rs1136410 — PARP1 Val762Ala

Missense variant in the PARP1 catalytic domain that reduces enzymatic activity by ~40%, impairing DNA single-strand break repair and altering NAD+ consumption dynamics

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PARP1 Val762Ala — When Your DNA Repair Engine Runs at Half Power

Every day your cells accumulate thousands of DNA single-strand breaks from oxidative stress, replication errors, and environmental exposures. PARP1 (Poly ADP-Ribose Polymerase 1) is the enzyme that detects these breaks and coordinates their repair — and it consumes NAD+ as fuel for every repair event it performs. The Val762Ala variant at rs1136410 reduces PARP1 enzymatic activity by roughly 40%, placing it directly at the intersection of two fundamental aging processes: DNA damage accumulation11 DNA damage accumulation
unrepaired breaks that accumulate with age and NAD+ depletion22 NAD+ depletion
NAD+ levels fall 40–60% between age 20 and 60 in humans.

The Mechanism

PARP1 sits in the sixth helix of its catalytic domain, where valine at position 762 forms part of the NAD+-binding pocket. The Val→Ala substitution introduces a smaller side chain that increases the Michaelis constant (Km)33 Michaelis constant (Km)
a measure of substrate affinity — higher Km means lower affinity for NAD+ for NAD+ binding. As a result, Ala762-PARP1 requires higher NAD+ concentrations to achieve the same catalytic output.

The in vitro characterization is precise: Wang et al. 200744 Wang et al. 2007 expressed both Val762 and Ala762 PARP1 recombinantly and measured activity directly. The Ala762 protein retains only 57.2% of the auto-poly(ADP-ribosyl)ation activity and 61.9% of the trans-poly(ADP-ribosyl)ation activity (on histone H1) of the Val762 protein. This is not a trivial reduction — halved repair capacity means slower response to DNA strand breaks and potentially more unrepaired lesions per cell division.

There is a crucial NAD+ feedback loop here. Normally, PARP1 consumes NAD+ during repair; the Ala762 variant needs more NAD+ to achieve equivalent repair throughput. Simultaneously, NAD+ levels decline with age due to PARP1 overactivation (from accumulating DNA damage), CD38 accumulation, and reduced biosynthesis. For Ala762 carriers, this age-related NAD+ decline creates an especially adverse environment: the enzyme is already less efficient per molecule of NAD+ consumed, and there is progressively less NAD+ available as the decades pass.

PARP1 also competes directly with SIRT155 SIRT1
a longevity-associated deacetylase enzyme that requires NAD+ and regulates metabolism, inflammation, and epigenetic aging for the same intracellular NAD+ pool. In PARP1-knockout mice, NAD+ levels rise, SIRT1 activity increases, and metabolic health improves — phenocopying the benefits of sirtuin activation.

The Evidence

The functional consequence of reduced PARP1 activity is measurable in humans, not just in test tubes. Associations of PARP-1 variant rs1136410 with PARP activities, oxidative DNA damage, and the risk of age-related cataract66 Associations of PARP-1 variant rs1136410 with PARP activities, oxidative DNA damage, and the risk of age-related cataract
Cui NH et al., Gene 2017 measured PARP activity directly in blood cells of 2,055 Chinese Han participants and found that G-allele carriers (AG and GG genotypes) had significantly lower PARP activity and higher levels of 8-OHdG — a direct biomarker of oxidative DNA damage — compared to AA individuals. Critically, this translated to a measurable disease outcome: an adjusted OR of 1.42 (P=0.001) for age-related cataract, a condition driven by accumulated oxidative DNA damage in the lens.

The cancer risk data paints a complex but interpretable picture. A meta-analysis of 43 studies encompassing 17,351 cases and 22,401 controls77 A meta-analysis of 43 studies encompassing 17,351 cases and 22,401 controls
Hua RX et al., PLoS One 2014 found no overall cancer risk increase globally, but significant cancer-type specificity: gastric cancer risk increased significantly in Ala carriers (OR 1.56 for homozygous model), while brain tumor risk paradoxically decreased (OR 0.77). In Asian populations (18 studies), Ala carriers showed consistently elevated overall cancer risk (OR 1.12–1.23). A subsequent East Asian focused meta-analysis of 24 studies (8,926 cases, 15,295 controls) confirmed these findings88 confirmed these findings with homozygous Ala/Ala carriers showing OR 1.19 for overall cancer.

The cancer risk paradox — increased gastric cancer but decreased brain tumor risk — is not fully explained but may reflect the dual nature of PARP1 in cancer: reduced repair capacity increases mutation rates and genomic instability (pro-tumorigenic), while reduced poly(ADP-ribosyl)ation may also impair certain inflammatory signaling and cell survival pathways (potentially tumor-suppressive in specific cancer contexts).

