CED
Clinical dermatology • Original article
Clinical and Experimental Dermatology
Familial aggregation of moderate to severe plaque psoriasis V. Di Lernia, E. Ficarelli, A. Lallas and C. Ricci Dermatology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy doi:10.1111/ced.12401
Summary
Background. Psoriasis is a highly heritable disease. It has been suggested that psoriasis is preferentially transmitted from fathers. Aim. To evaluate the degree of familial aggregation of psoriasis; to determine the recurrence risk ratio (kR) of psoriasis in first, second and third degree relatives of patients with psoriasis; and to investigate the transmission patterns of the disease and their relationships with the clinical profiles of patients. Methods. A cross-sectional study on 640 consecutive, unrelated adult patients with chronic plaque psoriasis was performed. The prevalence of psoriasis in first, second and third degree relatives of the patients was determined, and the kR was calculated under the assumption of a population prevalence of 2%. Age of onset and presence of facial, hand and foot psoriasis were evaluated in probands with paternal vs. maternal transmission. Results. A positive familial history of psoriasis was found in 380 patients (59.37%). Of these, 174 (27.18%) had at least one parent with psoriasis, with a kR of 13.59, while 106 patients (16.56%) had at least one second degree relative with psoriasis, and 34 patients (5.31%) had one third degree relative with psoriasis. No parent-of-origin effect in transmission of psoriasis from affected parent to offspring was observed, and there were no significant differences in the clinical profiles of the disease between patients grouped by transmission pattern of psoriasis. Conclusions. These results show a high familial recurrence risk of psoriasis, and suggest a balanced parental transmission of the disease.
Introduction Psoriasis is an autoinflammatory disease that is driven and maintained by multiple components of the immune system, involving both innate and acquired immunity. It affects 1–3% of the white population, and is associated with psoriatic arthritis in 20–30% of patients. There is evidence that the prevalence of psoriasis is increasing, possibly due to changes in lifestyle and environmental factors, or to increased awareness of the disease.1 The prevalence of psoriasis is approximately the same in males and females, although the Correspondence: Dr Vito Di Lernia, Dermatology Unit, Arcispedale Santa Maria Nuova-IRCCS, Viale Risorgimento 80, 42123 Reggio Emilia, Italy E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 3 February 2014
ª 2014 British Association of Dermatologists
disease may be more severe in males.2 Previous studies have shown an excessive paternal transmission in psoriasis and psoriatic arthritis.3,4 Psoriasis is a multifactorial disease, which is caused by a complex interplay of multiple genetic variants and environmental factors. Psoriasis is known to have a strong genetic component, with an estimated heritability of 66%,5 although this value may differ in different populations and subpopulations. The strong genetic component has been confirmed by the presence of larger concordance rates in monozygotic than in dizygotic twins.6 A potential role of epigenetic or environmental factors has been suggested, as the concordance rate between monozygotic twins is 35– 72%.5,7,8 In addition, population-based studies have shown reliably strong associations between human leucocyte antigens (HLA) and psoriasis. Early genetic association studies focused on segregation of microsatellite
Clinical and Experimental Dermatology (2014) 39, pp801–805
801
Familial aggregation of moderate to severe plaque psoriasis V. Di Lernia et al.
markers in families, with the only locus that was consistently identified residing in the major histocompatibility complex. HLA-Cw6 has been recognized as the major risk allele for psoriasis.9 More recent genomewide association studies (GWAS) have all confirmed the association of the PSORS1 gene with psoriasis, but have also recognized additional genetic markers associated with psoriasis, and provided clues to novel mechanistic pathways.10 Despite identification of a high number of genetic loci associated with psoriasis,10 the genetic transmission of psoriasis remains incompletely defined. The aim of this study was to assess the degree of familial aggregation of psoriasis in a cohort of patients with psoriasis, to confirm whether there is excessive paternal transmission, and to examine whether there are differences in the expression of the disease that are dependent on the affected parent.
