rs2034650 — IVD

IVD rs2034650 — Leucine Metabolism, Lung Health, and a Positively Selected Haplotype

Inside every cell's mitochondria, leucine — the most abundant branched-chain amino acid in dietary protein — is steadily broken down through a five-step enzymatic cascade. The third step belongs to isovaleryl-CoA dehydrogenase (IVD)¹¹ isovaleryl-CoA dehydrogenase (IVD)
A mitochondrial flavoenzyme that converts isovaleryl-CoA to 3-methylcrotonyl-CoA, a critical step in leucine catabolism. When IVD works efficiently, leucine flows through to energy production and biosynthetic building blocks. When it stalls, isovaleryl-CoA and its metabolites — most notably isovalerylcarnitine (C5-carnitine)²² isovalerylcarnitine (C5-carnitine)
A blood and urine metabolite that reflects IVD enzyme activity; elevated in IVD deficiency, used as a neonatal screening marker for isovaleric acidemia — accumulate.

rs2034650 is a common intronic variant in the IVD gene at chromosome 15q15.1 with no direct effect on the protein sequence. Instead, it lies within a regulatory haplotype that influences how much IVD protein the cell produces. The variant is notable for two reasons: it tags a GWAS signal for idiopathic pulmonary fibrosis (IPF) risk, and it sits on a haplotype under recent positive selection in Japanese populations — suggesting this region of the IVD locus has been shaped by evolutionary pressure in some ancestries. The evidence base is limited and the functional mechanisms remain incompletely resolved, placing this firmly in the emerging-evidence tier.

The Mechanism

The IVD enzyme is a flavoprotein³³ flavoprotein
An enzyme that requires FAD (flavin adenine dinucleotide) as a tightly bound cofactor; FAD is derived from riboflavin (vitamin B2) — its catalytic activity depends entirely on the availability and binding of FAD, which in turn depends on dietary riboflavin (vitamin B2) intake. Without sufficient riboflavin to maintain FAD cofactor supply, IVD enzyme activity can fall to 17% of normal levels⁴⁴ IVD enzyme activity can fall to 17% of normal levels
Demonstrated in riboflavin-deficient rat liver mitochondria; the enzyme matures normally but degrades rapidly without mitochondrial FAD, illustrating how nutritional status and genetic variation at this locus can interact.

rs2034650 itself is an intronic variant. Its functional significance is indirect: it lies in high linkage disequilibrium with a cluster of three regulatory variants⁵⁵ cluster of three regulatory variants
Identified by Brown et al. 2024 (PMID 37930192) — a 5-bp indel (rs66791338), and two flanking SNPs — that show synergistic and opposing effects on IVD enhancer activity in luciferase and CRISPR functional assays that together modulate IVD transcription. This haplotype is enriched in Japanese populations, who show the highest A-allele frequency at rs2034650 (~82%), consistent with positive selection driving the high-expression haplotype to higher frequency in East Asian ancestries.

The proposed mechanism linking IVD expression to pulmonary fibrosis is speculative but plausible: insufficient IVD activity could increase mitochondrial isovaleryl-CoA accumulation, potentially promoting lipid peroxidation, mitochondrial dysfunction, and fibrogenic signaling in lung epithelial cells. However, this mechanistic link has not been directly demonstrated.

The Evidence

The primary genetic signal at this locus comes from a landmark IPF GWAS⁶⁶ landmark IPF GWAS
1,616 non-Hispanic white IPF cases and 4,683 controls, with replication in 876 cases and 1,890 controls by Fingerlin et al. (Nature Genetics 2013), which identified the chromosome 15q14-15 region (encompassing IVD) as one of seven novel genome-wide significant IPF susceptibility loci.

Cross-ethnic replication came from a smaller targeted study⁷⁷ smaller targeted study
83 Mexican (IPF vs. 111 controls) and 239 Korean (IPF vs. 87 controls) cohorts by Peljto et al. (Chest 2015), which found rs2034650 A allele protective in both populations: OR 0.40 (P=.01) in Mexican and OR 0.13 (P=.0008) in Korean participants. Notably, the Korean effect was strong despite the small control group size. These sample sizes — 83 to 239 cases — are small by modern GWAS standards, and the study's primary focus was the MUC5B promoter variant, with rs2034650 as a secondary finding.

Functional dissection of the locus is provided by Brown et al. 2024⁸⁸ Brown et al. 2024
TwinsUK metabolomics cohort (n~4,600) plus Geuvadis eQTL dataset (n=373 LCLs), who demonstrated that the IVD locus contains at least three regulatory variants with opposing effects on IVD expression and isovalerylcarnitine levels. The peak eQTL variant is itself non-functional in reporter assays — a warning that rs2034650 (which is in LD with the locus) may not be the causal variant but rather a tag for a nearby functional site.

Taken together: this is a real and replicated genetic signal, but its effect size at rs2034650 specifically is uncertain because the true causal variant likely differs. The magnitude 0.0 classification on SNPedia reflects the limited individual-level interpretation utility rather than absence of population-level evidence.

Practical Actions

For GG carriers (reference homozygous), the modest increase in relative IPF risk (compared to AA carriers) does not translate to a clinical screening recommendation based on current evidence — IPF affects approximately 3 in 10,000 people and rs2034650 alone is not sufficient to stratify clinical screening decisions. However, two nutritional considerations are supported by the biochemistry:

First, IVD is exquisitely riboflavin-dependent: low riboflavin intake directly impairs IVD activity. Maintaining adequate riboflavin through dietary sources (liver, dairy, eggs, leafy greens) or supplementation is broadly indicated for those relying on efficient leucine catabolism. Second, moderate leucine intake — avoiding the very high leucine loads seen in aggressive BCAA supplementation — reduces the substrate burden on IVD, which is particularly relevant if IVD expression is on the lower end.

No drug interactions or clinical pharmacogenomics guidelines exist for rs2034650.

Interactions

IVD operates within the broader leucine catabolism pathway alongside several other enzymes. Variants in genes encoding downstream enzymes (3-methylcrotonyl-CoA carboxylase, 3-methylglutaconyl-CoA hydratase) and the electron transfer flavoprotein (ETFA/ETFB) that accepts electrons from IVD could theoretically interact with reduced IVD expression to further impair leucine flux. No published evidence for gene-gene interactions involving rs2034650 specifically has been identified.

The pulmonary fibrosis GWAS signal at 15q14-15 likely captures combined effects of multiple nearby regulatory variants in LD with rs2034650 (including rs66791338, rs17733719, rs8033249), rather than rs2034650 acting alone.