New gene identified that contributes to progression to typediabetes


Date:
November 16, 2021
Source:
Medical College of Georgia at Augusta University
Summary:
When the pro-inflammatory pair, a receptor called CCR2 and its
ligand CCL-2, get together, it increases the risk of developing
type 1 diabetes, scientists report.



FULL STORY ==========================================================================
When the pro-inflammatory pair, a receptor called CCR2 and its ligand
CCL-2, get together, it increases the risk of developing type 1 diabetes, scientists report.


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In this autoimmune disease that typically surfaces in childhood, the interaction of this natural lock and key recruits immune cells to the
pancreas, which attack the insulin-producing islet cells, resulting in a lifelong course of insulin therapy and a lifelong increased risk of other health problems like heart and kidney disease, says Dr. Sharad Purohit, biochemist in the Center for Biotechnology and Genomic Medicine at the
Medical College of Georgia.

The study, published in the Journal of Translational Autoimmunity,provides evidence the CCR2 gene promotes progression to type 1 as it provides
new insight on how to delay disease progression, says Paul Tran, MD/PhD
student at MCG at Augusta University. Tran and Purohit are the study's
first authors.

The scientists were able to put the pieces together by looking at the longitudinal data on 310 people enrolled in DAISY, a National Institutes
of Health-funded study based at the University of Colorado Anschutz
Medical Campus in Aurora, that has been following individuals considered
at risk for type 1 because of having a relative with it or having one
of the genes associated with it since 1993.

The new study focused on 42 individuals who persistently had antibodies
against the insulin-producing islet cells but never actually developed
type 1, 48 who did develop type 1 and the remainder who did neither and
served as the control group.

They found that blood levels of CCL-2, the ligand for CCR2, were lower
in both individuals who had antibodies but not actual disease as well
as those who progressed to type 1 diabetes, Tran says.



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They also found that both these groups have more of the receptors on
their immune cells, which get recruited by the ligand to the six-inch
organ in the abdomen that helps us break down the food we eat.

Conversely, less receptors mean less recruitment of immune cells, more
normal levels of CCL-2 in the blood and less cell destruction, they say.

Numerous human studies have indicated that blood levels of the ligand
CCL-2, or chemokine ligand 2, are associated with type 1 diabetes but
how was unclear, Tran says. The new study clarifies that direction.

It was also known that the locus, the physical location on a chromosome,
in this case the 3p21.31 locus, where CCR2 is located, was associated
with type 1 diabetes, although the specific genes within it had not been directly associated with the condition in humans, Purohit says.

They also found that two small genetic variants, or SNPs, in that locus
are what cause higher expression of CCR2 which causes the lower blood
levels of its ligand, Purohit says.



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More receptors means increased signaling between CCR2 and CCL-2, which
results in increased recruitment of immune cells, which are laden with
CCL-2 receptors, to the pancreas, although their work to date has not
clearly explained why, Tran says.

The increased signaling also depletes the CCL-2 supply, as immune cells
gobble it up along with the islet cells.

A bottom line is a seemingly contradictory scenario emerges of decreased
blood levels of a pro-inflammatory molecule in the face of an increased inflammatory state, they write. Purohit notes a similar scenario has been described in cardiovascular disease where lower levels of interleukin-6,
which is mostly associated with inflammation, are associated with a
worse prognosis.

CCR2 has not previously been directly associated with humans with type
1 diabetes, but it was known that when the gene is knocked out in mice
prone to developing type 1, they become less prone to disease development,
Tran says.

Generally speaking it's also known that individuals with higher
expression of the CCR2 gene are more likely to experience the likely
unwanted recruitment of immune cells into numerous areas of their body,
like what happens in conditions like rheumatoid arthritis and multiple sclerosis. There was also evidence that a protein associated with the
gene CCR2 was lower in patients with type 1 diabetes.

But correlation does not equal causation, Tran notes.

"There is some mouse evidence. There is some serum protein level
evidence. Now we are putting the genetic evidence in," Tran says.

Their findings support the potential of inhibiting the receptor, CCR2,
as a way to at least delay disease progression, they say. The failure of
CCR2 inhibition to delay disease progression in clinical trials in both rheumatoid arthritis and multiple sclerosis could be because therapy
was started too late, they say.

Better timing might been when blood levels of CCL-2 start going down
rather than when disease symptoms begin to surface, they write, and
trials to prevent type 1 diabetes should target patients with low blood
levels of CCL-2 who also are making antibodies to their islet cells.

The DAISY studyis led by Dr. Marian Rewers, pediatric endocrinologist
and a study coauthor. Statistician Fran Dong, also a study coauthor from
the Colorado group, worked with the other scientists to analyze data and
they were able to show that children who will develop type 1 diabetes
have a lower level of the ligand CCL-2 in their blood at birth and it
stays lower as they get older.

Everyone recruits CCL-2 at some level, as part of the body's natural
defense mechanism against something like a virus, but the problem is
when there is too much, Tran says. Levels of CCL-2, for example, do go
up when you have an infection of the pancreas.

Unlike type 2 diabetes, type 1 diabetes tends to surface in childhood or adolescence but with similar symptoms like increased thirst and urination, similar consequences like heart, blood vessel and kidney damage, and
all these patients will need insulin therapy. Type 1 is considered a
collision of the child having high-risk genes and environmental triggers,
and ongoing studies like those at MCG are working to uncover more of
those genes and triggers.

Scientists, including Purohit, reported in 2015 in theJournal of
Clinical Endocrinology & Metabolismthat patients with type 1 diabetes
have significantly lower blood levels of four proteins that help protect
tissue from attack by the immune system, including CCL-2, also called
MCP-1, while their healthy relatives, some of whom also had some of the high-risk genes for type 1, had normal levels.

Genome Wide Association Studies, or GWAS, which associate genetic
variations with particular diseases, have associated the 3p21.31 locus
with type 1 diabetes and other autoimmune disease in children, but exactly
what variants are responsible has been unknown, they write. The locus is
known to have a lot of chemokine receptors, which are largely associated
with promoting inflammation, like CCR2.

The research was supported by the National Institutes of Health and the Juvenile Diabetes Research Foundation.

Dr. Jin-Xiong She, former director of the MCG Center for Biotechnology
and Genomic Medicine and founder and CEO of Jinfiniti Precision Medicine,
is the study's corresponding author.

========================================================================== Story Source: Materials provided by Medical_College_of_Georgia_at_Augusta_University.

Original written by Toni Baker. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Paul MH. Tran, Sharad Purohit, Eileen Kim, Khaled bin Satter, Diane
Hopkins, Kathleen Waugh, Fran Dong, Suna Onengut-Gumuscu, Stephen S.

Rich, Marian Rewers, Jin-Xiong She. The 3p21.31 genetic locus
promotes progression to type 1 diabetes through the CCR2/CCL2
pathway. Journal of Translational Autoimmunity, 2021; 4: 100127 DOI:
10.1016/ j.jtauto.2021.100127 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211116102954.htm

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