Abstract 18788: Racial Differences in Polymorphisms of Genes for FCγR in Kawasaki Disease (KD): Influence on Susceptibility and IVIG treatment Response
Approximately 20% of KD patients in the U.S. demonstrate refractoriness to IVIG therapy and display higher rates of coronary artery disease than responders. KD incidence varies by racial origin. FCγ receptors (FCγR) modulate action of γ-globulin; the frequencies of single nucleotide polymorphisms (SNPs) in the FCγR genes also vary by race.
We hypothesized: SNPs in the FCγR genes influence on KD susceptibility and IVIG refractoriness varies by race.
Methods: We examined eight functionally relevant SNPs in activating (FCγRIIA, FCγRIIIA and FCγRIIIB) and inhibitory (FCγRIIB) genes in 245 KD patients: 149 index patients in a trio (with both parents), 69 index with a single parent, and 27 without either parent. DNA was extracted from participant whole blood or saliva and genotyping performed by pyrosequencing. Race and ethnicity were genetically determined using 162 ancestry informative markers.
Results: In the dominant model of the transmission disequilibrium test (TDT), the FCγRIIA+559 variant showed excess transmission of the A allele (encoding histidine) from heterozygous parents to affected offspring (z = 2.39, p = 0.02) in the entire trios set of mixed ethnicity. However, the effect was confined to Asian families (z = 2.11, p=0.03) and unapparent among Caucasians (z = 1.22, p = 0.22). In the KD cases compared with pseudo-sibling controls, AA homozygosity was associated with KD (OR= 4.35, p= 0.02), particularly in Asians (OR = 3.74, p=0.03). None of the variants was associated with IVIG treatment response overall (141 responders and 56 non-responders); but, three SNPs in FCγRIIB showed significant allelic associations in Caucasians (73 responders and 31 non-responders): the T allele of FCγRIIB+775 encoding isoleucine appeared as a protective factor (OR = 0.42 [0.17-1.00]; p-value = 0.05), the G allele of −386 as a risk factor (OR = 4.38 [1.28-15.1]; p-value = 0.01), and T allele of −120 as a risk factor (OR = 4.46 [1.30-15.3]; p-value = 0.01), with the latter two in complete linkage disequilibrium.
Conclusions: Genetic markers in FCγRs appear to predict KD susceptibility and response to therapy, and to identify patients who should receive alternate or novel treatment. Race may be an important factor in determining impact of FCγR SNPs on KD.
- © 2010 by American Heart Association, Inc.