Centenarian studies provide longevity context. Mangerich & Bürkle, Oxidative Medicine and Cellular Longevity 201299 Mangerich & Bürkle, Oxidative Medicine and Cellular Longevity 2012 reviewed evidence showing that poly(ADP-ribosyl)ation capacity correlates strongly with maximum lifespan across 13 mammalian species, and that human centenarians display significantly higher PARP activity than average-age populations — comparable to young healthy adults. This suggests that maintaining high PARP1 function throughout life is a feature of exceptional longevity, not just a marker of it. The Val762Ala variant, by reducing PARP1 function, may represent a genetic headwind against this pattern.

Practical Actions

The clearest actionable implication of Val762Ala is the NAD+ requirement. The Ala762 enzyme has higher Km for NAD+ — it needs more NAD+ to do the same amount of repair work. Supplementing with NAD+ precursors can raise intracellular NAD+ levels, potentially compensating for the reduced enzyme affinity. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) both raise blood and tissue NAD+ levels in human trials. In mouse studies, NMN treatment broke DBC1-PARP1 inhibitory complexes in aged mice and restored PARP activity to youthful levels1010 NMN treatment broke DBC1-PARP1 inhibitory complexes in aged mice and restored PARP activity to youthful levels
Mendelsohn & Larrick, Rejuvenation Research 2017.

Monitoring oxidative DNA damage biomarkers (urinary or blood 8-OHdG) provides direct feedback on whether DNA repair is keeping pace with damage accumulation — a particularly meaningful metric for Ala762 carriers given the demonstrated link between this genotype and elevated 8-OHdG.

Interactions

PARP1 operates within a larger DNA repair and NAD+ metabolism network. The related SNP rs3219145 in PARP1 (affecting mRNA stability and expression levels) can compound with Val762Ala: if total PARP1 protein is also reduced, the already-less-active Ala762 enzyme has less overall repair capacity. Similarly, rs2802292 in FOXO3 — a longevity-associated transcription factor that regulates oxidative stress response — is relevant because FOXO3 upregulates antioxidant defenses that reduce the DNA damage burden on PARP1 in the first place.

For individuals carrying both Val762Ala and variants in SIRT1 regulators, the NAD+ competition between PARP1 and sirtuins may be especially consequential. With reduced PARP1 efficiency requiring more NAD+ per repair event, and age-related NAD+ decline proceeding normally, sirtuin activity may be disproportionately compromised — a compound effect worthy of a combined supplementation strategy targeting NAD+ restoration.

Nutrient Interactions

nicotinamide adenine dinucleotide (NAD+) increased_need
niacin (vitamin B3) increased_need

Genotype Interpretations

What each possible genotype means for this variant.

AA Full Repair Activity Normal

Normal PARP1 catalytic activity with full DNA repair capacity

You have two copies of the Val762 (A) allele at rs1136410, meaning your PARP1 enzyme has its ancestral valine at position 762 in the catalytic domain. Your PARP1 binds NAD+ with normal affinity and performs DNA single-strand break repair at full capacity.

About 69% of people globally share this genotype, though rates vary widely by ancestry: roughly 71% of Europeans and 95% of Africans carry two A alleles.

AG Reduced Repair Activity Reduced

One copy of the low-activity variant with moderately impaired DNA repair

The dose-response relationship observed for rs1136410 means AG carriers have intermediate PARP activity — measurably lower than AA individuals but not as reduced as GG carriers. The cataract study (Cui NH et al. 2017) demonstrated that even heterozygous carriers had lower PARP activity and higher 8-OHdG oxidative damage markers in blood cells. Over decades, this moderate reduction in repair throughput allows slightly more unrepaired DNA lesions to accumulate with each cell division — a process that may not produce clinically apparent effects in youth but compounds with the age-related NAD+ decline that all humans experience after middle age.

The interaction with NAD+ availability is especially relevant for heterozygous carriers: as cellular NAD+ falls with age (due to reduced biosynthesis, CD38 accumulation, and ongoing PARP activation), the already higher Km of the Ala762 subpopulation of enzymes means an increasing fraction of your PARP1 becomes kinetically impaired at NAD+ concentrations that would still support near-full activity in AA individuals.

GG Significantly Reduced Repair Activity Decreased

Two copies of the low-activity variant with substantially reduced DNA repair capacity

The GG genotype represents homozygous carriage of the reduced-activity Ala762 enzyme. All your PARP1 protein runs at ~57–62% efficiency, and the dose-response relationship seen in population studies means this genotype carries the highest DNA damage biomarker levels and the strongest cancer risk associations. The East Asian meta-analysis (Xin et al. 2021, PMID 33706586) found OR 1.19 for overall cancer in GG carriers. Esophageal cancer in smokers showed particularly elevated risk with C/C (the coding-strand equivalent of GG on the plus strand) genotype.

The interaction with NAD+ is most consequential here: with all PARP1 molecules having elevated Km for NAD+, the age-related decline in cellular NAD+ progressively impairs your DNA repair more than in AA or AG carriers. This creates a compounding vulnerability that increases with each decade — proactive NAD+ support becomes more important with age.

The centenarian connection is also relevant: centenarians show PARP activity levels comparable to young adults, suggesting that high lifelong PARP activity is a feature of exceptional longevity. The GG genotype represents a genetic headwind against this pattern that can be partially mitigated by maintaining NAD+ availability.