Researchers Identify Strong Genetic Risk Factor for MS

Researchers have identified a genetic variation that significantly increases women’s risk of developing multiple sclerosis (MS). The variant, a single nucleotide polymorphism (SNP) in the gene serine-threonine-kinase 11 (STK11), occurs approximately 1.7 times more often in women with MS than in women without the disease, according to a study published February 18 in ASN Neuro.

Researchers zeroed in on the STK11 SNP after a woman told study coordinator and lead author Anne I. Boullerne, PhD, Research Assistant Professor of Anesthesiology at the University of Illinois at Chicago, that she and her four siblings all had MS or clinically isolated syndrome. The five siblings—four sisters, including twins, and a brother—were between ages 23 and 26.

The woman, who was participating in another medical study at the university, also described a prevalence of diseases associated with Peutz–Jeghers syndrome, a rare genetic disease caused by mutations in the STK11 gene, on her mother’s side of the family. The syndrome is characterized by an increased risk for certain cancers, including breast, ovary, and colon cancers.

Gene Tied to Loss of Myelin in Mice
A literature search by senior author Douglas L. Feinstein, PhD, Professor of Anesthesiology at the University of Illinois at Chicago and Research Biologist at the Jesse Brown VA Medical Center, uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the CNS, a defining characteristic of MS.

The woman consented to a complete DNA sequencing of her genome, and Dr. Boullerne examined the STK11 gene, where she discovered the SNP. Dr. Boullerne then obtained consent to sequence the genomes of two of the woman’s sisters and found that they carried the same SNP. Researchers do not know whether the other two siblings have the same variation.

The authors then screened DNA samples from approximately 1,400 people, including 754 people with MS. They found that the SNP was 1.66 times as prevalent in women with MS as in women without the disease. That makes the variant “one of the strongest genetic risk factors for MS discovered to date,” Dr. Feinstein said.

Researchers compared DNA samples from 654 patients with relapsing-remitting MS (RRMS), 100 patients with primary progressive MS (PPMS), and 661 controls.

While the STK11 SNP is present in about 7% of the general population, the variant was present in approximately 11% of the women with MS. In men, the risk of RRMS was only modestly increased by the STK11 SNP, and none of the male patients with PPMS had the variant.

Variant Associated With Reduced Disease Severity
The STK11 SNP was not associated with disease duration or onset. However, it was significantly associated with reduced disease severity, with the lowest MS severity scores in patients who also harbored the HLA-DRB1*1501 allele, the strongest known genetic risk factor for MS.

The researchers plan to continue looking for other genetic risk factors for MS among the five siblings and possibly their parents. Dr. Boullerne found no published studies that identified five siblings with MS. Identifying the five siblings with MS and suspected MS is an opportunity to pinpoint genes related to the disease, she said.

“I was immediately interested in the possibility of a genetic study of the family because all five siblings—an entire generation—are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease,” Dr. Boullerne said.

Researchers also will investigate the function of the STK11 gene in the laboratory, which could reveal molecular pathways involved in MS. Their findings raise the possibility that cells harboring the STK11 SNP could be targeted by drugs that increase metabolic stress.

Rarity of Cases Has Limited Analyses
Genetic factors are known to influence the risk of developing MS, but the rarity of multigenerational cases of MS, or families with four or more affected members, has limited further analyses, said the authors.

Several studies have identified the HLA-DRB1*1501 allele as a variant associated with increased risk, with an odds ratio of approximately 3 across various ethnic groups.

The STK11 SNP had odds ratios for females of 1.63 in RRMS, 1.88 in PPMS, and 1.66 for both MS forms.

The different ratios for women with RRMS and PPMS could result from the different group sizes used in the study (ie, 56 female patients with PPMS, compared with 396 female patients with RRMS) or because of differences in the development and evolution of PPMS and RRMS, said the authors.

—Jake Remaly

Researchers have identified a genetic variation that significantly increases women’s risk of developing multiple sclerosis (MS). The variant, a single nucleotide polymorphism (SNP) in the gene serine-threonine-kinase 11 (STK11), occurs approximately 1.7 times more often in women with MS than in women without the disease, according to a study published February 18 in ASN Neuro.

Researchers zeroed in on the STK11 SNP after a woman told study coordinator and lead author Anne I. Boullerne, PhD, Research Assistant Professor of Anesthesiology at the University of Illinois at Chicago, that she and her four siblings all had MS or clinically isolated syndrome. The five siblings—four sisters, including twins, and a brother—were between ages 23 and 26.

The woman, who was participating in another medical study at the university, also described a prevalence of diseases associated with Peutz–Jeghers syndrome, a rare genetic disease caused by mutations in the STK11 gene, on her mother’s side of the family. The syndrome is characterized by an increased risk for certain cancers, including breast, ovary, and colon cancers.

Gene Tied to Loss of Myelin in Mice
A literature search by senior author Douglas L. Feinstein, PhD, Professor of Anesthesiology at the University of Illinois at Chicago and Research Biologist at the Jesse Brown VA Medical Center, uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the CNS, a defining characteristic of MS.

The woman consented to a complete DNA sequencing of her genome, and Dr. Boullerne examined the STK11 gene, where she discovered the SNP. Dr. Boullerne then obtained consent to sequence the genomes of two of the woman’s sisters and found that they carried the same SNP. Researchers do not know whether the other two siblings have the same variation.

The authors then screened DNA samples from approximately 1,400 people, including 754 people with MS. They found that the SNP was 1.66 times as prevalent in women with MS as in women without the disease. That makes the variant “one of the strongest genetic risk factors for MS discovered to date,” Dr. Feinstein said.

Researchers compared DNA samples from 654 patients with relapsing-remitting MS (RRMS), 100 patients with primary progressive MS (PPMS), and 661 controls.