Methods The study met the quality standard described in the declaration of Helsinki and the Good Epidemiological Practices. Participation in the study was voluntary. This observational study did not modify the clinical practices of the physicians and informed consent was obtained from all patients. Patients
This was a cross-sectional study of 640 unrelated, consecutive adult patients with chronic moderate to severe plaque psoriasis, who were seen between January and June 2013 in a dermatology unit of a community and research hospital. All patients had psoriasis diagnosed clinically by an expert dermatologists. Patients were considered to have moderate or severe psoriasis if they had a Psoriasis Area and Severity Index (PASI)11 of ≥ 10 at baseline and/or if they were being treated with systemic therapies. Patients with psoriatic arthritis were included only if they had PASI ≥ 10 at baseline. At their presentation to the clinic, each proband was asked whether there was any history of psoriasis (of any degree of severity) or psoriatic arthritis diagnosed by a medical doctor among their first, second or third degree relatives. Information concerning familial prevalence was collected from family history, obtaining information from both the patient and their relatives. In particular, we asked patients to invite their relatives to take part in the study in order to provide additional information about any family history of psoriasis.
802
Clinical and Experimental Dermatology (2014) 39, pp801–805
First degree relatives were parents, offspring and siblings; second degree relatives were uncles, aunts, nephews, nieces, grandparents, grandchildren and halfsiblings; and third degree relatives were first cousins, great-grandparents and great-grandchildren. Patients who were not able to provide detailed information about their family history of psoriasis on both maternal and paternal sides were excluded. To ensure recruitment of a group of patients representative of a local population, all patients attending the psoriasis outpatient service were invited during consultations and by posters in the waiting areas to participate in the study. The final sample consisted of 640 unrelated patients with psoriasis (370 male, 270 female; mean SD age 53.83 16.45 years, range 18–86) who had detailed data about their family history of psoriasis on both the maternal and paternal sides. Analysis of patient demographics showed a mix of ethnicities in proportion to our practice population: 614 Italian, 4 other European (2 Albanian, 2 Russian), 8 North African, 2 African and 12 East Asian subjects (Indian, Pakistani, Sri Lankan). Using the Risch non-parametric approach, the recurrence risk ratio (kR, where R represents the degree of relatedness), was calculated, setting the population prevalence of psoriasis at 2%.12,13 Patients with a parental history of psoriasis were divided according to the psoriasis status of their families (paternal or maternal line) in order to verify differences in the parental transmission of psoriasis. Dissimilarity in the expression of psoriasis in individuals with paternal vs. maternal transmission was assessed at the time of each proband’s presentation to the clinic. The two groups were compared with respect to disease onset (early vs. late); guttate vs. nonguttate origin; and facial, hand and foot, or nail involvement.
Results Of the 640 patients in our cohort, 380 (59.37%) reported at least one relative with psoriasis. Using the classification given above, 240 (37.5%) reported at least one first degree relative with psoriasis. Of these, 174 (97 male, 77 female) had at least one parent with psoriasis: the affected parent was the father in 86 cases (50 male, 36 female) and the mother in a further 86 cases (46 male, 40 female), while in 2 cases, both parents were affected. Six of these cases had also at least one affected sibling. The remaining 26 patients with a first degree relative with psoriasis had at least one child with psoriasis. Of the 72 individuals who did not have any first degree relatives with psoriasis, 40 reported at least one sibling with psoriasis, but 36 of
ª 2014 British Association of Dermatologists
Familial aggregation of moderate to severe plaque psoriasis V. Di Lernia et al.
these had no known relative with psoriasis in the previous generation. There were 106 probands (16.56%) with at least one second degree relative with psoriasis on the paternal side (50 subjects), the maternal side (50 subjects) or both sides (6 subjects). There were 34 patients (5.31%) with at least one third degree relative with psoriasis on either the paternal (n = 22 patients) or maternal (12 patients) side. Thirty-two individuals (5%) had both first and second degree relatives with psoriasis (6 paternal, 18 maternal, 8 from both paternal and maternal sides); 6 individuals (0.94%) had first, second and third degree relatives on the maternal side affected with psoriasis. Details for distribution of relatives according to first, second and third degree are given in Fig. 1. The recurrence risk ratio, kR, estimates the relative proportion of a disease in relatives compared with the prevalence of that disease in the general population. kR is defined as the prevalence of the disease in patients with a family history of psoriasis divided by the prevalence in the general population, assumed as 2%, and was found to be 18.75, 8.28 and 2.65, respectively, for first (kR1), second (kR2) and third (kR3) degree relatives (Table 1). Analysis of parental transmission in the 174 patients with family history of psoriasis in first degree relatives revealed male to male transmission in 50 cases, male to female transmission in 36 cases, female to male transmission in 46 cases, and female to female transmission in 40 cases (Table 2). Age of onset (mean SD) of psoriasis in patients with a family history of psoriasis was 29.49 15.09
for those with an affected mother vs. 30.09 17.75 for those with an affected father. There was no influence of the type of parental transmission (maternal vs. paternal) on the incidence of guttate vs. nonguttate, or the incidence of facial, nail, or hand and foot psoriasis (data not shown).
