Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And joining me today is Dr. Margrit Urbanek, she's an Associate Professor of Medicine specializing in Genetic Endocrinology at Northwestern Medicine; and Rosie Bauer, a PhD student in the Driscoll Graduate Program at Northwestern Feinberg School of Medicine. Together, they're going to share key insights from their recent research on the potential role of a rare genetic variation in the LMNA gene in the development of polycystic ovary syndrome.

I'm so glad you both could join us today. And Dr. Urbanek, I'd like to start with you. Can you give us a little bit of an overview of your study on the role of rare variations in the LMNA gene in the pathogenesis of PCOS? What were the primary objectives of your research and why did you choose to focus on this?

Margrit Urbanek, PhD: Good morning, Melanie. Thank you very much for inviting us to Better Edge. So, PCOS is the most common endocrine disorder of reproductive age women. Between 5-10% of women between the age of 18 to 45 are affected by PCOS. It has a huge impact. It's characterized by elevated testosterone levels, irregular periods, and polycystic ovary morphology. It's also associated with insulin resistance, diabetes, obesity, and dyslipidemia. And this will become important as we talk more. We believe that this phenotypic heterogeneity that you observe in women with PCOS reflects an underlying heterogeneity in pathology. So, our lab is very interested in using genetics to try and tease apart what these different contributing factors are to the polycystic ovary syndrome.

We think that genetic approach is going to work because PCOS is very heritable, very genetic and genes that have a very strong effect and cause diseases that are very penetrant are also observed in common diseases like PCOS. And there are a couple which cause insulin resistance, which where if women have these genetic variants, they also present with the symptoms of PCOS.

And so, when Rosie joined our lab, she was very interested in this project and she started looking at one of these genes which is called lamin A. This gene causes dysregulated deposition of fat tissue, but these women are also very insulin-resistant, meaning they need a lot more insulin to manage glucose, and they have all the features of PCOS. And so, this is sort of the overlying reason for doing this project.

Rosie Bauer,PhD: Like Margrit said, people who have variation in this LMNA gene have a disease called Dunnigan type familial lipodystrophy, or it's abbreviated FPLD2 and particularly women who have this Lipodystrophy syndrome, have all of the features of PCOS. The phenotype overlaps a lot. And so, we wanted to start with this gene and ask kind of the inverse question. If you had a cohort of women with PCOS, how many of them would have variation in this same gene underlying the pathogenesis of their disease? So, that is why my project starts with this gene, LMNA.

Melanie Cole, MS: Well then, Rosie, can you explain the methodology used in your study, including the target sequencing of the discovery cohort, and the whole exome sequencing of the replication cohort? Give us an overview of your methodology.

Rosie Bauer,PhD: Yes. So, I think something that almost everybody knows about genetic sequencing is that the cost of it has really plummeted over time. So, it used to be that you had to be very specific and very hypothesis-driven about the genes you wanted to look at. So in the initial stages of this project, we had to pick very specific genes that we thought had a really good chance of having an implication in PCOS. And so, that is what the targeted sequencing was meant to do. And I'm just talking about LMNA, but that project involved a handful of hypothesized candidate genes. And so, we use that in our first cohort that we call the discovery cohort to sequence this gene. But then later in the study, we have the ability now to do whole exome sequencing, because like I said, the cost of sequencing has really decreased over time, and whole exome sequencing just means we don't have to pick anymore. We get to sequence the coding regions of every gene. And in this study, we just focused on the same gene because we wanted to have a nice discovery and replication. But with this data set, we also have the ability now to go look at any other gene we want to look at. So, that's the difference in the methodology between the two cohorts. It really doesn't make a huge difference in the end, but going forward, we now have this huge wealth of data to look at any gene we want to look at.

Margrit Urbanek, PhD: I kind of want to underscore the importance of discovery and replication cohort. One of the issues with genetic association studies for complex traits, which is what we're doing here, is that in the past they have not replicated very well. So, it is critical that you make a discovery and then you can repeat it in an independent cohort. And that's what Rosie did by first looking at it in the targeted sequencing data and then in the whole exome data.

