Lead Investigator: Barbara Pober, MD

Institution: Massachusetts General Hospital

LF Funding History: 2017 Proof of Concept Award

Hypothesis: Our hypothesis is that deletion of one or more of genes in the Williams Beuren syndrome (WS) critical interval generates excess lipedema risk by unmasking common genetic variants that are relevant to lipedema.

Collaborative Opportunities: We are eager to talk to and potentially collaborate with other researchers involved in genetic approaches or have candidate genes, either form clinical work in patients with lipedema or from animal models. We would also be eager to explore collaborations with researchers characterizing the lipedema phenotype by using imaging techniques and/or metabolic profiling.

Project: Chromosome 7q11.23 deletion (Williams Beuren syndrome) as a model for revealing genetic contributions to lipedema

Increasing clinical and research efforts are being directed to better understand potential etiologies, natural history and management of the disorder, Lipedema. The presence of multiple affected members in some families points to a genetic role in its causation, while the high preponderance of affected females suggests a hormonal component. We plan to study the relatively rare unique genetic condition, Williams syndrome (WS), as a model disorder to elucidate genetic and hormonal pathways involved in lipedema.

WS is a multi-system neurodevelopmental disorder with a complex phenotype. Among its many features, patients show a high frequency of abnormal fat distribution, ranging from relative adiposity in the lower body to lipedema; females as well as males are affected. WS is caused by deletion of the WS critical interval, a stretch of 26-28 genes on chromosome 7; accordingly, persons with WS have a single copy, rather than two copies, of these genes. We believe that deletion of one or more of these critical interval genes generates excess lipedema risk either by unmasking common genetic variants that alter functioning of the remaining copy of a critical interval gene, or by interacting with common variants elsewhere in the genome that predispose to general population lipedema.

This hypothesis will be tested by high density genotyping of three groups of individuals: WS with lipedema; WS without lipedema; and general population controls. Additionally, we will measure levels of sex steroids, sex hormones, cortisol, and adipokines in WS subjects; we predict that a higher frequency of abnormal levels will be observed among those with lipedema.