ESR1 Gene Variations More Common in Women With NMOSD: Study

Differences in estrogen receptor gene may increase risk of NMOSD, MS

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A scientist looks into a microscope in a laboratory, alongside a rack of vials and a flask.

Certain variations in the ESR1 gene — a protein-coding gene for estrogen receptor-alpha — are significantly more common among women with neuromyelitis optica spectrum disorder (NMOSD) or multiple sclerosis (MS) than among healthy women, a small study suggests.

Such differences were not observed between men with these neurodegenerative diseases and those without.

These preliminary findings point to ESR1 gene variations as potential genetic risk factors for these disorders. This information, combined with an observed link between such variations and disease duration, may help guide diagnosis and outcomes in NMOSD or MS, according to researchers.

“Further efforts should be made to conduct large sample size and multicenter studies, especially considering the effects of different ethnic genetic backgrounds,” the team wrote.

The study, “Correlation between ERα gene polymorphism and multiple sclerosis and neuromyelitis optica,” was published in the journal Medicine.

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Investigating the ESR1 gene in NMOSD

NMOSD was once considered a subtype of MS because both conditions are marked by abnormal immune attacks against myelin, the protective sheath around nerve fibers.

Since then, NMOSD has emerged as a separate condition impacting mainly the optic nerve and spinal cord. MS, in turn, affects multiple areas of the brain as well as the spinal cord and optic nerve.

Both conditions are more common among women than men, and many women may develop either disease during their childbearing years.

Prior research has suggested an association between the levels of estrogen, a key hormone for women’s reproductive development, and MS. Also, women with MS show reduced disease activity during pregnancy.

Clinical trial data showed that estriol — a type of estrogen produced during pregnancy — further reduced relapse rate, lessened fatigue, and slowed brain shrinkage in women with MS when used as an add-on therapy.

Preclinical studies in an MS mouse model also suggested that estrogen-based treatment protects against optic nerve myelin damage.

Estrogens exert their effects via the estrogen receptors (ERs), which are divided into ER-alpha and ER-beta. As such, variations in the genes encoding for these ERs may contribute to differences in estrogen’s biological effects — and ultimately in the development, progression, and treatment response of MS and NMOSD.

Now, a team of researchers in China analyzed variants in ESR1, the gene that provides instructions to produce ER-alpha, in NMOSD and MS patients and healthy individuals, who served as controls. Specifically, their study involved 46 NMOSD and MS patients — 41 females and five males — and 58 age- and sex-matched healthy people.

The patient group included 31 people with NMOSD and 15 with MS. Their mean age was 43.63 (range, 17– 67 years). They had lived with the disease for an average of 2.61 years (range, five days to 12 years).

The researchers focused on polymorphisms, or the presence of two or more variant forms of a specific DNA sequence in a population. In this case, they analyzed polymorphisms that result from the presence or absence of two known variations in the initial portion of the ESR1 gene.

ESR1 polymorphisms were analyzed with restriction fragment length polymorphism, a simple technique that uses so-called restriction enzymes that target specific DNA sequences.

Variants in a gene can change the position at which the enzyme cuts the DNA, resulting in different patterns of DNA fragments. Such genetic differences between people show up as changes in fragment length and number, demonstrating a polymorphism.

DNA cutting of that ESR1 region with the restriction enzyme Pvu II revealed two patterns (P or p), reflecting the absence or presence of one of the two common variations.  Two other patterns were obtained with the Xba I enzyme (X or x), representing the absence or presence of the other variation.

Overall, Pvu II cutting of both copies of the ESR1 gene revealed three genetically distinct forms, or genotypes: PP, pp, and Pp. Xba I cutting also revealed three genotypes, specifically XX, xx, and Xx.

There was no significant difference in the frequency of Pvu II-detected genotypes between patient and control groups. However, significant differences were observed for men. The Pp genotype was predominantly found in those in the patient group, while the PP genotype occurred more frequently in healthy men.

The frequency of Xba I-detected genotypes differed significantly between people with NMOSD/MS and those without the disorder, with the Xx genotype being 4.6 times more common among patients than controls.

Notably, this group difference was specific to women, as no significant frequency differences were observed in men.

The “Xx genotype was more frequent in women in the MS and NMO case group, while Xx and xx genotype were more common in women in the healthy control group,” the researchers wrote.

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Differences found for women versus men

The team then examined potential links between these genotypes and age of onset of the neurodegenerative diseases, as well as disease duration.

No significant association was detected between ESR1 genotypes, detected either by Pvu II or Xba I, and age of disease onset in the group of NMOSD and MS patients.

In contrast, there was a statistically significant difference in disease duration between genotypes XX and Xx. Patients carrying the Xx genotype had been living with the disease for longer than those with the XX genotype.

Additional analyses showed that patients with the Xx genotype were 7.5 times more likely to be women than those with the xx genotype.

There were no significant differences detected in terms of genotypes frequencies between NMOSD patients and those with MS, which “may be linked to the small sample size of the study,” the team wrote.

These findings indicate that Xba I-detected ESR1 polymorphism “could be a risk factor” of MS and NMOSD, especially the Xx genotype in women, the researchers wrote.

They also “may have clinical guiding significance” in the diagnosis and prediction of disease course of these conditions, the team added.

“It is hoped that the correlation between ER polymorphism and MS and [NMOSD] can be further clarified in the near future,” the researchers concluded.