciles for systolic pressure (32.4% versus 27.8%, P =0.66). In the entire group, men with the Hin dIII restriction site had significantly lower diastolic blood pressures (81.2 mm Hg, SD:8.3, versus 83.2 mm Hg, SD:8.7, P =0.03). No significant differences in systolic blood pressure (130.6 mm Hg, SD:14.7, versus 128.3 mm Hg, SD: 13.6) were observed in relation to genotypes. Our results indicate that genetic variation in the human Y chromosome is associated with high blood pressure and contributes significantly to the quantitative variation of male diastolic blood pressure in the general population.

Filaggrin loss-of-function mutations do not predict food allergy over and above the risk of food sensitization among infants.

Diagnosed allergic disease (any) 1.26 0.67-2.37 .47 1.34 0.68-2.63 .40 0.956 0.44-2.08 .91 1.07 0.80-1.44 .63 Doctor-diagnosed eczema (any) 1.11 0.59-2.11 .74 1.49 0.74-2.99 .26 1.95 0.76-5.03 .17 1.17 0.83-1.63 .37 Sensitized (SPT1) 2.0§ 1.05-4.09§ .04§ 1.32 0.62-2.78 .47 1.27 0.55-2.93 .58 1.27 0.91-1.78 .17 SPT1 and eczema 2.0§ 0.89-4.48§ .10§ 1.48 0.63-3.50 .37 1.70 0.59-4.92 .33 1.5§ 0.96-2.42§ .07§ Food allergy (IgE mediated) 1.65 0.65-4.22 .30 0.85 0.33-2.20 .73 1.83 0.43-7.78 .41 1.17 0.67-2.02 .58 Diagnosed asthma — — — 1.55 0.38-6.23 .54 1.40 0.39-5.00 .61 — — — Allergic rhinitis and inhalant SPT1 — — — — — — 0.506 0.16-1.61 .25 — — —

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ2 meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico–replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.

Gene‐wide association study between the aromatase gene (CYP19A1) and female pattern hair loss

Background  Female pattern hair loss (FPHL) is a common trait in which androgens and oestrogens may have a pathogenic role. The aromatase enzyme converts androgens to oestrogens in scalp hair follicles and is differentially expressed in balding and nonbalding scalps of women. Sequence variation in the gene encoding aromatase, CYP19A1, might influence the risk of developing FPHL.

The role of genetics and environment in the rise of childhood food allergy.

Food allergy is a growing clinical and public health problem world‐wide. The rising incidence is occurring more rapidly than changes to the genome sequence would allow, but it is yet to be determined whether environmental factors might act in interaction with genetic risk. That is to say, are environmental factors more likely to affect those genetically at risk? Family history is a strong risk factor for the development of food allergy as it co‐aggregates with other atopic diseases and as such genetic factors do play an important role in food allergy risk. However, significant interest has now turned to the role of epigenetic modifications of the genome as the major mediator of gene–environment interaction. The consideration of the role of epigenetics in food allergy is likely to provide an insight into aetiological and biological disease mechanisms. This paper discusses the current state of knowledge regarding genetic and environmental risk factors for food allergy, and considers the potential for furthering our understanding of food allergy aetiology by examining the role of epigenetic variation.

Male pattern baldness is not associated with established cardiovascular risk factors in the general population

A number of studies have shown an association between male pattern baldness (MPB) and cardiovascular disease. Few of these studies, however, have examined whether MPB is a novel risk factor, or is associated with abnormalities of established coronary risk factors. We have therefore performed an analysis of MPB and cardiovascular risk factors in the general population. A total of 1219 male participants aged 18-70 years from the Victorian Family Heart Study were surveyed using a validated questionnaire for degree and pattern of baldness. Carefully standardized measures of height, weight, blood pressure, pulse rate, total and high-density lipoprotein cholesterol, and plasma fibrinogen were made. Subjects were grouped according to the degree and pattern of baldness as: no baldness, frontal baldness and vertex baldness. Bald men were older than non-bald men (P < 0.0001). Age was also associated with increased levels of coronary risk factors (P < 0.0001). When multiple regression was used to adjust for age differences, the levels of coronary risk factors were not significantly different between the bald and non-bald groups. The lack of association between baldness and established coronary risk factors implies that baldness may predispose to coronary heart disease through novel mechanisms yet to be defined.