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A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.
This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.
The researchers have named this TNFSF13B variation “BAFF-var.”
Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world. 
They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).
The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).
Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).
BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.
Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.
“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.
Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.
“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.
“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.
The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
Perhaps the next challenge is the clinical application of the findings from Steri et al. is to determine whether BAFF-var status can be used to stratify patients for a specific therapy.
These data clearly point in that direction, but the discriminatory power of this single variant may not be sufficient for clinical decision making.
In contrast, it does seem reasonable to examine whether stratifying patients according to their BAFF-var status would be useful in clinical trials assessing B-cell–directed therapies.
Thomas Korn, MD, of the Technical University of Munich and the Munich Cluster for Systems Neurology, reported ties to Biogen, Novartis, Merck Serono, and Bayer. Mohamed Oukka, PhD, of the University of Washington, Seattle, and the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute, reported having no relevant disclosures. They made these remarks in an editorial accompanying Dr. Steri’s report (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMe1700720).
A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.
This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.
The researchers have named this TNFSF13B variation “BAFF-var.”
Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world.
They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).
The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).
Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).
BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.
Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.
“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.
Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.
“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.
“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.
The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus, according to a report published online April 26 in the New England Journal of Medicine.
This gene encodes the cytokine B-cell activating factor (BAFF), which is essential for B-cell activation, differentiation, and survival. BAFF is targeted by agents such as belimumab that are used in the treatment of autoimmune disorders, and is primarily produced by monocytes and neutrophils, said Maristella Steri, PhD, of Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche Monserrato (Italy), and her associates.
The researchers have named this TNFSF13B variation “BAFF-var.”
Previous genome-wide association studies have identified more than 110 independent signals for MS and 43 for SLE but have not yet delineated the effector mechanisms for most of these associations. To explore these mechanisms in greater detail, Dr. Steri and her associates studied the population in Sardinia, Italy, which has the highest prevalences of MS and SLE in the world.
They performed genome-wide association studies and other genetic investigations in case-control sets of 2,934 patients with MS, 411 with SLE, and 3,392 control subjects, analyzing roughly 12.2 million single-nucleotide polymorphisms (SNPs). They ruled out rs1287404 as a likely variant driving the association and identified BAFF-var as the variant most strongly associated with MS (odds ratio, 1.27).
The investigators then replicated their findings in a series of genetic studies in case-control sets from mainland Italy (2,292 patients with MS, 503 with SLE, and 2,563 controls), Sweden (4,548 patients with MS and 3,481 controls), the United Kingdom (3,176 patients with MS and 2,958 controls), and the Iberian peninsula (1,120 patients with SLE and 1,300 controls). BAFF-var was most common across Sardinia, with a frequency of 26.5%, and became progressively less common moving northward (5.7% in Italy, 4.9% in Spain, 1.8% in the United Kingdom and Sweden).
Taken together, “these findings pinpoint BAFF-var as the variant in TNFSF13B that is most strongly associated with MS,” wrote Dr. Steri and her associates (N Engl J Med. 2017 Apr 27. doi: 10.1056/NEJMoa1610528).
BAFF-var also proved to be associated with SLE in case-control sets from Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55). This indicates that “the effect of BAFF-var is not restricted to MS alone,” they noted.
Further analyses showed that BAFF-var “dramatically” increased levels of soluble BAFF and circulating B cells, especially CD24+CD27+ cells, as well as total IgG, IgA, IgM, and monocytes. In one notable analysis, preclinical blood samples taken from Sardinians participating in a longitudinal study showed elevated levels of soluble BAFF in people who did not go on to develop MS until years later.
“We infer [from this] that BAFF-var is the causal variant driving an increase in soluble BAFF and a cascade of immune effects leading to increased autoimmunity risk,” Dr. Steri and her associates said.
Further study suggested that positive selection specifically favoring BAFF-var, not random genetic drift, accounted for the high frequency of this mutation in Sardinia and its progressively lower frequency moving northward. The most likely possibility is that BAFF-var was positively selected because it provided resistance to malaria, which was “strikingly prevalent” in Sardinia until it was eradicated in the 1950s. In mouse models, BAFF overexpression confers protection against lethal malaria.
“In addition, as shown here, BAFF-var increases antibody production, and classic findings showed that antibody transfer from adults with immunity to malaria to acutely infected children reduced blood-stage parasitemia and disease severity,” the investigators said.
“The evolutionary scenario we propose is that BAFF-var was selected as an adaptive response to malaria infection, resulting in an increased present-day risk of autoimmunity,” they said.
The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.
Key clinical point: A variant in the TNFSF13B gene has been linked to susceptibility to both multiple sclerosis and systemic lupus erythematosus.
Major finding: BAFF-var was the TNFSF13B variant most strongly associated with MS in Sardinia (OR, 1.27), and was also associated with SLE in Sardinia (OR, 1.38), mainland Italy (OR, 1.49), and the Iberian peninsula (OR, 1.55).
Data source: A series of genome-wide association studies and other genetic studies involving thousands of patients with MS or SLE in Sardinia and confirmed in thousands of patients across Italy, Spain, Sweden, and the United Kingdom.
Disclosures: The Italian Foundation for Multiple Sclerosis, the National Institute on Aging, the Italian Ministry of Economy and Finance, the European Union, the National Human Genome Research Institute, and other organizations supported the study. Dr. Steri reported having no relevant disclosures; some of her associates reported ties to numerous industry sources.