rs3758391
mixedMag 3.5This is a upstream gene variant variant in the SIRT1 gene.
Key Literature Trait Associations
Bisphosphonate-related osteonecrosis of the jaw
A pharmacogenomic exome-wide association study identified the SIRT1/HERC4 locus as significantly associated with bisphosphonate-induced osteonecrosis of the jaw (BRONJ) in multiple myeloma patients. rs3758391, a functional promoter SNP and SIRT1 eQTL, showed an odds ratio of 0.26 (95% CI: 0.12–0.55) in the replication cohort, suggesting the T allele confers strong protection against BRONJ. However, the study is limited by very small sample sizes (total n<110) and requires replication in larger cohorts before clinical use.
Longevity / Cognitive Aging
The rs3758391 variant lies ~2 kb upstream of SIRT1, encoding sirtuin-1 — a NAD+-dependent deacetylase central to stress responses, DNA repair, and caloric restriction pathways. SIRT1 extends lifespan in model organisms. In a study of 482 Han Chinese (246 aging, 236 younger controls), the C allele was more common in aging subjects (OR 1.45, p=0.026). However, a larger 2016 Chinese study (616 long-lived, 846 controls) found no significant association, and results remain inconsistent across populations.
Major depressive disorder
Multiple independent studies across different populations have linked the C allele of rs3758391 to increased risk or severity of major depressive disorder (MDD). A 2018 meta-analysis (PMID 29786760) specifically examined this SNP and MDD, reporting pooled evidence of association for the T vs. C allele. A Finnish population-based study (n=5,910) provided further support for the association between rs3758391 and depressive disorders. Mechanistically, the C allele is associated with reduced SIRT1 mRNA expression, which may impair neuroplasticity and stress-resilience pathways. Results remain heterogeneous and effect sizes are modest, consistent with polygenic architecture of MDD.
Type 2 diabetes mellitus
The relationship between rs3758391 and type 2 diabetes mellitus (T2DM) is inconsistent across populations. Some studies report a protective effect of the C allele (reduced T2DM risk), while others associate T allele with reduced risk, and population-specific studies in Saudi Arabian and Bangladeshi cohorts find no significant association. A 2024 study in Chinese T2DM patients (n=750) found rs3758391 significantly associated with depression comorbidity in T2DM, linked to reduced SIRT1 mRNA. Given conflicting results and small study sizes, no definitive risk direction can be assigned at this time.
▶Research that mentions this SNP (1)
▶SIRT1 Gene SNP rs932658 Is Associated With Medication-Related Osteonecrosis of the JawAssociationN=104Yang G. et al.(2020)· Journal of Bone and Mineral Research
This case-control study of 104 cancer patients (46 MRONJ cases, 58 controls) validated three SIRT1 promoter SNPs (rs3758391, rs932658, rs2394443) as functional variants associated with medication-related osteonecrosis of the jaw (MRONJ) risk in patients treated with bisphosphonates. The minor alleles of these SNPs were associated with lower odds for MRONJ (OR=0.351, p=0.007 for rs932658; OR=0.351, p=0.007 for rs3758391; OR=0.331, p=0.0036 for rs2394443). Luciferase reporter assays confirmed that rs932658 variant allele A increases SIRT1 promoter activity, suggesting the protective mechanism involves increased SIRT1 expression.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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