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Biomedical subjects

Jonathan N W N Barker

Publications and source records attributed to Jonathan N W N Barker.

9 recordsLinked to original sources
PubMed2006

Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood.

Atopic dermatitis (AD) is a common disease with a complex etiology in childhood and adult life. A significant proportion of childhood AD is transient, but in many cases it persists into adulthood. We have recently shown that null mutations in the filaggrin gene (FLG) are an important predisposing factor for childhood eczema and eczema-associated asthma, but persistence to adulthood has not been analyzed. Here we studied a cohort of adult patients with persistent AD, which had been present since early childhood. In this cohort, the combined allele frequency of the two common FLG null variants was 0.270 (cf. population frequency 0.046). This represents an odds ratio of 7.7 with 95% confidence interval of 5.3-10.9 and a chi2 P-value of 1.7 x 10(-53). Our data conclusively demonstrate that identification of FLG null alleles is an indicator of a poor prognosis in AD, predisposing to a form of eczema that starts in early infancy and persists into adulthood. This study helps to further define the nature of the AD phenotype associated with FLG null alleles.

Adolescent↗
PubMed2006

Interaction between genetic control of vascular endothelial growth factor production and retinoid responsiveness in psoriasis.

Vascular endothelial growth factor (VEGF) promotes angiogenesis, and elevated levels are found in plaques of psoriasis. Two VEGF polymorphisms, +405 and -460, are associated with early-onset psoriasis and are close to the functional activator protein-1 site (+419) through which retinoids, an established systemic therapy for psoriasis, can block production of VEGF. We report that peripheral blood mononuclear cells (PBMCs) and epidermal keratinocytes (KC) from patients with psoriasis demonstrate differential, genotype-dependent, regulation of VEGF. For PBMCs, VEGF genotype distinguishes two groups of patients with psoriasis - "high and low VEGF producers" (P < 0.001). In contrast, KC production of VEGF is not genotype dependent. However, the effects of all-trans retinoic acid (RA) on cellular expression of VEGF are determined by both cell type and genotype. RA inhibits KC production of VEGF in a genotype-dependent manner (P < 0.005) whereas RA stimulates PBMCs production irrespective of VEGF genotype (P < 0.001). We also report that the -460 VEGF polymorphism appears to have a clinical pharmacogenetic role in predicting response or non-response of psoriasis to acitretin (P = 0.01). In future, determination of VEGF gene polymorphisms and thus individual patient VEGF "signatures" may be used as a prognostic factor for psoriasis susceptibility/severity and as a means for optimizing treatment response.

Acitretin↗
PubMed2006

A randomized, investigator-masked clinical evaluation of the efficacy and safety of clobetasol propionate 0.05% shampoo and tar blend 1% shampoo in the treatment of moderate to severe scalp psoriasis.

The clinical benefit of currently available tar blend shampoos for the treatment of scalp psoriasis is restricted due to their limited efficacy, low cosmetic appeal and potential for carcinogenicity. This 4-week multicentre, randomized, parallel-group, investigator-masked study included 162 subjects and aimed to compare the efficacy, safety and cosmetic acceptability of clobetasol propionate 0.05% shampoo versus a currently marketed tar blend 1% shampoo in subjects with moderate to severe scalp psoriasis. Clobetasol propionate shampoo was superior to tar blend shampoo with respect to all efficacy variables tested (p<0.001): Total and Global Severity Score; erythema; plaque thickening; desquamation; pruritus; total scalp area involved; and the subject's global assessment of clinical improvement. Both treatments were safe and well-tolerated. Furthermore, more subjects indicated that clobetasol propionate shampoo was more cosmetically acceptable than tar blend shampoo. Clobetasol propionate 0.05% shampoo is a good alternative to tar blend shampoo in the treatment of moderate to severe scalp psoriasis.

Administration, Cutaneous↗
PubMed2005

Genetic association analysis using data from triads and unrelated subjects.

The selection of an appropriate control sample for use in association mapping requires serious deliberation. Unrelated controls are generally easy to collect, but the resulting analyses are susceptible to spurious association arising from population stratification. Parental controls are popular, since triads comprising a case and two parents can be used in analyses that are robust to this stratification. However, parental controls are often expensive and difficult to collect. In some situations, studies may have both parental and unrelated controls available for analysis. For example, a candidate-gene study may analyze triads but may have an additional sample of unrelated controls for examination of background linkage disequilibrium in genomic regions. Also, studies may collect a sample of triads to confirm results initially found using a traditional case-control study. Initial association studies also may collect each type of control, to provide insurance against the weaknesses of the other type. In these situations, resulting samples will consist of some triads, some unrelated controls, and, possibly, some unrelated cases. Rather than analyze the triads and unrelated subjects separately, we present a likelihood-based approach for combining their information in a single combined association analysis. Our approach allows for joint analysis of data from both triad and case-control study designs. Simulations indicate that our proposed approach is more powerful than association tests that are based on each separate sample. Our approach also allows for flexible modeling and estimation of allele effects, as well as for missing parental data. We illustrate the usefulness of our approach using SNP data from a candidate-gene study of psoriasis.

Algorithms↗
PubMed2005

The major psoriasis susceptibility locus PSORS1 is not a risk factor for late-onset psoriasis.