Table 1 Recurrence risk ratio for psoriasis in relatives of individuals with psoriasis. Psoriasis in at least one
Affected, n Prevalence, % kR*
Parent
First degree relative
Second degree relative
Third degree relative
174 27.18 13.59
240 37.5 18.75
106 16.56 8.28
34 5.31 2.655
*Recurrence risk ratio. Table 2 Affected individuals with parents with psoriasis: analysis of parental transmission.
Transmission
Probands with affected parents (n = 174)*
Father to male, n (%) Father to female, n (%) Mother to male, n (%) Mother to female, n (%)
50 36 46 40
(29.06) (20.93) (26.74) (23.25)
P 0.53†
*Comprised 96 male and 76 female; 2 patients had both parents affected with psoriasis. †Nonsignificant.
Psoriatic patients N = 640
Family history of psoriasis N = 380 (59.37%) M 222, F158
1st degree relatives 240 (37.5%)
Affected Father* 86
Affected Mother* 86
Affected Siblings 40
No psoriatic relatives N = 260 (M 142, F 118)
2nd degree relatives 106 (16.56%)
Paternal side* 50
Maternal side** 50
3rd degree relatives 34 (5.31%)
Paternal side 22
Maternal side 12
Figure 1 Family history of psoriasis. Flow chart showing the frequency of psoriasis in relatives on the maternal and paternal sides. Data
are n (%) of index patients having at least one-first, second or third degree relative with psoriasis. *Two additional individuals reported a history of psoriasis in both parents; **six additional individuals had at least one-second degree relative with psoriasis from both sides.
ª 2014 British Association of Dermatologists
Clinical and Experimental Dermatology (2014) 39, pp801–805
803
Familial aggregation of moderate to severe plaque psoriasis V. Di Lernia et al.
Discussion Psoriasis is a highly heritable disease, as shown by an increased rate of concordance in monozygotic vs. dizygotic twins (35–72% vs. 12–23%, respectively).7 The influence of a family history of psoriasis may be underestimated if there is no known relative with psoriasis in the previous generation. To improve the accuracy of reported family history information, the assessment of our study included a comprehensive three-generation pedigree, the involvement of the patients’ relatives and the use of the ‘family study method’.14 We found a high frequency of a positive family history of psoriasis. Of the 640 patients enrolled, about 60% reported a family history of psoriasis involving at least one of their first, second or third degree relatives, specifically 37.5%, 16.56% and about 5%, respectively. A standard measure of familial aggregation is the kR of disease in relatives of an index case, defined as the risk of disease in relatives of a random individual with disease. Weak alterations in the population prevalence obviously have an effect on kR (recurrence risk/population prevalence). In previous studies, kR for psoriasis was estimated to be between 4 and 10.13 Our study found a higher familial recurrence risk, with the kR for offspring of parents with psoriasis being 13.59. If we had assumed a prevalence of psoriasis of 3%, the number ratio would fall to 9.6. This estimate is similar to the figure of about 10 found by Henseler and Christophers15 for first degree relatives of a patient with early-onset psoriasis. Our study also examined the effect of paternal vs. maternal transmission of psoriasis. Collectively, this cohort (n = 640) includes 20 paternally (3.1%) and 32 (5%) maternally transmitted cases of psoriasis (including double and triple generations). Although the gender difference was not statistically significant, a higher penetration of maternally transmitted psoriasis between three generations was indicated. When disease transmission to offspring from affected fathers was compared with that from affected mothers, no differences were found. Imprinting is the process by which genetic alleles responsible for a phenotype are derived from one parent only. It is an epigenetic phenomenon resulting from DNA methylation or modification of protruding histones. Although the sex of the affected parent was not considered significant in the cohort study of Lomholt,16 both psoriasis and psoriatic arthritis were considered in other studies to have a predominantly paternal mode of transmission.17,18
