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The easiest breakthough possible: MBL deficiency and CFS

Sea

Senior Member
Messages
1,286
Location
NSW Australia
rs5030737 C or T Risk allele T (reported on the minus strand so an A on 23andme) 2.8%
rs1800450 A or G Risk allele A (reported on the minus strand so a T on 23andme) 5-23% depending on ethnicity

I have neither of these mutations so as reported by 23andme I am
rs5030737 GG
rs1800450 CC
 

Hip

Senior Member
Messages
17,824
Sea
Can I ask: how were you able to find out what the risk alleles were for these two SNPs?

I have always wanted to know how you determine the risk alleles for any given SNP.

(Also: did you by mistake put the risk alleles the wrong way around? Shouldn't it be: rs5030737 A or G, Risk allele A; and rs1800450 C or T, Risk allele T ? Or does this "minus strand" business reverse everything? I'd be most grateful if you could give some elucidation here, just so I can learn for future reference.)
 

Aileen

Senior Member
Messages
615
Location
Canada
My 23andMe results are as follows:
rs5030737 -- GG
rs1800450 -- CC

So, if I am understanding this correctly, that means I do NOT carry any risk for this? That would make sense since until I got this dd I rarely had any infections of any kind.
 

Sea

Senior Member
Messages
1,286
Location
NSW Australia
Sea
Can I ask: how were you able to find out what the risk alleles were for these two SNPs?

I have always wanted to know how you determine the risk alleles for any given SNP.

I am very new to all of this and still learning as well.

http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?rs=5030737
Look under the heading Gene view. The information in this section tells you this snp is a missense variation, the allele change is from C to T, which changes the protein made from R(Arginine) to C(Cysteine).

That only tells you the change not the risk though. To find the risk you have to look through some of the research to see which protein is associated with any problems if they don't indicate which allele. In this case the research points to Cysteine which is the T allele.

Sometimes a change can be better for one thing but worse for something else so you can't identify one or the other as the risk allele, only what is risk in the context of the illness or effect you're looking at. Also some changes are better and give a protective effect. This often leads to the unchanged allele being designated a risk when really it's normal.

(Also: did you by mistake put the risk alleles the wrong way around? Shouldn't it be: rs5030737 A or G, Risk allele A; and rs1800450 C or T, Risk allele T ? Or does this "minus strand" business reverse everything? I'd be most grateful if you could give some elucidation here, just so I can learn for future reference.)

Look at your rs5030737 snp on your browse raw data page at 23andme. My genotype in this list is GG. On the left of the snp is a small plus sign. When you click on this a drop down menu appears with reference links to dbSNP and other places. On the right hand side of this menu it has the information about orientation in dbSNP - in this case minus. It also has what your genotype is in this orientation which for me is CC.

23andme report on the positive strand for all snps. dbSNP and other places sometimes report on the positive sometimes on the negative strand. I don't know why that is. The good thing is that by knowing what is on one strand we can always know what is on the opposite strand because they always pair up in the same way. So if A is on one strand T will be on the other, if C is on one strand G will be on the other.

When we're discussing snps and sharing data we need to be clear if we're using our data as reported by 23andme or as in the research because it can very easily lead to lots of confusion.
 

Hip

Senior Member
Messages
17,824
Sea
Thanks for writing that explanation. It is very helpful.

I noticed just now that SNPedia do actually specify which alleles entail a risk for the disease in question: if you look on the Rs5030737 page for example, on the right hand side, about two-thirds down, in the ClinVar table, you see that they give the risk allleles and the normal alleles, in the following format:

Risk: rs5030737(T;T)
Normal:rs5030737(C;C)

But from what you said, the trick appears to be to know whether these risk and normal alleles are reported on the minus strand or the plus strand. Because if on the minus strand, you have to replace these given risk and normal alleles with their complementary base pairs (A always complements T, and C always complements G), because 23andme always use the convention of reporting on the plus strand.

What I am not fully clear on is how you can know whether the alleles on SNPedia are reported on the minus strand or the plus strand.

