Ethnicity-stratified analysis of the association between IL-18 polymorphisms and systemic lupus erythematosus in a European population: a meta-analysis.

We performed a meta-analysis to identify the association between polymorphisms in the promoter of interleukin-18 (IL-18) and susceptibility for systemic lupus erythematosus (SLE) . Genotype data for three single-nucleotide polymorphisms (SNPs rs360719, rs1946518, and rs187238) in the IL-18 promoter were extracted from 20 studies of three different ethnicities (European, Asian, and South American). Data from each ethnicity group and their combinations were analyzed. We found distinct evidence of an association between rs360719 and SLE (P = 0.001) in the European/South American group [odds ratio (OR) 1.31 per C allele, 95% confidence interval (CI) 1.11-1.53]. Stratification analysis by ethnicity showed a significant association between rs360719 and SLE in the European population (OR 1.33 per C allele, 95% CI 1.11-1.61, P = 0.003) and a lesser effect in the same direction in the South American population (OR 1.18). A significant association was also identified between rs1946518 and SLE in the European population (OR 1.16 per A allele, 95% CI 1.03-1.30, P = 0.017), although there was no association in the Asian or the combined European/Asian population. We also examined genome-wide association study (GWAS) data from an Asian subpopulation (Chinese) for the association between rs1946518 and SLE, but found no association (P = 0.83). The third SNP, rs187238, was not significantly associated with SLE in any of the populations examined. In summary, this study identified a significant association between SLE and two SNPs within the IL-18 gene promoter region (rs360719 and rs1946518) in a European population, but not in populations of Asian origin.

Association between C-reactive protein gene +1059 G/C polymorphism and the risk of coronary heart disease: a meta-analysis.

BACKGROUND: C-reactive protein (CRP) gene +1059 G/C polymorphism has been reported to be associated with coronary heart disease (CHD) risk, but the results remain inconclusive. This meta-analysis was therefore conducted to clarify these controversies. METHODS: A comprehensive search was conducted to identify all case control studies on the association between CRP gene +1059 G/C polymorphism and CHD risk. All the related studies were further strictly selected according to the inclusion criteria. Meta-analysis was performed with STATA 10.1 (StataCorp, USA). The association was assessed by odds ratio (OR) and 95% confidence interval (CI); both Begg's funnel plot and Egger's regression test were used to assess the publication bias. RESULTS: This meta-analysis on a total of 13 studies comprising 6316 CHD cases and 4467 controls showed no significant association between CRP gene +1059 G/C polymorphism and CHD risk in the overall study (for C/C+C/G vs. G/G: OR = 1.01, 95% CI = 0.81-1.25, P = 0.96; for C/C vs. C/G+G/G: OR = 1.17, 95% CI = 0.77-1.77, P = 0.47; for C/C vs. G/G: OR = 1.17, 95% CI = 0.77-1.77, P = 0.47; for C allele vs. G allele: OR = 1.01, 95% CI = 0.81-1.24, P = 0.96). However, in the subgroup analysis by ethnicity, the results showed significant association between CRP gene +1059 G/C polymorphism and CHD risk among Caucasians (for C/C vs. G/G: OR = 2.54, 95% CI = 1.13-5.72, P = 0.02; C/C vs. C/G+G/G: OR = 2.45, 95% CI = 1.09-5.51, P = 0.03), but not among Asians and Africans (P > 0.05). CONCLUSION: CRP gene +1059 G/C polymorphism may be associated with increased CHD risk among Caucasians and more evidences need to validate the conclusion.

Exome sequencing identified a missense mutation of EPS8L3 in Marie Unna hereditary hypotrichosis.