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Clinical and Experimental Dermatology (2014) 39, pp801–805
Genetic anticipation was suggested because an earlier age of onset was found when the disease was inherited from the father.19 However, large studies investigating the familial aggregation and transmission patterns of psoriasis are lacking. In addition, potential reported biases, such as the fact that fathers of patients with psoriasis may be more likely to be affected with the more severe form of the disease, could be the reason for the apparently excess paternal transmission. Because the sex of the disease-transmitting parent has been considered a potential factor that may influence differential expression of the disease,17,18 particularly the penetrance, we investigated the effect of maternal and paternal inheritance on phenotypic expression of psoriasis. The influence of the two transmission patterns of psoriasis on clinical factors or subphenotypes of the disease [early vs. late onset, guttate vs. nonguttate origin, or psoriasis type (facial, hand and foot, or nail)] showed no significant differences between patients with paternal or maternal history of psoriasis. However, the small sample size of this study may have introduced potential biases toward enrichment of either the paternal or maternal inheritance models.
Conclusion Studying the family clustering of psoriasis in our population did not give insight into understanding the mechanisms underlying parental influences. We did not find that a sex-specific epigenetic inheritance pattern for psoriasis is a major contributing factor in family-specific risk in psoriasis. The presence of a parental effect on psoriasis transmission is but one of the issues that remain to be clarified. Further molecular investigations of candidate genes will help to better evaluate the true impact of parental transmission of psoriasis.
What’s already known about this topic? ● Psoriasis is a multifactorial disease, caused by
a complex interplay of multiple genetic variants and environmental factors. ● Psoriasis is known to have a strong genetic component. ● Previous studies have suggested an excessive paternal transmission in psoriasis and psoriatic arthritis.
ª 2014 British Association of Dermatologists
Familial aggregation of moderate to severe plaque psoriasis V. Di Lernia et al.
What does this study add? ● The results of this study confirm high familial
recurrence risk of psoriasis but suggest a balanced parental transmission of the disease. ● No parent-of-origin effect in transmission of disease from affected parent to offspring was observed. ● In addition, no significant differences in clinical profiles of the disease between patients according to the transmission pattern of psoriasis were observed.
References 1 Danielsen K, Olsen AO, Wilsgaard T, Furberg AS. Is the prevalence of psoriasis increasing? A 30-year follow-up of a population-based cohort. Br J Dermatol 2013; 168: 1303–10. 2 Hagg D, Eriksson M, Sundstr€ om A, Schmitt-Egenolf M. The higher proportion of men with psoriasis treated with biologics may be explained by more severe disease in men. PLoS One 2013; 8: e63619. 3 Rahman P, Gladman DD, Schentag CT, Petronis A. Excessive paternal transmission in psoriatic arthritis. Arthritis Rheum 1999; 42: 1228–31. 4 Karason A, Gudjonsson JE, Upmanyu R et al. A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting. Am J Hum Genet 2003; 72: 125–31. 5 Grjibovski AM, Olsen AO, Magnus P, Harris JR. Psoriasis in Norwegian twins: contribution of genetic and environmental effects. J Eur Acad Dermatol Venereol 2007; 21: 1337–43. 6 Lønnberg AS, Skov L, Skytthe A et al. Heritability of psoriasis in a large twin sample. Br J Dermatol 2013; 169: 412–16.
