Molecular genetics of cutaneous lupus erythematosus

Abstract

This article examines the evidence of a genetic basis for cutaneous forms of lupus erythematosus (LE), namely, subacute cutaneous LE (SCLE) and discoid LE (DLE). The current theory is that multiple genes, including particular allelic polymorphisms, may confer susceptibility to these LE-specific skin diseases (Sontheimer 1996) and that perhaps some of these alleles may be shared with polymorphous light eruption (PLE), a common condition that is clinically related to lupus (Nyberg et al. 1997). Sequeira (Sequeira 1903) described two pairs of sisters (not twins) affected by cutaneous LE (CLE), raising the possibility that it might be a familial condition. Since then, several studies have reported the occurrence of CLE, particularly DLE, in monozygotic twins (Steagall et al. 1962,Wojnarowska 1983) and first-degree relatives of lupus probands (Beckett and Lewis 1959, Leonhardt 1957). Gallo and Forde (Gallo and Forde 1966) suggested that inheritance of a dominant gene, with or without common environmental factors, may explain the observation of DLE across three generations of one family.A mathematical analysis of the age and sex distribution of DLE incidence in the population was also used in the 1960s by Rowell to support a genetic basis for DLE (Burch and Rowell 1968). More recently, Lawrence et al. (Lawrence et al. 1987) investigated first-degree relatives of 37 patients with DLE in a case-control study. They found a significantly increased prevalence of DLE (3.5%) in 255 first-degree relatives of DLE probands compared with 0.5% in 664 controls. Heritability analysis suggested a polygenic inheritance, with 44% heritability. Several recent genome-wide marker scans for systemic LE (SLE) have subsequently been performed in families with multiple affected individuals to identify regions of the genome that may be linked to the disease phenotype (Gaffney et al. 1998, 2000, Gray-McGuire et al. 2000, Lindqvist et al. 2000, Moser et al. 1998, Nath et al. 2001, Shai et al. 1999). These scans confirm that susceptibility to lupus is likely to be determined by multiple genetic regions, with different susceptibility loci in different ethnic groups. It has long been known that certain conditions predispose to CLE. For example, DLE has been described in patients and carriers of X-linked and autosomal-recessive chronic granulomatous disease (Arnett 1997, Yeaman et al. 1992) and is also associated with non-X-linked hyper-immunoglobulin M syndrome (Wolpert et al. 1998). We and others have found a higher prevalence of PLE in patients with both SCLE and DLE than in controls (Millard et al. 2001a, Nyberg et al. 1997), suggesting that they may share a common genetic background. The study of these conditions may help shed light on the genetic basis of LE in the future.