BACKGROUND: Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant disorder characterised by coarse, wiry, twisted hair developed in early childhood and subsequent progressive hair loss. MUHH is a genetically heterogeneous disorder. No gene in 1p21.1-1q21.3 region responsible for MUHH has been identified. METHODS: Exome sequencing was performed on two affected subjects, who had normal vertex hair and modest alopecia, and one unaffected individual from a four-generation MUHH family of which our previous linkage study mapped the MUHH locus on chromosome 1p21.1-1q21.3. RESULTS: We identified a missense mutation in EPS8L3 (NM_024526.3: exon2: c.22G->A:p.Ala8Thr) within 1p21.1-1q21.3. Sanger sequencing confirmed the cosegregation of this mutation with the disease phenotype in the family by demonstrating the presence of the heterozygous mutation in all the eight affected and absence in all the seven unaffected individuals. This mutation was found to be absent in 676 unrelated healthy controls and 781 patients of other disease from another unpublished project of our group. CONCLUSIONS: Taken together, our results suggest that EPS8L3 is a causative gene for MUHH, which was helpful for advancing us on understanding of the pathogenesis of MUHH. Our study also has further demonstrated the effectiveness of combining exome sequencing with linkage information for identifying Mendelian disease genes.

Exome sequencing identifies a COL14A1 mutation in a large Chinese pedigree with punctate palmoplantar keratoderma.

BACKGROUND: Punctate palmoplantar keratoderma (PPPK) is a rare autosomal dominant skin disorder characterised by numerous hyperkeratotic papules irregularly distributed on the palms and soles. To date, no causal gene for this disease has been identified. METHODS: We performed exome sequencing analysis of four affected individuals and two unaffected controls from one Chinese PPPK family where disease locus was mapped at 8q24.13-8q24.21 by our previous linkage analysis. RESULTS: We identified a novel heterozygous mutation in COL14A1 gene (c.4505C→T (p.Pro1502Leu)), which located within the linkage region that we previously identified for PPPK. The mutation was shared by the four affected individuals, but not for the two controls of the family. Sanger sequencing confirmed this mutation in another four cases from this family. This mutation was invisible in the normal controls of this family as well as the additional 676 unrelated normal controls and 781 patients with other disease. The shared COL14A1 mutation, p.Pro1502Leu, is a missense substitution at a highly conserved amino acid residue across multiple species. CONCLUSIONS: The power of combining exome sequencing and linkage information in the study of genetics of autosomal dominant disorders, even in simplex cases, has been demonstrated. Our results suggested that COL14A1 would be a casual gene for PPPK, which was helpful for advancing us on understanding of the pathogenesis of PPPK.

Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly inherited epidermal keratinization disorder whose etiology remains unclear. We performed exome sequencing in one unaffected and two affected individuals from a DSAP family. The mevalonate kinase gene (MVK) emerged as the only candidate gene located in previously defined linkage regions after filtering against existing SNP databases, eight HapMap exomes and 1000 Genomes Project data and taking into consideration the functional implications of the mutations. Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases), respectively. All 14 MVK mutations identified in our study were absent in 676 individuals without DSAP. Our functional studies in cultured primary keratinocytes suggest that MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from apoptosis induced by type A ultraviolet radiation. Our results should help advance the understanding of DSAP pathogenesis.

Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population.

Atopic dermatitis is a chronic, relapsing form of inflammatory skin disorder that is affected by genetic and environmental factors. We performed a genome-wide association study of atopic dermatitis in a Chinese Han population using 1,012 affected individuals (cases) and 1,362 controls followed by a replication study in an additional 3,624 cases and 12,197 controls of Chinese Han ethnicity, as well as 1,806 cases and 3,256 controls from Germany. We identified previously undescribed susceptibility loci at 5q22.1 (TMEM232 and SLC25A46, rs7701890, P(combined) = 3.15 × 10(-9), odds ratio (OR) = 1.24) and 20q13.33 (TNFRSF6B and ZGPAT, rs6010620, P(combined) = 3.0 × 10(-8), OR = 1.17) and replicated another previously reported locus at 1q21.3 (FLG, rs3126085, P(combined) = 5.90 × 10(-12), OR = 0.82) in the Chinese sample. The 20q13.33 locus also showed evidence for association in the German sample (rs6010620, P = 2.87 × 10(-5), OR = 1.25). Our study identifies new genetic susceptibility factors and suggests previously unidentified biological pathways in atopic dermatitis.