By Guy Eakin, PhD
Although we have much to learn about how a person’s genetic code can influence the probability that they will develop Lipedema, researchers generally believe that genes do play a role. It is not uncommon for women with Lipedema to be able to point to other members of their family who either had a Lipedema diagnosis or could be described as having similar body shapes. In fact, the earliest descriptions of Lipedema all point to the likelihood that the condition can be passed between generations [1–3].
In 1951, one seminal Lipedema study reported that 16% of women with Lipedema reported a “history of similar ‘large legs’ in female members of the family” [3]. In more recent studies, reports of a family history of Lipedema tend to be much higher, and consistently range from 64% to 89% [4–11], with some lower estimates ranging from 30% to 40% [12–16].
Two studies of women with Lipedema went further, characterizing family relationships that suggest women with Lipedema are most likely to have an affected mother (29-38%) followed by grandmother (17-35%), aunt (8-23%) and sister (5-14%) [11,17].
A Lack of Data
But precisely which genes increase the risk of Lipedema? This question is more difficult to answer. Specific genetic studies often include small numbers of women with Lipedema and are complicated by the difficulty of diagnosing the condition consistently. Some early reports suggested that Lipedema is likely to be most strongly influenced by a single dominant gene [18]. This view that a small number of genes might determine whether a woman develops Lipedema has evolved with science.
Currently, the best evidence suggests that dozens of genes may exist in the body, with each subtly adding or reducing the risk rather than any one guaranteeing development of Lipedema [6,19].
To find these genes, scientists generally take one of two philosophical approaches. The most straightforward is the “candidate gene” approach. Typically, a researcher will begin with a list of several “favorite” genes that are known to play a role in other diseases or important physiological processes. These genes can be thought of as the prime suspects for Lipedema. Several such genes have been explored and even found to be coded differently in the study participants with Lipedema. (As a side note, we aren’t going to use the word “mutated”. To date, researchers have documented genetic variations in some families and individuals amongst genes known to be involved in hormonal regulation, fat development, inflammation, and other processes involved in Lipedema [19–24] .
Unfortunately, there are several major concerns with candidate gene approaches. They are more likely to generate false positives than other techniques and are prone to several types of bias. For that reason, until a candidate finding is replicated by whole genome approaches, its presence in a single study should be considered exciting but not confirmatory.
Less biased approaches, such as genome-wide association studies (GWAS), survey hundreds of patients across thousands to millions of variations in their DNA, without focusing on one specific gene or cellular process. If the researchers know which patients have Lipedema and which do not, they can track the areas of the DNA that statistically predict the likelihood that the specific gene variant will be associated with Lipedema. Two recent studies approached the question of the genetic determinants of Lipedema through different techniques that each surveyed thousands of genomic areas [6,25]. The interesting news is that statistical techniques were applied in one of the studies to ask how much Lipedema could be explained by the variations seen in DNA. The answer was about 50-60%, which is similar to the family history numbers described above [6], and suggest that research is on the right track to understanding the heritability of Lipedema.
Genetics Testing for Lipedema
Should you get a genetics test for Lipedema?
Probably not. The development of any genetic profile to support a Lipedema diagnosis is too preliminary to allow any confidence in its value to support a diagnosis or to inform a treatment plan.
Replication of the findings of any of the studies reviewed here have not been satisfactorily reported or clinically replicated. Single gene reports that are not backed by data from less-biased approaches should be considered as intriguing, but preliminary data. These genes need to show up in multiple studies, and preferably be studied in a way that allows us to understand not just whether a variant is present, but also demonstrate the role of that gene in the development of Lipedema.
Thus, any genetic testing offered today could not be considered clinically validated for purposes of diagnosis, and likely provides no more information on the heritability of the condition than a patient report of a close female family member with similar symptoms.
What can be done with the existing genetics data?
The most near-term benefit is the continued legitimization of Lipedema as a unique condition. The heritability of Lipedema, now shown in many studies, strongly supports the unique nature of Lipedema in clinical (and research funding) environments where it is – far too often – dismissed as obesity or another related condition.
Longer term, these papers clearly form an exceptionally important cornerstone for human genetics research into Lipedema and point to the sophistication that is possible in future studies. With confirmation, some of the gene variants so far described may become part of a clinically meaningful genetic test. Furthermore, identifying genetic risk variants give us clues to the underlying biological mechanism of Lipedema and additional molecular targets for research.
CITED REFERENCES and LINKS
6 Grigoriadis, D. et al. (2021) [preprint] Investigation of clinical characteristics and genome associations in the ‘UK Lipoedema’ cohort,
16 Harwood, C.A. et al. (1996) Lymphatic and venous function in lipoedema. Br J Dermatol 134, 1–6
18 Child, A.H. et al. (2010) Lipedema: an inherited condition. Am J Med Genet A 152A, 970–976