ª 2014 British Association of Dermatologists
7 Bowcock AM. The genetics of psoriasis and autoimmunity. Annu Rev Genomics Hum Genet 2005; 6: 93–122. 8 Ballestar E. Epigenetics lessons from twins: prospects for autoimmune disease. Clin Rev Allergy Immunol 2009; 39: 30–41. 9 Elder JT, Bruce AT, Gudjonsson JE et al. Molecular dissection of psoriasis: integrating genetics and biology. J Invest Dermatol 2010; 130: 1213–26. 10 Hebert HL, Ali FR, Bowes J et al. Genetic susceptibility to psoriasis and psoriatic arthritis: implications for therapy. Br J Dermatol 2010; 166: 474–82. 11 Frederiksson T, Pettersson U. Severe psoriasis - oral therapy with a new retinoid. Dermatologica 1978; 157: 238–44. 12 Gelfand JM, Gladman DD, Mease PJ et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol 2005; 53: 573. 13 Langley RG, Krueger GG, Griffiths CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis 2005; 64 (Suppl 2): ii18–23; discussion ii24–5. 14 Rahman P, Elder T. Genetic epidemiology of psoriasis and psoriatic arthritis. Ann Rheum Dis 2005; 64 (Suppl 2): ii37–9; discussion ii 40–1. 15 Henseler T, Christophers E. Psoriasis of early and late onset: characterization of two types of psoriasis vulgaris. J Am Acad Dermatol 1985; 13: 450–6. 16 Lomholt G. Prevalence of skin diseases in a population: a census study from the Faroe islands. Dan Med Bull 1964; 11: 1–7. 17 Theuwees M, Morhenn V. Allelic instability in the mitosis model and the inheritance of psoriasis. J Am Acad Dermatol 1995; 32: 44–52. 18 Traupe H, van Gurp PJ, Happle R et al. Psoriasis vulgaris, fetal growth, and genomic imprinting. Am J Med Genet 1992; 42: 649–54. 19 Burden AD, Javed S, Bailey M et al. Genetics of psoriasis: paternal inheritance and a locus on chromosome 6p. J Invest Dermatol 1998; 110: 958–60.
Clinical and Experimental Dermatology (2014) 39, pp801–805
805
Clinical dermatology • Original article
Clinical and Experimental Dermatology
Familial aggregation of moderate to severe plaque psoriasis V. Di Lernia, E. Ficarelli, A. Lallas and C. Ricci Dermatology Unit, Arcispedale Santa Maria Nuova-IRCCS, Reggio Emilia, Italy doi:10.1111/ced.12401
Summary
Background. Psoriasis is a highly heritable disease. It has been suggested that psoriasis is preferentially transmitted from fathers. Aim. To evaluate the degree of familial aggregation of psoriasis; to determine the recurrence risk ratio (kR) of psoriasis in first, second and third degree relatives of patients with psoriasis; and to investigate the transmission patterns of the disease and their relationships with the clinical profiles of patients. Methods. A cross-sectional study on 640 consecutive, unrelated adult patients with chronic plaque psoriasis was performed. The prevalence of psoriasis in first, second and third degree relatives of the patients was determined, and the kR was calculated under the assumption of a population prevalence of 2%. Age of onset and presence of facial, hand and foot psoriasis were evaluated in probands with paternal vs. maternal transmission. Results. A positive familial history of psoriasis was found in 380 patients (59.37%). Of these, 174 (27.18%) had at least one parent with psoriasis, with a kR of 13.59, while 106 patients (16.56%) had at least one second degree relative with psoriasis, and 34 patients (5.31%) had one third degree relative with psoriasis. No parent-of-origin effect in transmission of psoriasis from affected parent to offspring was observed, and there were no significant differences in the clinical profiles of the disease between patients grouped by transmission pattern of psoriasis. Conclusions. These results show a high familial recurrence risk of psoriasis, and suggest a balanced parental transmission of the disease.
Introduction Psoriasis is an autoinflammatory disease that is driven and maintained by multiple components of the immune system, involving both innate and acquired immunity. It affects 1–3% of the white population, and is associated with psoriatic arthritis in 20–30% of patients. There is evidence that the prevalence of psoriasis is increasing, possibly due to changes in lifestyle and environmental factors, or to increased awareness of the disease.1 The prevalence of psoriasis is approximately the same in males and females, although the Correspondence: Dr Vito Di Lernia, Dermatology Unit, Arcispedale Santa Maria Nuova-IRCCS, Viale Risorgimento 80, 42123 Reggio Emilia, Italy E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 3 February 2014
ª 2014 British Association of Dermatologists
disease may be more severe in males.2 Previous studies have shown an excessive paternal transmission in psoriasis and psoriatic arthritis.3,4 Psoriasis is a multifactorial disease, which is caused by a complex interplay of multiple genetic variants and environmental factors. Psoriasis is known to have a strong genetic component, with an estimated heritability of 66%,5 although this value may differ in different populations and subpopulations. The strong genetic component has been confirmed by the presence of larger concordance rates in monozygotic than in dizygotic twins.6 A potential role of epigenetic or environmental factors has been suggested, as the concordance rate between monozygotic twins is 35– 72%.5,7,8 In addition, population-based studies have shown reliably strong associations between human leucocyte antigens (HLA) and psoriasis. Early genetic association studies focused on segregation of microsatellite
Clinical and Experimental Dermatology (2014) 39, pp801–805
801
Familial aggregation of moderate to severe plaque psoriasis V. Di Lernia et al.