EDIT: in fact, I now notice that SNPedia provide the orientation (minus or plus) at the very top of the right hand column of the page. So in the case of Rs5030737 it is minus, so in this case we have to take the complementary base pairs.
 

Sea

Senior Member
Messages
1,286
Location
NSW Australia
Sea
Thanks for writing that explanation. It is very helpful.

I noticed just now that SNPedia do actually specify which alleles entail a risk for the disease in question: if you look on the Rs5030737 page for example, on the right hand side, about two-thirds down, in the ClinVar table, you see that they give the risk allleles and the normal alleles, in the following format:

Risk: rs5030737(T;T)
Normal:rs5030737(C;C)

But from what you said, the trick appears to be to know whether these risk and normal alleles are reported on the minus strand or the plus strand. Because if on the minus strand, you have to replace these given risk and normal alleles with their complementary base pairs (A always complements T, and C always complements G), because 23andme always use the convention of reporting on the plus strand.

What I am not fully clear on is how you can know whether the alleles on SNPedia are reported on the minus strand or the plus strand.

EDIT: in fact, I now notice that SNPedia provide the orientation (minus or plus) at the very top of the right hand column of the page. So in the case of Rs5030737 it is minus, so in this case we have to take the complementary base pairs.

Sometimes SNPedia tells you the risk alleles, often not. Sometimes it tells you orientation, often not. Sometimes when you most want to know, it's just not there! SNPedia is a work in progress I think.

23andme do always show our alleles on the plus strand but the info is also there at 23andme as to whether it is plus or minus at SNPedia in the little drop down menu on the left of your results
 

Hip

Senior Member
Messages
17,824
23andme do always show our alleles on the plus strand but the info is also there at 23andme as to whether it is plus or minus at SNPedia in the little drop down menu on the left of your results

This drop down menu on 23andme, which gives whether it is plus or minus strand on dbSNP: is it safe to assume that in that the convention used by dbSNP will be the same one as used by SNPedia?
 

Sea

Senior Member
Messages
1,286
Location
NSW Australia
This drop down menu on 23andme, which gives whether it is plus or minus strand on dbSNP: is it safe to assume that in that the convention used by dbSNP will be the same one as used by SNPedia?

Yes, in SNPedia FAQ they say they use the same orientation as dbSNP
 

Adster

Senior Member
Messages
600
Location
Australia
Can this deficiency explain the symptoms of CFS/ME?

I don't think anyone could answer that definitively yet. From what I've read, it seems that it could explain it for some people. It might also be just one of multiple problems that add up to the CFS/ME symptoms in some people.
 

Hip

Senior Member
Messages
17,824
NOTE: for anyone performing Google searches:

mannan-binding lectin is also called:
mannose-binding lectin
mannan-binding protein
mannose-binding protein

HERE is a Google query set up to include all four possibilities.


Note: when mannan-binding lectin attaches to the surface of a bacterium, virus, protozoan or fungus, this is the first step in activating the lectin pathway of the complement system (the complement system has three pathways: the classical pathway, the alternative pathway, and the lectin pathway).

So it is a good idea to Google search on the lectin pathway, as in MBL deficiency, the lectin pathway will be weak.
 

roller

wiggle jiggle
Messages
775
CONCLUSION:
Our data indicate high prevalence of MBL deficiency, no evidence of association between MBL deficiency and HIV-1 infection. However, lower plasma MBL levels were protective against both S. haematobium and S. mansoni infections and MBL2 promoter and variants LY and LL increased susceptibility to S. haematobium infection.
http://www.ncbi.nlm.nih.gov/pubmed/25830474

MBL(-) then bacterial load(+)
MBL(-) then Schistosomiasis(-)
MBL - HIV - no link

MBL2 promoter variants LY and LL then Schisto(++)
MBL2*LYPA then Malaria(--)
MBL2*LXPA then Malaria (++)
http://www.ncbi.nlm.nih.gov/pubmed/24126531

MBL (unclear whether ++ or --) may activate clostridium difficile (perhaps other clostr too?)
http://www.ncbi.nlm.nih.gov/pubmed/25170052

seems:
MBL(++) then schisto(++) ..may be valid for other blood born pathogens, too?
MBL(++) then EBV(++)
MBL (-- ?) may activate clostridium


It is an mannose Lectin binding protein.
so, if bound to lectin or mannose, its inactivated (or reduced)?

or are the conclusions wrong?
 
