 1998 Oxford University Press

Human Molecular Genetics, 1998, Vol. 7, No. 10 Review

1537–1545

The genetics of psoriasis: a complex disorder of the skin and immune system Jayant Bhalerao and Anne M. Bowcock* Department of Internal Medicine, Pediatrics and McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-8591, USA Received April 30, 1998

In the last few years, molecular genetics analyses have permitted novel insights into psoriasis, a disease characterized by uncontrolled proliferation of keratinocytes and recruitment of T cells into the skin. The disease affects ∼1–2% of the Caucasian population and can occur in association with other inflammatory diseases such as Crohn’s disease and in association with human immunodeficiency virus (HIV) infection. Given that psoriasis has characteristics of an autoimmune disease, it is not surprising that HLA studies revealed an association with certain alleles, notably HLA-Cw6. Despite this HLA component, psoriasis in some families is inherited as an autosomal dominant trait with high penetrance. Loci at chromosome 17q25 and 4q have been identified following genome-wide linkage scans of large, multiply affected families. In the case of at least the susceptibility locus at 17q25, the development of psoriasis does not require the presence of HLA-Cw6. Sib-pair analyses have confirmed the association with HLA-Cw6, confirmed the existence of a locus at 17q25 and identified other possible susceptibility loci. Two independent groups have reported a third region on chromosome 20p. Despite these findings, the extent of genetic heterogeneity and the role of environmental triggers and modifier genes is still not clear. The precise role of HLA also still needs to be defined. The isolation of novel susceptibility genes will provide insights into the precise biochemical pathways that control this disease. Such pathways will also reveal additional candidate genes that can be tested for molecular alterations resulting in disease susceptibility. INTRODUCTION Although the skin disease psoriasis was first recognized as a distinct disease as early as 1808 (1), its pathogenic mechanisms have eluded investigators for decades. Recently, it has attracted the attention of molecular geneticists having fallen under the somewhat elusive descriptor ‘complex disease’. The development of localized lesions in response to skin trauma (Koebner reaction or isomorphic response) was first described by Koebner in 1872 (2) and is a hallmark of psoriasis, a disease that derives its name from the Greek ‘psora’ meaning ‘to itch’ (3). Psoriasis commonly begins between ages 20 and 40, with an average age of onset of 27. It is estimated that up to 80% of juvenile guttate psoriasis cases are preceded by streptococcal infections (4). Drugs, stress and climate can also be predisposing factors in susceptible individuals (5). Prevalence varies with race and geography, being highest in the northernmost regions of the Soviet Union and Norway (5–10% of individuals), of moderate prevalence in the UK, USA and Holland (2–3%) and of low prevalence among North American Indians, Latin American Indians, Mongoloids and Western Africans (0–0.3%) (6,7). Lesions generally occur on extensor surfaces with or without scalp involvement. However, they may occur on the flexor surfaces, the genitals and the hands and feet. Although plaqueforming psoriasis is most common, and affects 90% of patients,

other forms include guttate, erythrodermic and palmar–plantar psoriasis (reviewed in ref. 8). Five to ten percent of patients develop a co-existing, and sometimes debilitating, psoriatic arthritis. One confounding aspect of psoriasis is its waxing and waning; its recurrence and regression, and the variable extent of body involvement. Psoriasis can occur in association with other inflammatory disease such as inflammatory bowel disease (Crohn’s disease) and in association with human immunodeficiency virus (HIV) infection (9,10). Recent advances in semi-automated genonotyping and a variety of methods of genetic analysis are starting to yield insights into complex human diseases such as diabetes (11), asthma (12,13), rheumatoid arthritis (14), Crohn’s disease (15,16) and psoriasis (17–20). This article reviews the biological alterations in psoriasis and summarizes the latest genetic findings. For psoriasis, no predisposing gene has yet been identified, although susceptibility frequently appears to have a major genetic component. TWIN STUDIES Danish twin registry studies reveal that monozygotic twins have a concordance of psoriasis of 72% compared with 15% in dizygotic twins (21). This corresponds to a heritability of 90–100% given the 2–3% prevalence in the Danish population (21–24). Similarly, Farber et al. observed concordance rates of 70% in monozygotic twins and 23% in dizygotic twins in the USA (25). However, in an

*To whom correspondence should be addressed. Tel: +1 214 648 1675; Fax: +1 214 648 1666; Email: [email protected]

1538 Human Molecular Genetics, 1998, Vol. 7, No. 10 Review Australian study, the concordance rate was only 35% in monozygotic twins and 12% in dizygotic twins (26). Interestingly, when monozygotic twins are concordant for the disease, it tends to be similar in age of onset, body distribution, severity and course; an observation not made in dizygotic twin pairs (25). This would suggest that genetic factors play a role in these variables. Also evident from twin studies is that although genetic factors play a significant role in the pathogenesis of psoriasis, the actual expression of disease is under environmental influence, since concordance never reaches 100% in any given population. PATHOGENESIS Although clinical features and severity vary between individuals and with time, psoriasis is characterized by four abnormalities (27). (i) Vascular changes where the papillary blood vessels become dilated and tortuous. This results in redness or erythema, one hallmark of psoriasis. (ii) Inflammation, where polymorphonuclear leukocytes from the dermal vessels enter the epidermis. Lesions are also rich in activated CD4+ and CD8+ T cells that release proinflammatory cytokines. (iii) Hyperproliferation of the keratinocytic layer (acanthosis). (iv) Altered epidermal differentiation where keratinocytes retain their nuclei in the cornified layer (parakeratosis) and the granular layer is lost. These changes in the epidermis result in scaling, another hallmark of psoriasis. ASSOCIATION WITH HLA The autoimmune nature of psoriasis prompted investigations in the early 1970s into associations with the HLA complex on chromosome 6p. Russell et al. (28) first reported association with HLA-B13. Subsequently, strong associations with Cw6 and DR7 were identified in the Finnish population and in Germany (29–31), and were estimated to confer relative risk factors of 4–15 for the disease. Henseler and Christophers (30,32) proposed that there are two types of psoriasis: a familial, early age of onset (