Racial Disparities Among Clinical Trials for Inherited Forms of Lipodystrophy

Abstract

Background: There has been renewed interest in understanding how medical research serves minority communities disproportionally affected by disease. A recent study in a predominantly white population identified 12 subjects with partial lipodystrophy by genetics without clinical diagnosis of lipodystrophy (Gonzaga-Jauregui et al., 2020). Partial lipodystrophies are rare monogenic disorders leading to diabetes that can be challenging to diagnosis due to their similarity with common obesity-associated metabolic syndrome. We hypothesize minority populations may be underdiagnosed with lipodystrophy, and thus underrepresented in clinical trials. Methods: We compared racial demographics of lipodystrophic subjects participating in clinical trials to subjects with predicted loss-of-function (pLOF) mutations in 4 genes associated with lipodystrophy in the GnomAD dataset (>140K exome sequences): LMNA & PPARG (causing dominantly inherited partial lipodystrophy), and AGPAT2 & BSCL2 (causing recessively inherited generalized lipodystrophy, which is more phenotypically apparent, as an internal control for the study design). We also compared rates of synonymous mutations in these 4 genes among races to test if subjects of different ethnicities may be more genetically predisposed to developing inherited forms of lipodystrophy. Comparisons were done using chi-square analysis. Results: We identified 322 subjects with pLOF mutations in genes associated with lipodystrophy in the GnomAD dataset. The racial composition of GnomAD subjects with pLOF mutations in each gene was different than GnomAD subjects without pLOF mutations (p<0.001). 144 lipodystrophic subjects with known pathogenic variants in these genes participated in clinical trials. The racial composition of GnomAD and clinical trial subjects with LMNA mutations were significantly different (p=0.024) with the clinical trial cohort being more enriched for white patients (78 vs 21%) and less enriched for Latino patients (7 vs. 21%). There were no differences for other genes. The rates of synonymous mutations were different among patients of different ethnicities, p<0.001 for all genes. Discussion: Partial lipodystrophy due to LMNA mutations may be underdiagnosed in Latinos, leading to reduced participation in clinical trials. The lack of differences in other genes suggests there is no overall cohort bias. Different rates of synonymous mutations suggest there may be evolutionary drivers to racial differences in inherited forms of lipodystrophy, such as founder mutations or heterozygote advantage. Future work will determine prevalence of pLOF variants in lipodystrophy-associated genes in other genetic data sets enriched for minority subjects.