Melanie Cole, MS: This is really interesting because, as you said at the very beginning, this is something that so many women really have to live with. So Rosie, the results of the study indicate a notable association between the lamin A variants and high levels of triglycerides and severe insulin resistance, as we mentioned in women with PCOS. Help us to understand the relationship between these factors and PCOS.

Rosie Bauer,PhD: Yeah. So like Margrit said at the beginning, we think that some of the heterogeneity in this disease can be explained by heterogeneity in underlying cause. And so, we're talking about a small subset of women with PCOS at this point, the people that we identified who have variation in this gene, and variation in this gene is thought to cause a loss of ability to store fat. And so, this results in the phenotype of high-circulating triglycerides, which then down the line results in severe insulin resistance. And the mechanism for how this results in PCOS is relatively unknown. It could be through a couple of different mechanisms. Some think this is through direct insulin action on the ovary, increasing testosterone production, which happens when you have these high levels of insulin. It could also be through feedback into the neuronal reproductive axis regulating reproductive hormone cyclicity, but that part is relatively unknown still.

Margrit Urbanek, PhD: Lamin A/C is one of those genes that is fundamental. It's in every cell of our body and it's can have many different impacts. And in these women, it just happens to impact their fat deposition. I also want to sort of highlight a feature of this research, which is very interesting, it is now becoming clear in many different studies that there is a link between reproduction and metabolism. And generally in humans, obesity has a negative impact on your reproductive ability. So, it's very interesting that one of the first genes that we found that have true causal variants impact both of those traits.

Melanie Cole, MS: Well, then, Rosie, based on everything we've learned here today, how might these findings influence the treatment and management of PCOS, especially for patients with identified lamin A variants? Take us from bench to bedside for other providers that are working with these patients on a daily basis.

Rosie Bauer,PhD: The caveat we have to make is that both Margrit and I are researchers, we are not clinicians, but we do have some main messages that we would love for physicians to pick up on. And one of those is that when you're treating someone who has a diagnosis of PCOS, if an indicator of some other pathology comes up, to not ignore those things and attribute them to being consequences of their overall PCOS. So, things like an abnormally high triglyceride measurement could indicate a different underlying pathology in the mixed bucket that is PCOS patients. And I think a lot of people right now have this conventional wisdom that when someone has PCOS, they might develop all of these other metabolic abnormalities and not really get treatment targeted at the underlying pathology, which in this case for women with these variants is their lipodystrophy underlying their pathogenesis of PCOS.

Margrit Urbanek, PhD: So, I think one of the things with PCOS is at this point, it's very much symptom-driven. So, treatments are based on causing ovulation or reducing insulin levels. Those things are not going to fix the underlying problem with people that have these LMNA variants. For those, treatment of reducing lipids, those kinds of treatments will be much more effective.

Melanie Cole, MS: I'd like you each to have a final thought here. So Dr. Urbanek, starting with you. As you look forward, where do you see this going? What would you like to see happening as far as future research?

Margrit Urbanek, PhD: I like the huge picture. As I keep saying, PCOS is very heterogeneous. So, there are many different buckets that women with PCOS fall into. And my dream is to identify all the buckets and to be able to place any given woman with PCOS in a bucket that defines her underlying genetic predisposition. With the idea that that will improve her treatment, make it much more targeted, and much more effective. That is my long range goal.

Melanie Cole, MS: Rosie, what about you? What future research do you believe is needed and critical for further understanding of the role of the lamin A gene and other lipodystrophy genes in PCOS? What's next for your own research?

Rosie Bauer,PhD: So, like Margrit said, we overall in our lab are studying all these different buckets. And we really want to identify several different pathways that could underlie pathogenesis. But my own thesis project for my PhD thesis is about kind of a broader metabolism category, even broader than just lipodystrophies. But there are about 10 different genetic lipodystrophies, not just the one caused by variation in lamin, so we're interested in the rest of those lipodystrophy genes. But on top of that, the rest of my project involves looking at other genes related to diseases of severe insulin resistance, type 2 diabetes genes, MODY genes, and some monogenic obesity and genes associated with BMI. So hopefully, I'll be able to kind of wrap up that bucket before I'm through with my thesis project.

Melanie Cole, MS: Well, thank you both for joining us so much. This is so interesting and good luck on all your continued research and be sure to come back and update us as you find out more. I hope that you do. And to refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/endocrinology to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole.