Genetics of Scarring

Student thesis: Doctoral ThesisDoctor of Philosophy


Excessive scarring (keloids and hypertrophic scars) is complex with incompletely understood genetic underpinnings. The manifestation of a severe excessive scarring phenotype in an Israeli pedigree carrying a very rare homozygous frameshift variant (p.Asn43fs/rs571313759) in the C1QTNF12 gene, encoding adipolin, provided an opportunity to study its potential role as a highly penetrant causal variant.

Both in vitro and bioinformatics approaches were adopted, with the latter extended to examine risk patterns of excessive scarring in a wider population. To characterise the phenotype of dermal fibroblasts carrying the variant, cells isolated from the proband were analysed for their morphology, proliferation, and contractility. These cells had enhanced transforming growth factor beta 1 (TGFβ1)-induced contractility but no differences in morphology or proliferation. To assess the effect of adipolin on fibroblast contractility, wild-type normal human dermal fibroblasts were treated with recombinant adipolin and contraction assays performed. No effect on intrinsic or TGFβ1-induced contractility was demonstrated.

To generate insight into the effect of adipolin on the fibroblast transcriptome, normal human dermal fibroblasts were treated with adipolin-conditioned media and bulk RNA-sequencing was performed. No significant transcriptomic changeswere induced, suggesting that adipolin may not have a striking direct effect on dermal fibroblasts. To further substantiate the evidence for or against C1QTNF12 loss-of-function (LOF) in fibrosis, exome data for ~200000 participants in the UK Biobank (UKB) was interrogated for potentially relevant phenotypic traits. No phenotypes of clinical relevance to excessive scarring were observed in individuals with C1QTNF12 LOF variants.

Multivariable logistic regressions and a phenome-wide association study (Phe-WAS) was performed within the UKB excessive scarring cohort to characterise comorbid associations with excessive scarring. Previously reported associations withhypertension, vitamin D deficiency and atopic eczema were identified in models adjusting for age, sex and ethnicity, but only the association with atopic eczema (OR 1.68, p<0.001) was statistically significant after accounting for additional potential confounders. Ethnic differences in these comorbid associations were highlighted. The PheWAS identified numerous previously unreported disease associations that may inform on common pathological mechanisms, including musculoskeletal disease and pain symptoms.

To investigate for common genetic variations that associated with excessive scarring, a genome-wide association study (GWAS) was performed for the UKB cohort and meta-analysed with GWAS summary statistics from FinnGen, comprising anindependent European population. Three of four previously associated loci were identified: two at genome-wide significance (1q32.1: rs35383942, odds ratio [OR] 1.46, p-value 7.0×10-11; 1q41: rs10863683, OR 0.69, p-value 3.0×10-25) and one just short thereof (15q21.3: rs60890210, OR 1.24, p-value 6.7×10-8). Bayesian finemapping offered strong evidence for causality of the lead SNP at 1q32.1 (posterior probability [PP] 0.79) and 1q41 (PP 1.0) but was inconclusive at 15q21.3. Expression quantitative trait loci (eQTL) were identified for ten genes including PHLDA3 and NEDD4 but colocalisation analysis did not support the hypothesis that these eQTLs shared a causal variant with keloid susceptibility. A known association with Dupuytren’s contracture was identified at the 15q21.3 locus, notable as a fibrotic disorder, hinting at a shared genetic architecture.

Data from this work suggest that the C1QTNF12 variant may not be a highly penetrant cause of excessive scarring in our pedigree but does not fully rule out a contributory role to the development of this complex disease. The UKB analyseswere a broad examination of the phenotypic and genetic characteristics of excessive scars, with findings that parallel previous reports and shed light on new associations. Importantly, they highlighted the need for better representation of skin phenotypes in electronic health records for future research.
Date of Award1 Apr 2023
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJohn McGrath (Supervisor), Madeline Parsons (Supervisor) & Tanya Shaw (Supervisor)

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