rs2034650 — IVD

Intronic regulatory variant in IVD (isovaleryl-CoA dehydrogenase) associated with altered IVD expression, isovalerylcarnitine levels, and modest pulmonary fibrosis susceptibility

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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.

Nutrient Interactions

leucine altered_metabolism
riboflavin increased_need

Genotype Interpretations

What each possible genotype means for this variant.

AA High Expression Beneficial

Highest IVD expression and most protective metabolite profile

The AA genotype sits on the haplotype that Brown et al. (2024, PMID 37930192) identified as positively selected in Japanese populations, where A-allele frequency reaches ~82%. This selection signal suggests the high-expression IVD haplotype conferred some fitness advantage in East Asian ancestral environments — possibly related to leucine-rich diets or other metabolic pressures.

In the Peljto et al. 2015 study (PMID 25275363), the A allele was associated with OR 0.13 for IPF in a Korean cohort (P=.0008), the strongest protective association observed. While the sample size was small (239 cases, 87 controls), the magnitude is notable.

Because rs2034650 is a tag variant rather than the causal regulatory variant, the functional interpretation should be held lightly: AA at this position reflects a haplotype background that tends toward higher IVD expression, but individual variation in riboflavin status and other regulatory factors will dominate actual IVD activity in practice.

AG Intermediate Expression Intermediate

One protective allele; IVD expression and leucine metabolism likely near average

For most metabolic variants, heterozygotes show intermediate biochemistry between the two homozygous states. For rs2034650, this is likely true at a population level, but because rs2034650 is an intronic tag variant rather than the causal regulatory site, the AG genotype may not show clean intermediate IVD expression — haplotype phasing matters, and which allele is on which chromosome (i.e., whether the A is in cis with the functional regulatory alleles) will influence the actual expression level.

The IPF associations in the Fingerlin 2013 GWAS (PMID 23583980) were identified at the 15q14-15 locus level; individual genotype effect sizes for AG at rs2034650 were not reported in the available literature.

GG Lower Expression High Risk

G-allele homozygous; lowest IVD expression haplotype and modestly elevated IPF association

The Fingerlin et al. 2013 GWAS (Nature Genetics, PMID 23583980) identified the IVD locus at 15q14-15 as a novel IPF susceptibility locus in non-Hispanic white individuals. Peljto et al. 2015 (Chest, PMID 25275363) extended this to Mexican (OR 0.40 for A allele, meaning GG carries ~2.5× relative odds compared to AA) and Korean (OR 0.13 for A allele, suggesting much stronger risk in GG homozygotes) cohorts.

However, the small sample sizes in the Korean cohort (87 controls) limit confidence in the extreme OR estimates. The primary causal variant(s) are likely within the 5-bp indel rs66791338 and nearby regulatory sites identified by Brown et al. (2024, PMID 37930192); rs2034650 is a tag variant in LD with these functional sites.

GG carriers may have relatively lower IVD expression, potentially leading to mildly elevated isovalerylcarnitine levels and less efficient leucine catabolism under metabolic stress. The riboflavin-dependence of IVD is particularly relevant for GG carriers: if IVD expression is lower, maintaining maximal enzyme activity from available protein through adequate riboflavin cofactor is especially important.

No clinical management guidelines exist for rs2034650. The evidence does not support pulmonary function screening based on this variant alone.