Increased Serum Calcium Levels reduce AD? I could do that!

[J11]

"IVW analysis showed that a genetically increased serum calcium level (per 1 standard deviation (SD) increase 0.5-mg/dL) was significantly associated with a reduced AD risk (OR=0.56, 95% CI: 0.34-0.94, P=5.00E-03). "
Seems like a fairly large effect.

https://www.biorxiv.org/content/early/2018/01/27/255059

[Julie G]

Interesting, J11. I think this is the opposite of Dr. Bredesen's conclusion...

[J11]

JulieG, genetics might finally let us answer some of these tricky questions.
We have never been sure what caused what, is something correlated or causal? It all gets hopelessly confusing.
Yet, with Mendelian Randomization you have a fairly solid technique that can start to unravel things.

If all we need to do is increase serum calcium... well, that should be easy!
The OR reported above is LARGE or I guess you could say small OR=0.56.

[Stavia]

It's impossible to increase serum calcium by increasing its intake. It's extremely tightly regulated in a narrow range. For obvious reasons it needs to be, as the calcium gradient across the cell membrane is critical to many processes.

Calcium supplements may increase cardiovascular risk especially in post menopausal women. But they don't increase serum calcium.

Sent from my SM-G930F using Tapatalk

[J11]

Stavia, thank you your medical insight. I am not sure though why the authors talk of pursuing this with further research using supplements even when they note the homeostasis aspect of calcium regulation.

Those on the forum might be interested in looking up the below calcium SNPs to help determine their genetic calcium serum levels.


"a genetically increased serum calcium level (per 1 standard deviation (SD)
increase 0.5-mg/dL) was significantly associated with a reduced AD risk (OR=0.56, 95% CI: 0.34-0.94,
P=5.00E-03). Meanwhile, both the weighted median estimate (OR=0.60, 95% CI: 0.34-1.06, P=0.08) and MR-Egger estimate (OR=0.66, 95% CI: 0.26-1.67, P=0.381) were consistent with the IVW estimate in terms of direction and magnitude. ...

and further clarify whether diet calcium intake or calcium supplement, or both could
reduce the risk of AD."

Table 1 below is from the url I posted at the top of this thread. The table might be more easily visualized as it is presented in the article. I found it of note that the below SNPs in IGAP had fairly large p-values last column for each of the below SNPs
(e.g. first SNP p-value = 0.1132, the third one was 0.8673!.) Yet, apparently when these SNPs were put into a polygenic score, there was a large reduction in AD risk with increased serum calcium levels:

{ increased serum calcium level (per 1 standard deviation (SD) increase 0.5-mg/dL) was significantly associated with a reduced AD risk (OR=0.56, 95% CI: 0.34-0.94,
P=5.00E-03).}

What I take from this is that there is probably a substantial amount of genetic risk for AD lurking still lurking out there in the genome.
It would be very cool if researchers could run through all the KEGG pathways with existing genome datasets (similar to the research in this study), construct polygenic scores for these pathways and then apply this research to AD genetics.


Table 1, Characteristics of 8 genetic variants in serum calcium and AD GWAS datasets
SNP Chromosome Nearby Genes EAa NEA EAFb Stage Serum calcium GWAS AD GWAS Beta (mg/dL)c SEc P valuec Betad SEd Pvalued

x rs780094 2 GCKR T C 0.42 Discovery+replication 0.017 0.003 1.30E-10 -0.0358 0.0226 0.1132

rs1550532 2 DGKD C G 0.31 Discovery+replication 0.018 0.003 8.20E-11 -0.0206 0.0167 0.2179

rs1801725 3 CASR T G 0.15 Discovery+replication 0.071 0.004 8.90E-86 -0.0027 0.0161 0.8673

rs10491003 10 GATA3 T C 0.09 Discovery+replication 0.027 0.005 4.80E-09 -0.0158 0.0276 0.5673

rs7336933 13 DGKH/KIAA0564 G A 0.85 Discovery+replication 0.022 0.004 9.10E-10 -0.0048 0.0221 0.8273

rs1570669 20 CYP24A1 G A 0.34 Discovery+replication 0.018 0.003 9.10E-12 -0.0059 0.017 0.7269

x rs7481584 11 CARS G A 0.7 Discovery+replication 0.018 0.003 1.20E-10 0.0267 0.017 0.1153

rs17711722* 7 VKORC1L1 T C 0.47 Discovery 0.021 0.003 2.80E-11 -0.0275 0.0231 0.2342

Abbreviations: SNP, single-nucleotide polymorphism; EA, Effect Allele; NEA, Non-Effect Allele; EAF, Effect Allele Frequency; AD, Alzheimer’s disease; GWAS,genome-wide association studies; SE, standard error.

a Serum calcium raising allele (effect allele).
b Frequency of the serum calcium raising allele in the serum calcium GWAS dataset including up to 61079 individuals of European
ancestry 15.
c Summary statistics (beta coefficient, standard error and
P value) were obtained from a serum calcium GWAS dataset including up to 61079 individuals of European
ancestry 15. Beta (mg/dL) is the regression coefficient based on the serum calcium raising allele (effect allele). Beta > 0 and Beta < 0 means that this effect allele regulates
increased and reduced serum calcium levels, respectively.
d Summary statistics (beta coefficient, standard error and
P value) were obtained from International Genomics of Alzheimer’s Project including 17,008 cases and 37,154
controls of European descent 16. Beta is the regression coefficient based on the serum calcium raising allele (effect allele). Beta > 0 and Beta < 0 means that this effect allele
regulates increased and reduced AD risk, respectively. Beta is the overall estimated effect size for the effect allele, beta=ln
(odd ratio);
* rs17711722 is not available in AD GWAS dataset. We selected rs1829942, which showed high LD with rs17711722 (r²=0.91 and D’=0
.96) using the HaploReg v4.1 based on LD information in 1000 Genomes Project (CEU) 23.


"our pleiotropy analysis showed that rs780094 and rs7481584 may have potential violation of assumption 2 and 3 through pleiotropy. To meet the Mendelian randomization assumptions (Figure 1), we excluded both variants in following analysis. "

[J11]

I looked up the 8 SNPs above on a 23andme v3 chip.

rs7481584 was not on the chip though rs3814964 was and is a perfect proxy.
rs17711722 was also not on the chip and there was no proxy for it.