Parental Consanguinity and Family History in Relation to Psoriasis and the Role of Sex: A Case-Control Study

Psoriasis is a chronic, immune-mediated inflammatory skin disease that is characterized by erythematous, thickening, and scaly skin patches [1]. Estimates suggest that the global prevalence of psoriasis is around 2%; however, prevalence estimates vary across populations [2‒5]. Studies have shown that the prevalence of psoriasis has increased over the past decades, whereas evidence as to whether psoriasis incidence has increased over time is inconsistent [6‒10]. In terms of years lived with disability, the Global Burden of Disease (GBD) 2019 study estimated the worldwide age-standardized rate of years lived with disability attributed to psoriasis to be 43.3 per 100,000 people [5]. Moreover, psoriasis has been shown to be associated with multiple comorbid diseases, such as psoriatic arthritis, metabolic syndrome (obesity, hypertension, type 2 diabetes, and dyslipidemia), cardiovascular disease (stroke and myocardial infarction), inflammatory bowel disease, and mental health conditions (depression and anxiety) [11, 12]. In addition, psoriasis negatively affects the quality of life of affected individuals and their care givers [13, 14]. Collectively, psoriasis places substantial physical, psychological, and economic burden on patients and their families.

The etiology of psoriasis is not fully elucidated, but a complex interplay between genetic predisposition, environmental factors, and immunologic dysregulation contributes to the development of psoriasis [15, 16]. The genetic basis of psoriasis was initially demonstrated by higher incidence of the disease in first-degree and second-degree relatives than the general population [17, 18]. Genetic linkage analysis, candidate-gene studies, and genome-wide association studies have identified a number of psoriasis susceptibility loci, with findings implicating mainly adaptive/innate immune- and skin barrier-regulatory genes [17, 19, 20]. More than 80 genetic loci have been identified to be associated with psoriasis risk, with variants in human leukocyte antigen (HLA) genes being the most strongly associated with psoriasis risk [20]. Moreover, genetic variants in interleukin (IL)-12B and IL-23R genes, as part of the IL-23/Th-17 pathway, have shown strong association with psoriasis [17, 20]. Such evidence further demonstrates the significance of genetics in psoriasis development.

A less investigated factor in the epidemiology of psoriasis is the effect of parental consanguinity (inbreeding) on psoriasis risk in the offspring. The practice of consanguineous marriages, mating among close relatives, differs around the world, with the prevalence of consanguinity being low in Europe and North America and high in the Middle East, north and sub-Saharan Africa, and west, central, and south Asia [21, 22]. Biologically, consanguinity increases stretches of homozygosity in the genome that are identical by descent (a phenomenon known as autozygosity), leading to increased risk of autosomal recessive disorders [21, 23]. Moreover, consanguinity reduces any potential heterozygote advantage due to increased homozygosity [24]. Autozygosity has been shown to be associated with a wide range of disorders, including low fertility and fluid intelligence and increased risk of type 2 diabetes, post-traumatic stress disorder, Alzheimer’s disease, and coronary artery disease [25‒27]. Given that genetic factors contribute to the development of psoriasis, we sought to assess the association of parental consanguinity and family history of psoriasis with psoriasis among offspring in a case-control study. Moreover, we have explored whether the effects of parental consanguinity and family history of psoriasis on offspring psoriasis are modulated by sex.

A case-control study, with a 2:1 control-to-case ratio was conducted by enrolling cases of psoriasis (n = 139) and controls (subjects without psoriasis; n = 278) aged 21 years or more. Cases were recruited from five governmental/public dermatology clinics across the State of Kuwait situated within public hospitals or specialized dermatology centers. These clinics provide medical care free of charge to Kuwaiti nationals, and charge minimal fees to non-Kuwaiti nationals. Psoriasis cases were approached by the study personnel at the time of their clinical visit at the psoriasis clinics, and were invited to participate in the study. Controls, working adults, were enrolled from randomly selected governmental workplaces. Study personnel visited workplaces during working hours and invited employees to participate in the study. Both cases and controls were enrolled using convenience sampling methodology. Data collection occurred between October 1, 2023, and December 31, 2023. Ethical approval was obtained from the Standing Committee for the Coordination of Health and Medical Research, Ministry of Health, Kuwait (No. 2332/2023). Both cases and controls provided written informed consent prior to participating in the study.

A psoriasis case was defined as a patient with a dermatologist-confirmed diagnosis of psoriasis. A control was defined as a subject without prior diagnosis or history of psoriasis. Eligibility criteria of cases and controls were as the following: aged 21 years or older, of any gender, of any nationality, and being a residence of Kuwait.

A self-completed structured questionnaire was developed and used to collect information from cases and controls. The questionnaire collected data on sociodemographic characteristics, lifestyle factors, and parental/family history. Specifically, participants self-reported their gender, age, nationality, education level, and governorate of residence. Current cigarette smoking was defined as any reported use of cigarettes in the past 30 days. Former cigarette smoking was defined as ever cigarette smoking, but not current use. Body mass index (BMI) was calculated using self-reported weight and height as the weight in kilograms divided by the height in meters squared (kg/m²). BMI was categorized as follows: underweight (<18.5 kg/m²), normal weight (18.5 to <25.0 kg/m²), overweight (25.0 to <30.0 kg/m²), and obese (≥30.0 kg/m²).

Family history of psoriasis was assessed by an affirmative answer to the following question: “Has any of your family members ever been diagnosed by a doctor with Psoriasis?” Parental consanguinity was assessed by asking the following question: “Are your parents relatives?” Participants who answered the previous question with “yes,” were asked to indicate whether their parents are first-degree cousins (share a grandparent; children of their parents’ siblings), second-degree cousins (share a great-grandparent), or beyond second-degree cousins.

All statistical analysis was conducted using SAS 9.4 (SAS Institute, Cary, NC, USA). The statistical significance level was set to α = 0.05. Descriptive analyses were conducted to calculate frequencies and proportions of categorical variables. Continuous variables were described by calculating the median and interquartile range. To assess differences between cases and controls, univariable analyses were conducted by using χ² test to evaluate associations between categorical variables, and differences in medians of continuous variables were assessed by using the Wilcoxon rank-sum test. Univariable and multivariable binary logistic regression models were used to evaluate associations between psoriasis status (outcome variable) and parental consanguinity, degree of parental consanguinity, and family history of psoriasis (exposure variables). Crude and adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated. Variables that demonstrated possible association (p < 0.2) with psoriasis status in the univariable analyses were considered as potential confounders and were included in the multivariable regression models as covariates. Moreover, to assess whether sex is an effect modifier, statistical interactions on multiplicative scale were evaluated by including the following product terms in separate logistic regression models: “sex × parental consanguinity” and “sex × family history of psoriasis.” Subsequently, sex-stratified associations were evaluated.

In total, 417 individuals (139 cases and 278 controls) were enrolled in this study. The distribution of characteristics of cases and controls is presented in Table 1. Although the distribution of gender was similar among cases and controls, the study sample included higher proportion of females (64.8% of cases and 71.6% of controls). The median age was 33.0 years and 32.0 years among cases and controls (p = 0.147), respectively, with more cases being in the 50+ years age group compared to controls (13.0% vs. 2.9%). Additionally, the median BMI was higher among cases (28.4 kg/m²) compared to controls (26.0 kg/m²; p < 0.001). Parental consanguinity was more frequent among cases (59.7%) compared to controls (35.6%; p < 0.001). Similarly, family history of psoriasis was more common among cases compared to controls (56.8% vs. 23.7%; p < 0.001; Table 1). The online supplementary Table S1 (for all online suppl. material, see https://doi.org/10.1159/000543351) shows associations of demographic characteristics and risk factors with parental consanguinity. Subjects with family history of psoriasis compared to those with no family history of psoriasis reported higher frequency of parental consanguinity (58.6% vs. 35.7%, p < 0.001; online suppl. Table S1).

Univariable (crude) and multivariable logistic regression models were used to assess the relationship of parental consanguinity and family history of psoriasis with psoriasis status (Table 2). Parental consanguinity, independent of the effects of family history of psoriasis and potential confounders, was associated with increased odds of having psoriasis (aOR: 2.13, 95% CI: 1.29–3.50). We further assessed the association of the degree of parental consanguinity with psoriasis (Table 2) and found that the associations did not statistically significantly differ according to the degree of relatedness of the parents (pairwise comparisons: first-degree cousins vs. second-degree cousins, p = 0.857; first-degree cousins vs. beyond second-degree cousins, p = 0.396; second-degree cousins vs. beyond second-degree cousins, p = 0.601, data not shown). Moreover, family history of psoriasis was associated with increased odds of having psoriasis (aOR: 3.43, 95% CI: 2.07–5.67; Table 2) after adjusting for the effects of parental consanguinity and potential confounders.

