Genetic Susceptibility to Acute Rheumatic Fever: A Systematic Review and Meta-Analysis of Twin Studies

Abstract

BackgroundAcute rheumatic fever is considered to be a heritable condition, but the magnitude of the genetic effect is unknown. The objective of this study was to conduct a systematic review and meta-analysis of twin studies of concordance of acute rheumatic fever in order to derive quantitative estimates of the size of the genetic effect.MethodsWe searched PubMed/MEDLINE, ISI Web of Science, EMBASE, and Google Scholar from their inception to 31 January 2011, and bibliographies of retrieved articles, for twin studies of the concordance for acute rheumatic fever or rheumatic heart disease in monozygotic versus dizygotic twins that used accepted diagnostic criteria for acute rheumatic fever and zygosity without age, gender or language restrictions. Twin similarity was measured by probandwise concordance rate and odds ratio (OR), and aggregate probandwise concordance risk was calculated by combining raw data from each study. ORs from separate studies were combined by random-effects meta-analysis to evaluate association between zygosity status and concordance. Heritability was estimated by fitting a variance components model to the data.Results435 twin pairs from six independent studies met the inclusion criteria. The pooled probandwise concordance risk for acute rheumatic fever was 44% in monozygotic twins and 12% in dizygotic twins, and the association between zygosity and concordance was strong (OR 6.39; 95% confidence interval, 3.39 to 12.06; P<0.001), with no significant study heterogeneity (P = 0.768). The estimated heritability across all the studies was 60%.ConclusionsAcute rheumatic fever is an autoimmune disorder with a high heritability. The discovery of all genetic susceptibility loci through whole genome scanning may provide a clinically useful genetic risk prediction tool for acute rheumatic fever and its sequel, rheumatic heart disease.

Rheumatic Heart Disease: Key Points on Valve Lesions Development

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“…11 Other evidence for a genetic predisposition comes from a meta-analysis of twin studies showing a concordance risk for RF of 44% in monozygotic and 12% in dizygotic twins. 12 The obvious association of RF with conditions of living, and the widely disparate frequency in the same geographical region between the more and less privileged strata of society, as seen in South Africa, Asia, and Australasia, can only lead to the conclusion that the frequency and severity of rheumatogenic group A streptococcus (GAS) infection and the lack of prompt antibiotic treatment is the preeminent cause of RF and chronic RHD. Nevertheless, at a more fundamental level, variation in the frequency of RF has to be related to the epidemiology of GAS pharyngitis, in general, and infection with rheumatogenic subtypes, in particular, although this observation has only been confirmed in previous epidemics occurring in Europe and North America.…”