markers in families, with the only locus that was consistently identified residing in the major histocompatibility complex. HLA-Cw6 has been recognized as the major risk allele for psoriasis.9 More recent genomewide association studies (GWAS) have all confirmed the association of the PSORS1 gene with psoriasis, but have also recognized additional genetic markers associated with psoriasis, and provided clues to novel mechanistic pathways.10 Despite identification of a high number of genetic loci associated with psoriasis,10 the genetic transmission of psoriasis remains incompletely defined. The aim of this study was to assess the degree of familial aggregation of psoriasis in a cohort of patients with psoriasis, to confirm whether there is excessive paternal transmission, and to examine whether there are differences in the expression of the disease that are dependent on the affected parent.
Methods The study met the quality standard described in the declaration of Helsinki and the Good Epidemiological Practices. Participation in the study was voluntary. This observational study did not modify the clinical practices of the physicians and informed consent was obtained from all patients. Patients
This was a cross-sectional study of 640 unrelated, consecutive adult patients with chronic moderate to severe plaque psoriasis, who were seen between January and June 2013 in a dermatology unit of a community and research hospital. All patients had psoriasis diagnosed clinically by an expert dermatologists. Patients were considered to have moderate or severe psoriasis if they had a Psoriasis Area and Severity Index (PASI)11 of ≥ 10 at baseline and/or if they were being treated with systemic therapies. Patients with psoriatic arthritis were included only if they had PASI ≥ 10 at baseline. At their presentation to the clinic, each proband was asked whether there was any history of psoriasis (of any degree of severity) or psoriatic arthritis diagnosed by a medical doctor among their first, second or third degree relatives. Information concerning familial prevalence was collected from family history, obtaining information from both the patient and their relatives. In particular, we asked patients to invite their relatives to take part in the study in order to provide additional information about any family history of psoriasis.
802
Clinical and Experimental Dermatology (2014) 39, pp801–805
First degree relatives were parents, offspring and siblings; second degree relatives were uncles, aunts, nephews, nieces, grandparents, grandchildren and halfsiblings; and third degree relatives were first cousins, great-grandparents and great-grandchildren. Patients who were not able to provide detailed information about their family history of psoriasis on both maternal and paternal sides were excluded. To ensure recruitment of a group of patients representative of a local population, all patients attending the psoriasis outpatient service were invited during consultations and by posters in the waiting areas to participate in the study. The final sample consisted of 640 unrelated patients with psoriasis (370 male, 270 female; mean SD age 53.83 16.45 years, range 18–86) who had detailed data about their family history of psoriasis on both the maternal and paternal sides. Analysis of patient demographics showed a mix of ethnicities in proportion to our practice population: 614 Italian, 4 other European (2 Albanian, 2 Russian), 8 North African, 2 African and 12 East Asian subjects (Indian, Pakistani, Sri Lankan). Using the Risch non-parametric approach, the recurrence risk ratio (kR, where R represents the degree of relatedness), was calculated, setting the population prevalence of psoriasis at 2%.12,13 Patients with a parental history of psoriasis were divided according to the psoriasis status of their families (paternal or maternal line) in order to verify differences in the parental transmission of psoriasis. Dissimilarity in the expression of psoriasis in individuals with paternal vs. maternal transmission was assessed at the time of each proband’s presentation to the clinic. The two groups were compared with respect to disease onset (early vs. late); guttate vs. nonguttate origin; and facial, hand and foot, or nail involvement.
Results Of the 640 patients in our cohort, 380 (59.37%) reported at least one relative with psoriasis. Using the classification given above, 240 (37.5%) reported at least one first degree relative with psoriasis. Of these, 174 (97 male, 77 female) had at least one parent with psoriasis: the affected parent was the father in 86 cases (50 male, 36 female) and the mother in a further 86 cases (46 male, 40 female), while in 2 cases, both parents were affected. Six of these cases had also at least one affected sibling. The remaining 26 patients with a first degree relative with psoriasis had at least one child with psoriasis. Of the 72 individuals who did not have any first degree relatives with psoriasis, 40 reported at least one sibling with psoriasis, but 36 of
ª 2014 British Association of Dermatologists
Familial aggregation of moderate to severe plaque psoriasis V. Di Lernia et al.
these had no known relative with psoriasis in the previous generation. There were 106 probands (16.56%) with at least one second degree relative with psoriasis on the paternal side (50 subjects), the maternal side (50 subjects) or both sides (6 subjects). There were 34 patients (5.31%) with at least one third degree relative with psoriasis on either the paternal (n = 22 patients) or maternal (12 patients) side. Thirty-two individuals (5%) had both first and second degree relatives with psoriasis (6 paternal, 18 maternal, 8 from both paternal and maternal sides); 6 individuals (0.94%) had first, second and third degree relatives on the maternal side affected with psoriasis. Details for distribution of relatives according to first, second and third degree are given in Fig. 1. The recurrence risk ratio, kR, estimates the relative proportion of a disease in relatives compared with the prevalence of that disease in the general population. kR is defined as the prevalence of the disease in patients with a family history of psoriasis divided by the prevalence in the general population, assumed as 2%, and was found to be 18.75, 8.28 and 2.65, respectively, for first (kR1), second (kR2) and third (kR3) degree relatives (Table 1). Analysis of parental transmission in the 174 patients with family history of psoriasis in first degree relatives revealed male to male transmission in 50 cases, male to female transmission in 36 cases, female to male transmission in 46 cases, and female to female transmission in 40 cases (Table 2). Age of onset (mean SD) of psoriasis in patients with a family history of psoriasis was 29.49 15.09
for those with an affected mother vs. 30.09 17.75 for those with an affected father. There was no influence of the type of parental transmission (maternal vs. paternal) on the incidence of guttate vs. nonguttate, or the incidence of facial, nail, or hand and foot psoriasis (data not shown).
Table 1 Recurrence risk ratio for psoriasis in relatives of individuals with psoriasis. Psoriasis in at least one
Affected, n Prevalence, % kR*
Parent
First degree relative
Second degree relative
Third degree relative
174 27.18 13.59
240 37.5 18.75
106 16.56 8.28
34 5.31 2.655
*Recurrence risk ratio. Table 2 Affected individuals with parents with psoriasis: analysis of parental transmission.
Transmission
Probands with affected parents (n = 174)*
Father to male, n (%) Father to female, n (%) Mother to male, n (%) Mother to female, n (%)
50 36 46 40
(29.06) (20.93) (26.74) (23.25)
P 0.53†
*Comprised 96 male and 76 female; 2 patients had both parents affected with psoriasis. †Nonsignificant.
Psoriatic patients N = 640
Family history of psoriasis N = 380 (59.37%) M 222, F158
1st degree relatives 240 (37.5%)
Affected Father* 86
Affected Mother* 86
Affected Siblings 40
No psoriatic relatives N = 260 (M 142, F 118)
2nd degree relatives 106 (16.56%)
Paternal side* 50
Maternal side** 50
3rd degree relatives 34 (5.31%)
Paternal side 22
Maternal side 12
Figure 1 Family history of psoriasis. Flow chart showing the frequency of psoriasis in relatives on the maternal and paternal sides. Data
are n (%) of index patients having at least one-first, second or third degree relative with psoriasis. *Two additional individuals reported a history of psoriasis in both parents; **six additional individuals had at least one-second degree relative with psoriasis from both sides.
ª 2014 British Association of Dermatologists
Clinical and Experimental Dermatology (2014) 39, pp801–805
803
Familial aggregation of moderate to severe plaque psoriasis V. Di Lernia et al.
Discussion Psoriasis is a highly heritable disease, as shown by an increased rate of concordance in monozygotic vs. dizygotic twins (35–72% vs. 12–23%, respectively).7 The influence of a family history of psoriasis may be underestimated if there is no known relative with psoriasis in the previous generation. To improve the accuracy of reported family history information, the assessment of our study included a comprehensive three-generation pedigree, the involvement of the patients’ relatives and the use of the ‘family study method’.14 We found a high frequency of a positive family history of psoriasis. Of the 640 patients enrolled, about 60% reported a family history of psoriasis involving at least one of their first, second or third degree relatives, specifically 37.5%, 16.56% and about 5%, respectively. A standard measure of familial aggregation is the kR of disease in relatives of an index case, defined as the risk of disease in relatives of a random individual with disease. Weak alterations in the population prevalence obviously have an effect on kR (recurrence risk/population prevalence). In previous studies, kR for psoriasis was estimated to be between 4 and 10.13 Our study found a higher familial recurrence risk, with the kR for offspring of parents with psoriasis being 13.59. If we had assumed a prevalence of psoriasis of 3%, the number ratio would fall to 9.6. This estimate is similar to the figure of about 10 found by Henseler and Christophers15 for first degree relatives of a patient with early-onset psoriasis. Our study also examined the effect of paternal vs. maternal transmission of psoriasis. Collectively, this cohort (n = 640) includes 20 paternally (3.1%) and 32 (5%) maternally transmitted cases of psoriasis (including double and triple generations). Although the gender difference was not statistically significant, a higher penetration of maternally transmitted psoriasis between three generations was indicated. When disease transmission to offspring from affected fathers was compared with that from affected mothers, no differences were found. Imprinting is the process by which genetic alleles responsible for a phenotype are derived from one parent only. It is an epigenetic phenomenon resulting from DNA methylation or modification of protruding histones. Although the sex of the affected parent was not considered significant in the cohort study of Lomholt,16 both psoriasis and psoriatic arthritis were considered in other studies to have a predominantly paternal mode of transmission.17,18
804
Clinical and Experimental Dermatology (2014) 39, pp801–805
Genetic anticipation was suggested because an earlier age of onset was found when the disease was inherited from the father.19 However, large studies investigating the familial aggregation and transmission patterns of psoriasis are lacking. In addition, potential reported biases, such as the fact that fathers of patients with psoriasis may be more likely to be affected with the more severe form of the disease, could be the reason for the apparently excess paternal transmission. Because the sex of the disease-transmitting parent has been considered a potential factor that may influence differential expression of the disease,17,18 particularly the penetrance, we investigated the effect of maternal and paternal inheritance on phenotypic expression of psoriasis. The influence of the two transmission patterns of psoriasis on clinical factors or subphenotypes of the disease [early vs. late onset, guttate vs. nonguttate origin, or psoriasis type (facial, hand and foot, or nail)] showed no significant differences between patients with paternal or maternal history of psoriasis. However, the small sample size of this study may have introduced potential biases toward enrichment of either the paternal or maternal inheritance models.
Conclusion Studying the family clustering of psoriasis in our population did not give insight into understanding the mechanisms underlying parental influences. We did not find that a sex-specific epigenetic inheritance pattern for psoriasis is a major contributing factor in family-specific risk in psoriasis. The presence of a parental effect on psoriasis transmission is but one of the issues that remain to be clarified. Further molecular investigations of candidate genes will help to better evaluate the true impact of parental transmission of psoriasis.
What’s already known about this topic? ● Psoriasis is a multifactorial disease, caused by
a complex interplay of multiple genetic variants and environmental factors. ● Psoriasis is known to have a strong genetic component. ● Previous studies have suggested an excessive paternal transmission in psoriasis and psoriatic arthritis.
ª 2014 British Association of Dermatologists
Familial aggregation of moderate to severe plaque psoriasis V. Di Lernia et al.
What does this study add? ● The results of this study confirm high familial
recurrence risk of psoriasis but suggest a balanced parental transmission of the disease. ● No parent-of-origin effect in transmission of disease from affected parent to offspring was observed. ● In addition, no significant differences in clinical profiles of the disease between patients according to the transmission pattern of psoriasis were observed.
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