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wastwater

Senior Member
Messages
1,271
Location
uk
I possibly have some mannose deficiency via a different gene GMDS
Classed as a very common 5-30% primary immunodeficiency
surely just throwing some d-mannose at it doesn't fix it
 
Last edited:

pattismith

Senior Member
Messages
3,931
Inherited lack of functional MBL is conferred by LXPA/O (referred to also as LXA/O or XA/O) and O/O genotypes.

They correspond to six single nucleotide polymorphisms (SNPs) of the MBL2 gene.

Two of them are localized in the promoter region:
−550 G>C (rs11003125, commonly called H/L)
and −221 C>G (rs7096206, Y/X);
one to the 5′-untranslated region (+4 C>T, rs7095891, P>Q).

The coding region (exon 1) polymorphisms:
+223 C>T (Arg52Cys, rs5030737),
+230 G>A (Gly54Asp, rs1800450)
and +239 G>A (Gly57Glu, rs1800451)

are called
A>D,
A>B
and A>C, respectively

(D, B, and C variants are collectively designated O).

Promoter SNPs affect the gene expression level (and thus MBL concentration in serum),
while D/B/C alleles are related to markedly diminished ability to opsonize microbial cells and to activate complement.

Those structural mutations lead to impaired oligomerization of subunits and diminished complex formation with associated serine proteases.

Moreover, an increased sensitivity to endogenous metalloproteases is associated with shorter MBL half-life resulting in a lower serum level.

Frontiers | The Influence of the Lectin Pathway of Complement Activation on Infections of the Respiratory System | Immunology (frontiersin.org)


I browsed my 23andme, and found one of the two is homozygous for the pathogenic variant allele

rs5030737 A or G....... GG ....... (T or A is the risk allele)
rs1800450 C or T ....... TT ....... (T or A is the risk allele)

MBL deficiency is believed to be a risk for covid, but datas have shown that high MBL is a risk for covid thrombo-embolism.

Another 2020 paper also showed that
" Low Mannose Binding Lectin, but Not L-Ficolin, Is Associated With Spontaneous Clearance of Hepatitis C Virus After Infection"

One possible reason might be that during infection a strong and durable HCV-specific CD4+ and CD8+ T cell response is associated with a spontaneous clearance of the HCV infection (16).

It is known that MBL can bind to T cells surface, induce cell arrest in the G0/G1 phase of the cell cycle, and thus suppresses the T cell activation (17).

In fact, MBL2 deficiency high frequency is a proof that pathogenic variants were probably selected because they were giving some advantage to their carriers, in an environment with increasing population and circulating infections.

The fact that MBL can suppress T Lymphocytes activation means that low MBL goes with higher T lymphocyte activation.
This higher T cells activation may compensate some of the loss of innate immunity from low MBL, but it may trigger more auto-immune response....

@sometexan84
 
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Messages
15
My 23andme genotyping came back, and when I looked further into the raw data there was a strong link to MBL deficiency. But I haven't had any proper blood tests about it. It's fascinating that it's so common with CFS.
 

pattismith

Senior Member
Messages
3,931
My 23andme genotyping came back, and when I looked further into the raw data there was a strong link to MBL deficiency. But I haven't had any proper blood tests about it. It's fascinating that it's so common with CFS.

MBL deficiency is the immunodeficiency the most common, so I guess MBL levels can vary a lot within the low ranges.

The best way to assess the MBL deficiency is to ask for a blood MBL dosage test, I plan to ask for it