Genome-wide linkage and association mapping identify susceptibility alleles in ABCC4 for Kawasaki disease
ABSTRACT Kawasaki disease (KD) is a self limited vasculitis in which host genetics plays a prominent role. To further the understanding of the role of host genetics in KD, a three-stage genetic study was conducted that began with a family linkage study and ultimately involved more than 3000 individuals to identify new genetic contributions to KD susceptibility.
A 26-family linkage study followed by fine mapping was performed in a cohort of 1284 KD subjects and their family members (total 3248 individuals). Suggestive evidence of disease linkage (logarithm of odds (LOD) ≥3.0, p<1.00×10(-4)) was found for five genomic locations (Chr 3q, 4q, 10p, 13q, 21q). Two of these loci (Chr 4q and Chr 13q) overlapped with validated findings from a recent KD genome-wide association study. Fine mapping analysis revealed three single nucleotide polymorphisms (SNPs) in ATP-binding cassette, subfamily C, member 4 (ABCC4) underlying the Chr 13q linkage peak showing evidence of association to KD (lowest p=8.82×10(-5); combined OR 2.00, 95% CI 1.41 to 2.83). ABCC4 is a multifunctional cyclic nucleotide transporter that stimulates the migratory capacity of dendritic cells. It is also a mediator of prostaglandin efflux from human cells and is inhibited by non-steroidal anti-inflammatory medications such as aspirin.
These genetic data suggest that ABCC4 could play a fundamental role in KD pathogenesis with effects on immune activation and vascular response to injury.
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ABSTRACT: Furocoumarins are a group of natural products with many biological activities. Clinical evidences have demonstrated the important contribution of furocoumarins to the toxicity of some foods and herbs. In order to assess liver and kidney toxicity of furocoumarins, male mice were orally administrated with psoralen, isopsoralen, imperatorin, isoimperatorin and xanthotoxin at 20 and 40 mg/kg once daily for 28 days, respectively. No changes of food or water intake were observed in furocoumarins-treated mice. Only 40 mg/kg isopsoralen reduced body weight. 40 mg/kg furocoumarins altered serum activities of alanine transaminase, aspartate aminotransferase, alkaline phosphatase, and/or levels of albumin, showing hepatotoxicity. Furthermore, furocoumarins increased activity and protein expression of hepatic microsomal cytochrome P450 (CYP450) 3A11. CYP 2E1 activity and protein expression were suppressed by psoralen and isopsoralen and increased by xanthotoxin. Renal protein levels of organic cation/carnitine transporters (OCT1, OCT2 and OCTN2) and organic anion transporter 3 were increased by most furocoumarins. Renal urate transporter 1, glucose transporter 9 and multidrug resistance protein 4 were influenced by furocoumarins. These findings suggest that furocoumarins may interfere in metabolism, excretion and bioavailability of endogenous and exogenous compounds to impair liver and kidney functions mediated by affecting hepatic CYP450 and renal organic ion transport system.Toxicology Letters 12/2011; 209(1):67-77. DOI:10.1016/j.toxlet.2011.11.030 · 3.36 Impact Factor
Article: Kawasaki Disease[Show abstract] [Hide abstract]
ABSTRACT: Kawasaki disease is a systemic vasculitis and the leading cause of acquired heart disease in North American and Japanese children. The epidemiology, cause, and clinical characteristics of this disease are reviewed. The diagnostic challenge of Kawasaki disease and its implications for coronary artery outcomes are discussed, as are the recommended treatment, ongoing treatment controversies, concerns associated with treatment resistance, and the importance of ongoing follow up.Pediatric Clinics of North America 04/2012; 59(2):425-45. DOI:10.1016/j.pcl.2012.03.009 · 2.20 Impact Factor
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ABSTRACT: This paper explores the genetic structure and signatures of natural selection in different sub-populations from the Island of Sardinia, exploiting information from nearly 700 000 autosomal SNPs genotyped with the Affymetrix Genome-Wide Human SNP 6.0 Array. The genetic structure of the Sardinian population and its position within the context of other Mediterranean and European human groups were investigated in depth by comparing our data with publicly available data sets. Principal components and admixture analyses suggest a clustering of the examined samples in two significantly differentiated sub-populations (Ogliastra and Southern Sardinia), as confirmed by AMOVA (F(ST)=0.011; P<0.001). Differentiation of these sub-populations was still evident when they were pooled together with supplementary Sardinian samples from HGDP and compared with several other European, North-African and Near Eastern populations, confirming the uniqueness of the Sardinian genetic background. Moreover, by applying several statistical approaches aimed at assessing differences at the SNP level, the highest differentiated genomic regions between Ogliastra and Southern Sardinia were thus investigated via an extended haplotype homozygosity (EHH)-based test to point out potential selective sweeps. Using this approach, 40 genomic regions were detected, with significant differences between Ogliastra and Southern Sardinia. These regions were subsequently investigated using a long-range haplotype test, which found significant REHH values for SNPs rs11070188 and rs11070192 in the Ogliastra sub-population. In the light of these results and the overlap of the different computed statistics, the region encompassing these loci can be considered a strong candidate to have undergone selective pressure in Ogliastra.European journal of human genetics: EJHG 04/2012; 20(11):1155-61. DOI:10.1038/ejhg.2012.65 · 4.23 Impact Factor