• New gene identified that contributes to

    From ScienceDaily@1:317/3 to All on Tue Nov 16 21:30:40 2021
    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.


    ==========================================================================
    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.



    ==========================================================================
    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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