Abstract
Rheumatic fever (RF) and its subsequent progression to rheumatic heart disease (RHD) are chronic inflammatory disorders prevalent in children and adolescents in underdeveloped countries, and a contributing factor for high morbidity and mortality rates worldwide. Their primary cause is oropharynx infection by Streptococcus pyogenes, whose acetylated residues are recognized by ficolin-1. This is the only membrane-bound, as well as soluble activator molecule of the complement lectin pathway (LP). Although LP genetic polymorphisms are associated with RF, FCN1 gene's role remains unknown. To understand this role, we haplotyped five FCN1 promoter polymorphisms by sequence-specific amplification in 193 patients (138 with RHD and 55, RF only) and 193 controls, measuring ficolin-1 serum concentrations in 78 patients and 86 controls, using enzyme-linked immunosorbent assay (ELISA). Patients presented lower ficolin-1 serum levels (p < 0.0001), but did not differ according to cardiac commitment. Control's genotype distribution was in the Hardy-Weinberg equilibrium. Four alleles (rs2989727: c.−1981A, rs10120023: c.−542A, rs10117466: c.−144A, and rs10858293: c.33T), all associated with increased FCN1 gene expression in whole blood or adipose subcutaneous tissue (p = 0.000001), were also associated with increased protection against the disease. They occur within the *3C2 haplotype, associated with an increased protection against RF (OR = 0.41, p < 0.0001) and with higher ficolin-1 levels in patient serum (p = 0.03). In addition, major alleles of these same polymorphisms comprehend the most primitive *1 haplotype, associated with increased susceptibility to RF (OR = 1.76, p < 0.0001). Nevertheless, instead of having a clear-cut protective role, the minor c.−1981A and c.−144A alleles were also associated with additive susceptibility to valvar stenosis and mitral insufficiency (OR = 3.75, p = 0.009 and OR = 3.37, p = 0.027, respectively). All associations were independent of age, sex or ethnicity. Thus, minor FCN1 promoter variants may play a protective role against RF, by encouraging bacteria elimination as well as increasing gene expression and protein levels. On the other hand, they may also predispose the patients to RHD symptoms, by probably contributing to chronic inflammation and tissue injury, thus emphasizing the dual importance of ficolin-1 in both conditions.
Highlights
Rheumatic fever (RF) is an immune-mediated disease occurring in genetically susceptible individuals, as a sequelae of group A (GAS) Streptococcus pyogenes pharyngitis
The c.−1981A, c.−542A, c.−144A, and c.33T alleles were associated with an increased level of protection against RF, presenting an additive effect with homozygotes protecting more than heterozygotes
Among studies focusing on complement genetic polymorphisms [30,31,32,33,34], this is the first considering the role of a complement membrane-bound molecule of the lectin pathway in the development of RF and rheumatic heart disease (RHD)
Summary
Rheumatic fever (RF) is an immune-mediated disease occurring in genetically susceptible individuals, as a sequelae of group A (GAS) Streptococcus pyogenes pharyngitis. It affects predominantly children and adolescents in low-income and developing countries, where it remains a considerable public health problem [1, 2]. Rheumatic heart disease (RHD) is associated with high morbidity and mortality, causing 9 million disability-adjusted life years lost, 33 million cases [5] and 275,000 deaths each year [6]. This multifactorial disorder involves multiple genetic and environmental factors, not yet fully elucidated. Well-designed case-control studies strive to unravel the genetic susceptibility to this disease, given that the only genome-wide association study done with RHD has rendered no relevant results [7]
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