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KLOTHO: Good news for 20% of us!

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
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Julie G
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KLOTHO: Good news for 20% of us!

Postby Julie G » Tue Apr 14, 2020 11:18 am

First, I know that members of our community have been taking part in a study with Dr. Michael Greicius at Stanford focused on identifying protective genetics. I suspect that some of you may be included in his recent paper below. Thank you for your participation! Apparently, two snips make up the “KL-VS” protective variant. They are rs9536314 and rs9527025. Being heterozygous for both appears to be protective. My version of 23andMe only reports on the first. It looks like I may have a part of the “golden ticket.” :? If anyone can offer elucidation on how these snips relate to one another and whether both are necessary for protection, I'd appreciate it.

Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4
https://jamanetwork.com/journals/jamane ... le=2763597 (Full-text is available on SciHub.)

Key Points
Question  Does Klotho-VS heterozygosity protect against Alzheimer disease (AD) in individuals who carry APOE4?
Findings  In this study, associations were evaluated across 22 AD cohorts (n = 20 928), 3 longitudinal cohorts (n = 3008), and 4 cohorts collecting β-amyloid measurements (cerebrospinal fluid, n = 556; brain, n = 251). In individuals who carry APOE4, Klotho-VS heterozygosity was associated with reduced AD risk and more favorable β-amyloid profiles in the brain and cerebrospinal fluid of older control participants. Klotho-VS heterozygosity was also associated with reduced AD conversion risk in individuals who carry APOE4.
Meaning  Pathways associated with KL merit exploration for novel AD drug targets, and the KL-VS genotype should be considered in conjunction with APOE genotype to refine prediction models used in clinical trial enrichment.
___
Abstract
Importance  Identification of genetic factors that interact with the apolipoprotein e4 (APOE4) allele to reduce risk for Alzheimer disease (AD) would accelerate the search for new AD drug targets. Klotho-VS heterozygosity (KL-VSHET+ status) protects against aging-associated phenotypes and cognitive decline, but whether it protects individuals who carry APOE4 from AD remains unclear.
Objectives  To determine if KL-VSHET+ status is associated with reduced AD risk and β-amyloid (Aβ) pathology in individuals who carry APOE4.
Design, Setting, and Participants  This study combined 25 independent case-control, family-based, and longitudinal AD cohorts that recruited referred and volunteer participants and made data available through public repositories. Analyses were stratified by APOE4 status. Three cohorts were used to evaluate conversion risk, 1 provided longitudinal measures of Aβ CSF and PET, and 3 provided cross-sectional measures of Aβ CSF. Genetic data were available from high-density single-nucleotide variant microarrays. All data were collected between September 2015 and September 2019 and analyzed between April 2019 and December 2019.
Main Outcomes and Measures  The risk of AD was evaluated through logistic regression analyses under a case-control design. The risk of conversion to mild cognitive impairment (MCI) or AD was evaluated through competing risks regression. Associations with Aβ, measured from cerebrospinal fluid (CSF) or brain positron emission tomography (PET), were evaluated using linear regression and mixed-effects modeling.
Results  Of 36 530 eligible participants, 13 782 were excluded for analysis exclusion criteria or refusal to participate. Participants were men and women aged 60 years and older who were non-Hispanic and of Northwestern European ancestry and had been diagnosed as being cognitively normal or having MCI or AD. The sample included 20 928 participants in case-control studies, 3008 in conversion studies, 556 in Aβ CSF regression analyses, and 251 in PET regression analyses. The genotype KL-VSHET+ was associated with reduced risk for AD in individuals carrying APOE4 who were 60 years or older (odds ratio, 0.75 [95% CI, 0.67-0.84]; P = 7.4 × 10−7), and this was more prominent at ages 60 to 80 years (odds ratio, 0.69 [95% CI, 0.61-0.79]; P = 3.6 × 10−8). Additionally, control participants carrying APOE4 with KL-VS heterozygosity were at reduced risk of converting to MCI or AD (hazard ratio, 0.64 [95% CI, 0.44-0.94]; P = .02). Finally, in control participants who carried APOE4 and were aged 60 to 80 years, KL-VS heterozygosity was associated with higher Aβ in CSF (β, 0.06 [95% CI, 0.01-0.10]; P = .03) and lower Aβ on PET scans (β, −0.04 [95% CI, −0.07 to −0.00]; P = .04).
Conclusions and Relevance  The genotype KL-VSHET+ is associated with reduced AD risk and Aβ burden in individuals who are aged 60 to 80 years, cognitively normal, and carrying APOE4. Molecular pathways associated with KL merit exploration for novel AD drug targets. The KL-VS genotype should be considered in conjunction with the APOE genotype to refine AD prediction models used in clinical trial enrichment and personalized genetic counseling.

You can read a press release here.

