NEW YORK, July 16, 2020 /PRNewswire-PRWeb/ -- Mount
Sinai researchers have for the first time identified reproductive
and metabolic subtypes of polycystic ovary syndrome (PCOS) that are
associated with novel gene regions. The findings, which used
clustering of clinical, metabolic, and hormonal data from women
with the syndrome, promise to transform understanding of the cause
of PCOS and, accordingly, will have far-reaching implications for
its diagnosis and treatment. The results were published in PLOS
Medicine on Tuesday, June 23.
PCOS is among the most common endocrine conditions in
reproductive-age women, affecting up to 15 percent of this
population worldwide. It is a leading cause of infertility and type
2 diabetes in young women. The cause of PCOS is unknown, but there
is a strong inherited susceptibility to the disorder. It is
currently diagnosed using different sets of clinical criteria based
on expert opinion. There is considerable controversy about which
criteria are the most appropriate.
"We're starting to make headway on what causes PCOS. It's very
frustrating for patients because it's poorly understood and
patients often see several physicians before PCOS is diagnosed,"
said senior author Andrea Dunaif,
MD, Chief of the Hilda and J. Lester Gabrilove Division of
Endocrinology, Diabetes and Bone Disease at the Mount Sinai Health
System. "Through genetics, we're beginning to understand the
condition and may have specific targeted therapies in the
not-too-distant future."
Using clinical, biochemical, and genotype data from their
previously published PCOS genome-wide association study (GWAS), Dr.
Dunaif and her team identified the subtypes using cluster analysis,
a way of aggregating similar data in an unbiased manner.
Unsupervised cluster analysis, meaning there are no predetermined
models of data, was performed in the GWAS cohort of 893 PCOS cases.
The clusters were then replicated in an independent group of 263
PCOS cases.
The clustering revealed two distinct PCOS subtypes: a
"reproductive" group characterized by higher luteinizing hormone
(LH), a hormone that triggers ovulation and acts on the ovaries,
and higher levels of sex hormone binding globulin (SHBG), a protein
that regulates the ability of testosterone to enter its target
tissues, with relatively low body mass index (BMI) and insulin
levels; and a "metabolic" group characterized by higher BMI,
glucose, and insulin levels with lower SHBG and LH levels.
This current paper builds upon a study that Dr. Dunaif and her
team published in The Journal of Endocrinology and Metabolism in
April 2019 where they found, using
family-based genetic analysis, that rare genetic variants in a gene
involved in male hormone production, DENND1A, play major roles in
the development of PCOS. This genetic variation could serve as a
marker for early PCOS detection.
In the study published today, the researchers developed a
predictive model and classified the reproductive and metabolic
subtypes in a family-based cohort of 73 women with PCOS, including
their sisters. They found that the subtypes tended to cluster in
families. They also found that carriers of the previously reported
rare variants in DENND1A were more likely to have the reproductive
subtype of PCOS. The results suggest that these subtypes are
biologically relevant since they have distinct genetic
architectures. The findings will substantially assist in gene
discovery by allowing the selection of more homogeneous PCOS
subtypes, which could increase the likelihood of identifying
disease-associated genes.
"In contrast to classifying disorders based on expert opinion,
this is a very powerful objective approach to categorizing
syndromes like PCOS into distinct subtypes with different causes,
treatment and clinical outcomes," said Dr. Dunaif.
The study was supported by grants from the National Institutes
of Health.
SOURCE Mount Sinai Health System