We further assessed whether the associations of parental consanguinity and family history of psoriasis with psoriasis differ according to sex by evaluating statistical interactions (Table 3). In the univariable (crude) analysis, the association between parental consanguinity and psoriasis in the offspring differed according to sex (p_{sex × parental consanguinity} = 0.013), with parental consanguinity being associated with psoriasis more strongly among male subjects (crude OR: 5.98, 95% CI: 2.39–14.82) than among female subjects (crude OR: 1.82, 95% CI: 1.10–3.03; Table 3). In the multivariable (adjusted) analysis, the association between parental consanguinity and psoriasis remained different between the sexes (p_{sex × parental consanguinity} = 0.008), with parental consanguinity being associated with psoriasis among male subjects (aOR: 5.96, 95% CI: 2.39–14.82), but not among female subjects (aOR: 1.36, 95% CI: 0.75–2.49; Table 3). On the other hand, the association of family history of psoriasis with psoriasis did not differ according to sex (p_{sex × family history of psoriasis} = 0.492), with family history of psoriasis being associated with psoriasis among male subjects (aOR: 4.69, 95% CI: 1.85–11.9) and female subjects (aOR: 3.17, 95% CI: 1.72–5.83; Table 3).

This case-control study showed that parental consanguinity is associated with psoriasis in a sex-specific manner, with the association being present only among male subjects, but not among female subjects. Moreover, our study showed that family history of psoriasis is associated with psoriasis in both male and female subjects. These observed associations further highlight the importance of genetic factors in psoriasis development.

The genetic basis of psoriasis was first recognized by increased disease incidence among relatives as compared to the general population, with up to 91% of patients with psoriasis reporting disease history in relatives [18]. Family-based studies have shown that the risk of developing psoriasis among offspring of affected parents reaches 50% if the two biological parents are affected by psoriasis, and drops to 16% if only one parent is affected by psoriasis [18]. Moreover, twin studies have shown higher concordance rates among monozygotic twins (up to 72%) than dizygotic twins (up to 23%), with elevated estimates of heritability (up to 90%) further highlighting the importance of genetic factors in disease pathogenesis [18, 28‒31]. Nonetheless, the previously estimated concordance rates of psoriasis among monozygotic twins never reached 100%; hence, indicating that in addition to genetic predisposition, environmental factors are important in the etiology of psoriasis.

Our analysis showed that psoriasis cases compared to controls were significantly more likely to report parental consanguinity. Among controls, the observed parental consanguinity prevalence of 35.6% aligns with what has been reported for the general population in Kuwait (22.6–42.1%) [32] and the broader Arab region (17–80%) [33]. On the other hand, the prevalence of parental consanguinity among cases was 59.7%, which is higher than the aforementioned prevalence range of consanguinity in the general population of Kuwait [32]. Increased risk of disease that is associated with consanguinity is explained by the fact that consanguinity increases runs of homozygosity in the genome (i.e., autozygosity), leading to increased expression of autosomal recessive diseases in the population [21, 23, 34]. Although confounding by environmental and social factors cannot be excluded, prior studies utilizing within-sibling analysis, presumably removing the effects of nongenetic factors, further confirmed that the effect of autozygosity on diseases is mainly explained by genetic components [25, 27]. A prior meta-analysis showed that offspring of consanguineous marriages have an increased likelihood of experiencing immunodeficiency diseases characterized by an autosomal recessive pattern of inheritance [35]. Moreover, increased stretches of homozygosity in the genome due to parental consanguinity has been shown to be associated with a wide range of diseases, including type 2 diabetes, post-traumatic stress disorder, Alzheimer’s disease, and coronary artery disease [25‒27]. Two genetic linkage studies among consanguineous families identified an autosomal recessive loss-of-function variant in interleukin 36 receptor antagonist (IL36RN) gene that predisposes to the development of generalized pustular psoriasis, a rare and yet potentially lethal form of psoriasis [36, 37]. Nonetheless, uncontrolled confounding factors may explain the observed association in our study between parental consanguinity and psoriasis. For instance, a prior study showed that population stratification by cultural factors explained the observed association between autozygosity and depression [38]. Hence, the observed associations in our study should not be interpreted as evidence of causation.

Regarding the observed sex differences in our findings, which showed that parental consanguinity is associated with psoriasis only among male subjects, a prior study using genomic inbreeding coefficients for more than 1.4 million people reported sex-specific effects in the associations between homozygosity due to inbreeding and a range of diseases, with men compared to women being more vulnerable to the effects of inbreeding [27]. Emerging knowledge suggests that intrinsic biological differences between the sexes influence the sex-specific effects of inbreeding in nonhuman species, specifically in terms of fitness [39]. Nonetheless, in humans, the biological explanation of the observed sex-specific effect of parental consanguinity on psoriasis in the offspring in this report is unclear and needs further elucidation. The rationale for investigating sex-specific effects in this report is driven by the emerging and accumulating evidence that suggest that genetic and epigenetic mechanisms underlie the widely observed sex differences in disease development, prognosis, and treatment [40, 41]. For instance, Huang et al. sought to investigate sex-specific genetic basis that underlie sex differences in a wide range of phenotypes and have identified a number of male-specific and female-specific genetic loci that predispose males and females to diseases in a sex-specific manner [42]. Hence, identifying sex-specific risk factors of diseases is an important step for risk stratification and future precision medicine efforts. Given the lack of prior studies reporting sex-specific associations between parental consanguinity and psoriasis in the offspring, future studies are needed to corroborate our findings.

