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. 2023 Dec;143(12):2416-2426.e1.
doi: 10.1016/j.jid.2023.04.033. Epub 2023 May 26.

A Polygenic Risk Score for Predicting Racial and Genetic Susceptibility to Prurigo Nodularis

Chirag Vasavda  1 , Guihong Wan  2 , Mindy D Szeto  3 , Melika Marani  3 , Nishadh Sutaria  3 , Ahmad Rajeh  4 , Chenyue Lu  2 , Kevin K Lee  3 , Nga T T Nguyen  4 , Waleed Adawi  3 , Junwen Deng  3 , Varsha Parthasarathy  3 , Zachary A Bordeaux  3 , Matthew T Taylor  3 , Martin P Alphonse  3 , Madan M Kwatra  5 , Sewon Kang  3 , Yevgeniy R Semenov  4 , Alexander Gusev  6 , Shawn G Kwatra  7
Affiliations

A Polygenic Risk Score for Predicting Racial and Genetic Susceptibility to Prurigo Nodularis

Chirag Vasavda et al. J Invest Dermatol. 2023 Dec.

Abstract

Prurigo nodularis (PN) is an understudied inflammatory skin disease characterized by pruritic, hyperkeratotic nodules. Identifying the genetic factors underlying PN could help to better understand its etiology and guide the development of therapies. In this study, we developed a polygenic risk score that predicts a diagnosis of PN (OR = 1.41, P = 1.6 × 10-5) in two independent and continentally distinct populations. We also performed GWASs, which uncovered genetic variants associated with PN, including one near PLCB4 (rs6039266: OR = 3.15, P = 4.8 × 10-8) and others near TXNRD1 (rs34217906: OR = 1.71, P = 6.4 × 10-7; rs7134193: OR = 1.57, P = 1.1 × 10-6). Finally, we discovered that Black patients have over a two-times greater genetic risk of developing PN (OR = 2.63, P = 7.8 × 10-4). Combining the polygenic risk score and self-reported race together was significantly predictive of PN (OR = 1.32, P = 4.7 × 10-3). Strikingly, this association was more significant with race than after adjusting for genetic ancestry. Because race is a sociocultural construct and not a genetically bound category, our findings suggest that genetics, environmental influence, and social determinants of health likely affect the development of PN and may contribute to clinically observed racial disparities.

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Conflict of interest statement

Conflicts of Interest and Financial Disclosures

Dr. Vasavda is a paid consultant and stockholder of AstraZeneca. Dr. Kwatra is an advisory board member/consultant for Abbvie, Aslan Pharmaceuticals, Arcutis Biotherapeutics, Castle Biosciences, Celldex Therapeutics, Galderma, Genzada Pharmaceuticals, Incyte Corporation, Johnson & Johnson, Kiniksa Pharmaceuticals, Leo Pharma, Novartis Pharmaceuticals Corporation, Pfizer, Regeneron Pharmaceuticals, and Sanofi and has served as an investigator for Galderma, Incyte, Pfizer, and Sanofi. The remaining authors state no conflict of interest.

Figures

Figure 1.
Figure 1.. Prurigo nodularis genetic discovery study design.
Base data for computing polygenic risk scores (PRS) were centered on genome-wide polymorphism profiling in FinnGen, a population cohort that includes 309 patients with prurigo nodularis (PN) and 198,740 control patients. PRSs were then calculated for all individuals in the Partners Biobank, an independent repository that includes genome-wide single-nucleotide polymorphism profiling of 171 patients with PN and 36,328 control patients. Association between the calculated PRS and a diagnosis of PN was evaluated with a logistic regression model with and without adjusting for covariates, such as age, sex, and self-reported race.
Figure 2.
Figure 2.. Identification of a replicable polygenic risk score for prurigo nodularis.
a, Frequency histograms of polygenic risk scores (PRS) of patients with prurigo nodularis (pink) compared to control patients of patients within the Partners BioBank. b, Receiver operating characteristic (ROC) curves of 6 independent PRS for prurigo nodularis within the Partners BioBank patient cohort. PRS3 (pink) denotes the best functioning PRS for prurigo nodularis as defined by the greatest area under the curve (AUC) deviance from 0.5. c-d, ROC curves of PRS3 for prurigo nodularis alone (pink) and PRS3 combined with the final logistic prediction model for prurigo nodularis (teal) within the Partners BioBank (c) and UK Biobank (d) patient cohorts. The model includes demographic and clinical predictors.
Figure 3.
Figure 3.. Patients of African and Asian genetic ancestry are at increased risk of developing PN.
a, Ancestry cluster dimensions among patients by self-reported racial groups and genetic principal component (PC) score. X-axis relates the PC cline for Black ancestry, whereas Y-axis relates the PC cline for Asian ancestry. Highlighted clusters represent self-declared racial or ethnic group (green = Black, purple = Asian, orange = Hispanic, black = All). b-c, Case (prurigo nodularis) versus control status as a function of genetic ancestry with PC being (b) Asian (Asian race OR of 2.36 (95% CI 0.95–5.85, P = 0.06465) or (c) African (Black race OR of 2.63 (95% CI 1.49–4.61, P = 7.8 × 10−4). Mean ± 95% CI depicted.
Figure 4.
Figure 4.. Association of single-nucleotide variants with prurigo nodularis.
a-f, (a, c, and e) Manhattan plots of the –log10(P)-values of the variants tested for genome-wide association with prurigo nodularis in the (a) Partners Biobank (n = 6,874,147 variants), (c) FinnGen Biobank (n = 16,380,425 variants), and (e) meta-analyzed combined cohorts (n = 6,572,020 variants). Variants are positioned according to the XYZ assembly and clustered by chromosome. The upper and lower dotted lines indicate thresholds for genome-wide significance (P = 5.0×10−8) and suggestive genome-wide significance (P = 1.0×10−5), respectively. (b, d, and f) Quantile-quantile plot of observed versus expected –log10(P)-values in the (b) Partners Biobank, (d) FinnGen Biobank, and (f) meta-analyzed combined cohorts.
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References

    1. Aggarwal P, Choi J, Sutaria N, Roh YS, Wongvibulsin S, Williams KA, et al. Clinical characteristics and disease burden in prurigo nodularis. Clin Exp Dermatol. 2021;46(7):1277–84 - PubMed
    1. Belzberg M, Alphonse MP, Brown I, Williams KA, Khanna R, Ho B, et al. Prurigo Nodularis Is Characterized by Systemic and Cutaneous T Helper 22 Immune Polarization. J Invest Dermatol. 2021;141(9):2208–2218.e14 - PMC - PubMed
    1. Boozalis E, Tang O, Patel S, Semenov YR, Pereira MP, Stander S, et al. Ethnic differences and comorbidities of 909 prurigo nodularis patients. J Am Acad Dermatol. 2018;79(4):714–719.e3 - PMC - PubMed
    1. Boyle EA, Li YI, Pritchard JK. An Expanded View of Complex Traits: From Polygenic to Omnigenic. Cell. 2017;169(7):1177–86 - PMC - PubMed
    1. Brenaut E, Halvorsen JA, Dalgard FJ, Lien L, Balieva F, Sampogna F, et al. The self-assessed psychological comorbidities of prurigo in European patients: a multicentre study in 13 countries. J Eur Acad Dermatol. 2019;33(1):157–62 - PubMed

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