While the STK11 SNP is present in about 7% of the general population, the variant was present in approximately 11% of the women with MS. In men, the risk of RRMS was only modestly increased by the STK11 SNP, and none of the male patients with PPMS had the variant.

Variant Associated With Reduced Disease Severity
The STK11 SNP was not associated with disease duration or onset. However, it was significantly associated with reduced disease severity, with the lowest MS severity scores in patients who also harbored the HLA-DRB1*1501 allele, the strongest known genetic risk factor for MS.

The researchers plan to continue looking for other genetic risk factors for MS among the five siblings and possibly their parents. Dr. Boullerne found no published studies that identified five siblings with MS. Identifying the five siblings with MS and suspected MS is an opportunity to pinpoint genes related to the disease, she said.

“I was immediately interested in the possibility of a genetic study of the family because all five siblings—an entire generation—are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease,” Dr. Boullerne said.

Researchers also will investigate the function of the STK11 gene in the laboratory, which could reveal molecular pathways involved in MS. Their findings raise the possibility that cells harboring the STK11 SNP could be targeted by drugs that increase metabolic stress.

Rarity of Cases Has Limited Analyses
Genetic factors are known to influence the risk of developing MS, but the rarity of multigenerational cases of MS, or families with four or more affected members, has limited further analyses, said the authors.

Several studies have identified the HLA-DRB1*1501 allele as a variant associated with increased risk, with an odds ratio of approximately 3 across various ethnic groups.

The STK11 SNP had odds ratios for females of 1.63 in RRMS, 1.88 in PPMS, and 1.66 for both MS forms.

The different ratios for women with RRMS and PPMS could result from the different group sizes used in the study (ie, 56 female patients with PPMS, compared with 396 female patients with RRMS) or because of differences in the development and evolution of PPMS and RRMS, said the authors.

—Jake Remaly

Researchers have identified a genetic variation that significantly increases women’s risk of developing multiple sclerosis (MS). The variant, a single nucleotide polymorphism (SNP) in the gene serine-threonine-kinase 11 (STK11), occurs approximately 1.7 times more often in women with MS than in women without the disease, according to a study published February 18 in ASN Neuro.

Researchers zeroed in on the STK11 SNP after a woman told study coordinator and lead author Anne I. Boullerne, PhD, Research Assistant Professor of Anesthesiology at the University of Illinois at Chicago, that she and her four siblings all had MS or clinically isolated syndrome. The five siblings—four sisters, including twins, and a brother—were between ages 23 and 26.

The woman, who was participating in another medical study at the university, also described a prevalence of diseases associated with Peutz–Jeghers syndrome, a rare genetic disease caused by mutations in the STK11 gene, on her mother’s side of the family. The syndrome is characterized by an increased risk for certain cancers, including breast, ovary, and colon cancers.

Gene Tied to Loss of Myelin in Mice
A literature search by senior author Douglas L. Feinstein, PhD, Professor of Anesthesiology at the University of Illinois at Chicago and Research Biologist at the Jesse Brown VA Medical Center, uncovered an article that described how mice with a disabled STK11 gene had a higher incidence of loss of myelin from the nerves of the CNS, a defining characteristic of MS.

The woman consented to a complete DNA sequencing of her genome, and Dr. Boullerne examined the STK11 gene, where she discovered the SNP. Dr. Boullerne then obtained consent to sequence the genomes of two of the woman’s sisters and found that they carried the same SNP. Researchers do not know whether the other two siblings have the same variation.

The authors then screened DNA samples from approximately 1,400 people, including 754 people with MS. They found that the SNP was 1.66 times as prevalent in women with MS as in women without the disease. That makes the variant “one of the strongest genetic risk factors for MS discovered to date,” Dr. Feinstein said.

Researchers compared DNA samples from 654 patients with relapsing-remitting MS (RRMS), 100 patients with primary progressive MS (PPMS), and 661 controls.

While the STK11 SNP is present in about 7% of the general population, the variant was present in approximately 11% of the women with MS. In men, the risk of RRMS was only modestly increased by the STK11 SNP, and none of the male patients with PPMS had the variant.

Variant Associated With Reduced Disease Severity
The STK11 SNP was not associated with disease duration or onset. However, it was significantly associated with reduced disease severity, with the lowest MS severity scores in patients who also harbored the HLA-DRB1*1501 allele, the strongest known genetic risk factor for MS.

The researchers plan to continue looking for other genetic risk factors for MS among the five siblings and possibly their parents. Dr. Boullerne found no published studies that identified five siblings with MS. Identifying the five siblings with MS and suspected MS is an opportunity to pinpoint genes related to the disease, she said.

“I was immediately interested in the possibility of a genetic study of the family because all five siblings—an entire generation—are affected by MS, and so we could have a very good chance of discovering key genes related to inheritance of the disease,” Dr. Boullerne said.

Researchers also will investigate the function of the STK11 gene in the laboratory, which could reveal molecular pathways involved in MS. Their findings raise the possibility that cells harboring the STK11 SNP could be targeted by drugs that increase metabolic stress.

Rarity of Cases Has Limited Analyses
Genetic factors are known to influence the risk of developing MS, but the rarity of multigenerational cases of MS, or families with four or more affected members, has limited further analyses, said the authors.

Several studies have identified the HLA-DRB1*1501 allele as a variant associated with increased risk, with an odds ratio of approximately 3 across various ethnic groups.

The STK11 SNP had odds ratios for females of 1.63 in RRMS, 1.88 in PPMS, and 1.66 for both MS forms.

The different ratios for women with RRMS and PPMS could result from the different group sizes used in the study (ie, 56 female patients with PPMS, compared with 396 female patients with RRMS) or because of differences in the development and evolution of PPMS and RRMS, said the authors.

—Jake Remaly