In our study, family history of psoriasis was significantly more frequently reported by cases compared to controls (56.9% of cases and 23.9% of controls). The observed frequency of family history of psoriasis among cases in this study is in agreement with findings from previous studies. A school-based study in Kuwait reported that 50% of psoriasis cases had a family history of psoriasis [43]. Comparable results were observed globally, with 47–52.9% of psoriasis patients in Spain [44, 45] and 45.9% of psoriasis patients in Italy [46] having a positive family history of psoriasis. Nonetheless, a multicenter study among psoriasis patients from western Japan reported that only 10.8% of patients have family history of psoriasis [47]. Among control subjects, the frequency of family history of psoriasis in our study was unexpectedly high (23.7%), which might be explained by the assessment method that asked about psoriasis history in “any” family member. Such an overestimation could have biased (underestimated) the measure of effect relating family history of psoriasis with psoriasis. Nonetheless, our finding of a strong association between family history of psoriasis and psoriasis is consistent with the existing scientific literature [45, 48, 49], which indicates that genetic predisposition is an important factor in the development of psoriasis. Moreover, our observation of similar effect of family history of psoriasis in male and female subjects is further support by findings of a prior study that showed family history of the diseases is associated with psoriasis in both male and female subjects [50].

Dermatologist-confirmed cases of psoriasis were enrolled from different psoriasis clinics across the State of Kuwait; hence, the enrolled cases provide a good representation of cases in the underlying population. This speculation is further corroborated by the fact that the prevalence of family history of psoriasis among cases in this study (56.8%) is similar to that estimated among a random school-based sample of psoriasis cases in Kuwait (50%) [43]. Moreover, population-based controls were enrolled from the source population that produced the cases. The prevalence of parental consanguinity among controls (35.6%) is within the previously reported range of consanguinity among the general population in Kuwait (22.6–42.1%) [32]. Hence, the exposure (i.e., parental consanguinity) frequency among the enrolled controls resembles the expected frequency in the source population, which further assures that the enrollment of controls was independent of the exposure status. Nonetheless, given that convenience sampling was used to enroll both cases and controls, effect of selection bias on the results cannot be eliminated. Moreover, our results are unlikely to be influenced by reverse causation as parental consanguinity (main exposure of interest) occurred before the development of the disease. Although recall bias is a common limitation in case-control design, we speculate that both cases and controls have the same extent of motive of recalling/reporting their parental consanguinity status and family history of psoriasis. Thus, the effect of recall bias, if any, should be minimal on the results of this report. Nonetheless, given that the magnitude of the association between parental degree of consanguinity and psoriasis in the offspring did not differ according to the degree of parental relatedness (see Table 2), which is against our expectation, we speculate that study participants might have misreported the degree of their parental relatedness leading to misclassification bias. Hence, results of the association analysis between degree of parental consanguinity and psoriasis in the offspring should be interpreted with caution.

The finding of an association between parental consanguinity and psoriasis in this study is novel, and this association was sex-specific, with an effect among male subjects, but not among female subjects. If the identified association between parental consanguinity and psoriasis in this study is corroborated and deemed causal, future genetic studies of psoriasis in consanguineous populations may lead to identifying novel risk alleles for psoriasis. Moreover, the observed association between family history of psoriasis and psoriasis further confirms findings of prior studies. The finding of an association between parental consanguinity and psoriasis calls for further corroborations by future studies. Parental consanguinity and family history of psoriasis can be surrogate variables of familial genetic predisposition. Therefore, our empirical findings highlight the importance of genetic factors in the development of psoriasis, in addition to environmental triggers.

We would like to thank all the study participants for their time and help. Also, we would like to thank all the physicians and the staff at the clinics for their cooperation and facilitating the enrollment of cases.

This study was reviewed and approved by the Standing Committee for the Coordination of Health and Medical Research, Ministry of Health, Kuwait (No. 2332/2023). Study participants provided written informed consent.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

All authors participated in the conceptualization and design of this study. A.N.A.: collected the data, contributed to data analysis and interpretation, and drafted the manuscript. A.H.Z.: supervised the project administration and data collection, contributed to data analysis and interpretation, and contributed to drafting the manuscript. All authors critically revised the manuscript for important intellectual content. The manuscript has been read and approved by all authors.

The data that support the findings of this study are not publicly available to protect participants’ privacy and comply with the Ethics Committee requirements, but de-identified, participant level data pertaining to the current study are available from the corresponding author (A.H.Z.) upon reasonable request.