PSORS1 is the major susceptibility locus for psoriasis vulgaris (PV) and lies within an approximately 200 kb segment of the major histocompatibility complex on chromosome 6p21.3. Alleles of candidate genes in this region including human leukocyte antigen (HLA)-C, alpha-helical coiled coil rod (HCR), and corneodesmosin (CDSN) show association with early-onset PV. Late-onset psoriasis (LOP) is defined as a disease with onset after 40 y of age and is typically sporadic. We assessed the role of PSORS1 in genetic susceptibility to LOP. Genotyping for HLA-C alleles and seven single nucleotide polymorphisms (SNP) within the genes HCR and CDSN was performed in LOP (n=145) and normal controls (n=309). Statistical analysis of allelic frequencies included calculation of odds ratio and chi2 comparisons. LOP demonstrated only a weak association to PSORS1 alleles HLA-Cw*6 (p=0.037), CDSN*5 (p=0.041), HCR*WC (p=0.013), and HCR SNP +325 (p=0.038). Patients with age of onset for psoriasis of 50 y or above provided no evidence of association with any of these alleles. These data suggest that the study cohort may include a number of subjects who harbor PSORS1 predisposition to early-onset psoriasis and yet do not present with disease by the age of 40 y. Thus this study demonstrates that PSORS1 is not a major inherited risk factor in the pathogenesis of LOP. These data suggest that the exclusion of LOP subjects from case-control studies will aid further delineation of the PSORS1 locus. Future genome-wide studies will be required to identify loci conferring risk for late-onset disease.

Adult↗
PubMed2003

Genetic analysis of PSORS1 distinguishes guttate psoriasis and palmoplantar pustulosis.

The PSORS1 locus in the major histocompatibility complex region is the major genetic determinant for psoriasis vulgaris. Within the PSORS1 region reside at least three potential candidate genes for psoriasis susceptibility. Specific allelic variants of the genes HLA-Cw*6, HCR*WWCC, and CDSN*5 are strongly associated with psoriasis vulgaris and are in strong linkage disequilibrium with each other. We have genotyped the three psoriasis vulgaris susceptibility alleles of the PSORS1 locus in two clinical variants of psoriasis (guttate psoriasis and palmoplantar pustulosis) to study whether PSORS1 is also involved in the pathogenesis of these variants. We also asked whether these two clinical subgroups could help us to distinguish the causative gene within the high-risk PSORS1 haplotype. The association of guttate psoriasis with the three PSORS1 susceptibility alleles was similar and even stronger than seen with psoriasis vulgaris. Palmoplantar pustulosis, however, did not show association with any of the three candidate genes at this locus. Finally, no correlation with the age of onset for disease was observed. Our results show conclusively that psoriasis vulgaris and guttate psoriasis have a similar genetic basis for their association to PSORS1, whereas palmoplantar pustulosis appears to be a distinct disorder.

Diagnosis, Differential↗
PubMed2003

Basal cell carcinoma is associated with high TNF-alpha release but nor with TNF-alpha polymorphism at position--308.

The mechanisms underlying induction of UVB-induced immunosuppression are not fully understood, but tumor necrosis factor alpha (TNF-alpha) is suggested to play a central role. A single base pair polymorphism at position --308 in the promoter region of the TNF-alpha gene associated with an enhanced secretion of TNF-alpha has been identified in humans. We have therefore investigated the association of the --308 polymorphism with the risk of basal cell carcinoma (BCC) in humans. The frequency of TNF G and TNF A alleles among Caucasian patients with a previous BCC (n=191) and health adults (n-107) were compared. For the TNF--308 polymorphism there was significant association between the genotype or allele frequencies and having BCC. To determine whether patients with a previous BCC had an increased capacity to secrete TNF-alpha, mononuclear cells were stimulated with lipopolysaccharide. Mononuclear cells from patients with a previous BCC (n=15) demonstrated a significantly increased release of TNF-alpha upon stimulation with lipopolysaccharide (P<0.03) compared with mononuclear cells age-matched control subjects (n=16). Further studies of other polymorphisms of the TNF-alpha gene associated with increased TNF-alpha production and BCC and necessary.

Adult↗
PubMed2002

Family-based analysis using a dense single-nucleotide polymorphism-based map defines genetic variation at PSORS1, the major psoriasis-susceptibility locus.

Psoriasis is a common skin disorder of multifactorial origin. Genomewide scans for disease susceptibility have repeatedly demonstrated the existence of a major locus, PSORS1 (psoriasis susceptibility 1), contained within the major histocompatibility complex (MHC), on chromosome 6p21. Subsequent refinement studies have highlighted linkage disequilibrium (LD) with psoriasis, along a 150-kb segment that includes at least three candidate genes (encoding human leukocyte antigen-C [HLA-C], alpha-helix-coiled-coil-rod homologue, and corneodesmosin), each of which has been shown to harbor disease-associated alleles. However, the boundaries of the minimal PSORS1 region remain poorly defined. Moreover, interpretations of allelic association with psoriasis are compounded by limited insight of LD conservation within MHC class I interval. To address these issues, we have pursued a high-resolution genetic characterization of the PSORS1 locus. We resequenced genomic segments along a 220-kb region at chromosome 6p21 and identified a total of 119 high-frequency SNPs. Using 59 SNPs (18 coding and 41 noncoding SNPs) whose position was representative of the overall marker distribution, we genotyped a data set of 171 independently ascertained parent-affected offspring trios. Family-based association analysis of this cohort highlighted two SNPs (n.7 and n.9) respectively lying 7 and 4 kb proximal to HLA-C. These markers generated highly significant evidence of disease association (P<10-9), several orders of magnitude greater than the observed significance displayed by any other SNP that has previously been associated with disease susceptibility. This observation was replicated in a Gujarati Indian case/control data set. Haplotype-based analysis detected overtransmission of a cluster of chromosomes, which probably originated by ancestral mutation of a common disease-bearing haplotype. The only markers exclusive to the overtransmitted chromosomes are SNPs n.7 and n.9, which define a 10-kb PSORS1 core risk haplotype. These data demonstrate the power of SNP haplotype-based association analyses and provide high-resolution dissection of genetic variation across the PSORS1 interval, the major susceptibility locus for psoriasis.

Case-Control Studies↗