rs11189867 (HPSE2): HIV Neuropathy & Brain Expression
Key takeaways
- This variant is located in HPSE2 (heparanase 2), a gene expressed in the nervous system
- A genome-wide study of 254 HIV patients found no single genetic variant significantly drives stavudine/didanosine-related nerve damage
- GTEx data from 953 donors shows the ALT allele raises HPSE2 expression in the brain's hippocampus
- The same allele lowers expression of the nearby CNNM1 gene in visceral body fat
- Clinical meaning of these expression differences has not been established
Key takeaways
- This variant is located in HPSE2 (heparanase 2), a gene expressed in the nervous system
- A genome-wide study of 254 HIV patients found no single genetic variant - across roughly 936,000 loci - significantly drives nerve damage caused by the antiretroviral drugs stavudine and didanosine
- GTEx data from 953 donors shows the ALT allele raises HPSE2 expression in the brain's hippocampus
- The same allele lowers expression of the nearby CNNM1 gene in visceral body fat
- Clinical meaning of these expression differences has not been established
What the research says A genome-wide association study (GWAS) - a method that screens hundreds of thousands of inherited DNA variants simultaneously to find statistical links to a trait - analyzed approximately 936,149 nuclear polymorphisms in 254 HIV-infected patients receiving stavudine (d4T) and didanosine (ddI), two antiretroviral drugs known to cause peripheral neuropathy (nerve damage causing tingling, numbness, or pain) by inhibiting mitochondrial DNA polymerase gamma; no variant reached the genome-wide significance threshold (P < 5.0 × 10^-8) in the full cohort or in any ancestry-stratified subgroup, and the study concluded that susceptibility to this drug-induced neuropathy is not explained by any single variant with a marked effect. Independently, GTEx v11 expression-QTL (eQTL) data - which measures whether a variant statistically predicts higher or lower expression of a nearby gene - from 953 donors identifies the rs11189867 ALT allele as associated with increased HPSE2 expression in hippocampal brain tissue and decreased CNNM1 expression in visceral adipose (body fat surrounding internal organs) tissue GTEx Portal.
Reported associations
- Peripheral neuropathy with stavudine/didanosine (HIV treatment): No genome-wide significant association detected in a GWAS of 254 patients (90 cases, 164 controls); the authors concluded that susceptibility to d4T/ddI-associated neuropathy is not explained by a single variant with a marked effect
- HPSE2 expression - brain hippocampus (eQTL): The ALT allele is linked to increased expression of this gene in hippocampal tissue (slope +0.56, p = 2.9 × 10^-8) GTEx Portal
- CNNM1 expression - visceral adipose tissue (eQTL): The ALT allele is linked to decreased CNNM1 expression in omental fat tissue (slope −0.23, p = 2.5 × 10^-5) GTEx Portal
Evidence quality The peripheral neuropathy GWAS was modest in scale - 254 participants enrolled in a 1998-1999 US multicenter trial, comprising 90 cases and 164 controls across White (49%), Black (34%), and Hispanic (17%) ancestry groups. No variant cleared the genome-wide significance threshold in the overall cohort or in any of the three race/ethnicity strata, making this a broadly null result; no specific association can be attributed to rs11189867 on the basis of this study. The GTEx eQTL results are better powered (953 donors, FDR < 0.05): the hippocampal HPSE2 signal reaches genome-wide-level p-values (p = 2.9 × 10^-8), while the visceral adipose CNNM1 signal is significant but more modest (p = 2.5 × 10^-5); however, eQTL evidence describes gene-expression regulation, not clinical outcomes, and the physiological significance of altered expression in these tissues is not addressed by the available data GTEx Portal.
Tissue-specific expression effects
- HPSE2: The ALT allele is associated with increased expression in brain hippocampus tissue GTEx Portal
- CNNM1: The ALT allele is associated with reduced expression in visceral adipose (omentum) tissue GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is the HPSE2 gene?
HPSE2 encodes heparanase 2. GTEx expression data from 953 donors shows that the rs11189867 variant influences how strongly this gene is expressed in the brain's hippocampus, with the ALT allele associated with higher expression at genome-wide significance levels.
Is rs11189867 linked to peripheral neuropathy?
A GWAS of 254 HIV-infected patients taking stavudine (d4T) and didanosine (ddI) found no genome-wide significant association between any of roughly 936,000 genetic variants and peripheral neuropathy. The study concluded that neuropathy susceptibility from these drugs is not explained by any single variant with a marked effect.
Does rs11189867 affect gene expression in the brain?
Yes, according to GTEx v11 data from 953 donors. The ALT allele is associated with increased HPSE2 expression in hippocampal tissue (p = 2.9 × 10^-8). This is an expression-level observation and has not been linked to a specific disease outcome.
What drugs were studied in relation to this variant?
The GWAS studied stavudine (d4T) and didanosine (ddI), antiretroviral drugs used in HIV treatment that can cause peripheral neuropathy by inhibiting mitochondrial DNA polymerase gamma. No specific variant in or near HPSE2 was identified as a significant risk factor.
How strong is the evidence for rs11189867?
Evidence for clinical outcomes is limited: the neuropathy GWAS was small (n=254) and produced a null result across all ancestry groups. The GTEx eQTL finding for hippocampal HPSE2 expression is statistically well-powered (n=953, p=2.9×10^-8), but describes gene-expression regulation rather than disease risk.