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Re: KLOTHO: Good news for 20% of us!

Postby Matisse » Thu Apr 16, 2020 12:30 am

Julie, I believe those two snps are in linkage disequilibrium.

https://www.ncbi.nlm.nih.gov/pmc/articl ... 0-7-51.pdf

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Re: KLOTHO: Good news for 20% of us!

Postby Julie G » Thu Apr 16, 2020 9:05 am

Julie, I believe those two snps are in linkage disequilibrium.

Thank you, my friend. :D Help this non-scientist understand what that means. From what I can glean— that the frequency of association of their different alleles is higher than what would be expected if the loci were independent and associated randomly. Does that mean if you have one, you most likely have the other? Thanks to Theresa, members of our Facebook page have been all over this and one member recently discovered that even though her 23andMe reported on neither snip, Promethease (now owned and operated by my heritage.com) reported on BOTH. So for the curious, $12 might get you answers.

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Re: KLOTHO: Good news for 20% of us!

Postby Matisse » Thu Apr 16, 2020 11:25 pm

Matisse wrote:Julie, I believe those two snps are in linkage disequilibrium.

https://www.ncbi.nlm.nih.gov/pmc/articl ... 0-7-51.pdf


Julie, the way I look at it, as an also-non-scientist, is that they travel together to a greater extent than chance. In this case they are in "perfect" linkage disequilibrium, according to the authors of the article. So if you're hetero on one, you are on the other.

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Re: KLOTHO: Good news for 20% of us!

Postby Julie G » Fri Apr 17, 2020 3:38 pm

Thank you, Matisse! I'll take it. It looks like I have the golden ticket. :D Anyone else?

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Re: KLOTHO: Good news for 20% of us!

Postby Plumster » Sun Apr 19, 2020 8:31 am

They did not appear in my 23andme, unfortunately.

Good for you, Julie!
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Re: KLOTHO: Good news for 20% of us!

Postby floramaria » Sun Apr 19, 2020 1:10 pm

Julie G wrote:It looks like I have the golden ticket. :D

Congratulations!
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Julie G
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Re: KLOTHO: Good news for 20% of us!

Postby Julie G » Mon Apr 20, 2020 7:00 am

They did not appear in my 23andme, unfortunately.

One of our Facebook members had the same experience, then ran her raw data through Promethease.com for $12 and was able to find the information. Just a thought for those who's snips aren't showing up on 23andMe.

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Re: KLOTHO: Good news for 20% of us!

Postby SusanJ » Mon Apr 20, 2020 9:12 am

So I went to Promethease and followed their link to Snpedia. Here's what they have to say about this combo:

rs9536314, also known as c.1062T>G, p.Phe352Val and F352V, represents a variant in the KL (Klotho) gene on chromosome 13. Together with rs9527025 (C370S), which it co-segregates with, a haplotype ("KL-VS") has been described that is reported to increase klotho secretion and may alter its functions; the alternative haplotype is named KL-FC (due to the F from F352V and C from C370S).

The klotho protein is a hormone found primarily in the kidney and choroid plexus of the brain. At the genetic level, the Klotho gene is reported to affect longevity in mice [PMID 9363890] and perhaps humans [PMID 11792841OA-icon.png], and KL-VS heterozygosity (but not homozygosity) has been associated with greater brain cortical volume [PMID 25815349OA-icon.png]. At the protein level, older adults with higher plasma klotho concentrations tend to show lower less decline with age on standardized cognitive tests [PMID 26297657OA-icon.png], adults with higher stress tend to have lower plasma klotho levels [PMID 26080320OA-icon.png], and transgenic mice bred to have excess human amyloid precursor protein (to simulate Alzheimer's disease) score better on some tests when their klotho levels are increased [PMID 25673831OA-icon.png].

Most of the studies cited above for studies of klotho in humans should be considered preliminary for at least two reasons: they are not based on large sample sizes, and, they haven't been replicated by independent investigators. In addition, there is a report showing no difference in the klotho plasma levels between FC/FC and FC/VS individuals [PMID 28076518OA-icon.png], as well as a report showing KL-VS heterozygotes had poorer cognitive function than noncarriers [PMID 26405063OA-icon.png], in contrast to the studies cited above.

https://www.snpedia.com/index.php/rs9536314

So who knows where this one is going...

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Re: KLOTHO: Good news for 20% of us!

Postby Plumster » Mon Apr 20, 2020 9:22 am

One of our Facebook members had the same experience, then ran her raw data through Promethease.com for $12 and was able to find the information. Just a thought for those who's snips aren't showing up on 23andMe.


Thanks, I just tried and nothing came up. My 23andme report is from 2017.
e3/4 MTHFR C677T/A1298C COMT V158M++ COMT H62H++ MTRR A66G ++ HLA DR


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