rs1800591 — MTTP MTTP -493G/T

Promoter-region variant in MTTP that reduces hepatic MTTP transcription; the G allele (common) is associated with lower MTTP expression, impaired VLDL secretion, and increased hepatic triglyceride accumulation

See your personal result for MTTP

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

MTTP -493G/T — The Promoter Variant That Quiets Hepatic Fat Export

Your liver continuously performs a balancing act: synthesize and receive fats, then package and ship them out as VLDL particles11 VLDL particles
Very-low-density lipoprotein: triglyceride-rich particles assembled in the liver and secreted into the bloodstream, where they deliver fat to peripheral tissues. The enzyme that loads triglycerides into those outbound VLDL packages is MTTP — microsomal triglyceride transfer protein22 MTTP — microsomal triglyceride transfer protein
MTTP transfers triglycerides, phospholipids, and cholesteryl esters onto nascent apolipoprotein B during VLDL assembly. Without functional MTTP, triglycerides cannot be exported and instead accumulate within hepatocytes. A common polymorphism in the MTTP promoter region — rs1800591, known in the literature as the -493G/T variant — directly controls how much MTTP the liver makes, and therefore how efficiently it clears fat.

The Mechanism

The -493G/T variant sits in the promoter region upstream of the MTTP gene. A 2008 functional study33 2008 functional study
Rubin et al., Human Mutation, 2008, PMID 17854051 dissected promoter activity across MTTP haplotypes in hepatic cells, finding that the common haplotype carrying the -493G allele showed approximately two-fold lower transcriptional activity44 two-fold lower transcriptional activity
Rubin et al. demonstrated that differences at nearby positions — particularly -164 — govern SREBP1a binding affinity, and -493G travels in linkage with the lower-activity haplotype across most European populations than the rarer haplotype carrying the -493T allele. The mechanism operates through differential binding of SREBP1a55 SREBP1a
Sterol regulatory element binding protein 1a: a transcription factor that activates genes involved in lipid synthesis and transport — the T allele promotes a promoter configuration that recruits SREBP1a more effectively, driving higher MTTP expression. The downstream consequence of the G allele's reduced expression: less MTTP protein, less efficient triglyceride loading onto VLDL, and greater hepatic triglyceride retention.

The Evidence

The earliest clinical evidence came from a 2004 Japanese study66 2004 Japanese study
Namikawa et al., Journal of Hepatology, 2004, 63 biopsy-confirmed NASH patients vs 150 controls. The G allele was significantly more frequent in NASH cases (P=0.001), and homozygous G/G patients showed more advanced NASH histology than G/T carriers (P=0.04) — a dose-response pattern consistent with the variant acting through reduced MTTP expression rather than chance association.

Two independent meta-analyses in 2014 reinforced this finding. Zheng et al.77 Zheng et al.
11 case-control studies, 636 NAFLD cases and 918 controls, DNA and Cell Biology, 2014 found the MTP -493G/T polymorphism was "strongly correlated with an increased risk of NAFLD" across both Caucasian and non-Caucasian populations. Li et al.88 Li et al.
11 studies in a complementary analysis, Genetics and Molecular Research, 2014 quantified the risk: G allele vs T allele OR = 1.39 (95% CI 1.17–1.65, P<0.001); dominant model (GG+GT vs TT) OR = 1.46 (95% CI 1.02–2.09).

A larger 2020 meta-analysis99 larger 2020 meta-analysis
Tan et al., Saudi Journal of Gastroenterology, 10 studies, 1,388 NAFLD cases and 1,690 controls found no significant overall correlation between rs1800591 and general NAFLD (OR 1.08, P=0.76), but when the analysis was restricted to biopsy-confirmed NASH patients, the G allele emerged strongly: heterozygote model GT vs TT OR = 3.16 (95% CI 1.13–8.83) and dominant model GT+GG vs TT OR = 3.03 (95% CI 1.13–8.09). This pattern — stronger association with NASH than with simple steatosis — is consistent with the variant's effect on MTTP expression amplifying the progression to hepatic inflammation rather than merely increasing fat deposition.

In the context of chronic hepatitis C1010 chronic hepatitis C
Prata et al. 2022, 236 HCV-infected patients, Clinics (Sao Paulo), the interaction is dramatically amplified: GT/TT genotype combined with HCV genotype 3 produced an 11.51-fold increase in steatosis risk (OR 11.51, 95% CI 2.08–63.59), a gene-virus interaction that dwarfs the variant's independent effect. HCV genotype 3 is itself steatogenic, and reduced MTTP-mediated fat export appears to compound the viral lipid dysregulation.

Practical Actions

The G allele is the common form — roughly 56% of people are G/G homozygotes. What the evidence shows is that this common background state is associated with a modestly less efficient hepatic fat export system. The T allele (approximately 25% frequency globally) is the rarer, higher-expression variant that confers somewhat better MTTP-mediated VLDL secretion and a lower risk of hepatic triglyceride accumulation.

For G/G homozygotes, the key clinical implication is that dietary and metabolic factors imposing hepatic triglyceride load — saturated fat, fructose, alcohol — meet a slightly less efficient clearance system. Diets high in these substrates may promote hepatic fat retention more readily than in T/T individuals. Reducing hepatic triglyceride substrate (through limiting saturated fat and refined carbohydrates) and avoiding alcohol directly addresses the bottleneck this variant creates.

T/T homozygotes carry two copies of the higher-expression promoter variant and appear to have the most efficient MTTP-driven hepatic fat export, conferring measurably lower hepatic triglyceride accumulation and NASH risk. This is a relatively rare genotype (~6% globally).

Interactions

The most clinically important interaction is with HCV genotype 3 infection: reduced MTTP expression (G allele) combined with HCV genotype 3's intrinsic steatogenicity creates a 11.5-fold elevation in steatosis risk. Any G-allele carrier with known or suspected hepatitis C infection should have this discussed with their hepatologist.

Within the MTTP gene itself, rs1800591 interacts biologically with the coding variant rs3816873 (MTTP I128T): rs1800591 controls how much MTTP protein is made, while rs3816873 affects the functional properties of the protein made. Carriers of the G allele at rs1800591 who also carry the T/T (Ile128) genotype at rs3816873 may face a double disadvantage — both reduced MTTP expression and a less efficient form of the protein produced. The reverse combination (T allele at rs1800591 + C allele at rs3816873) would represent the highest-expression and most-efficient MTTP phenotype.

MTTP also functions downstream of PNPLA3 rs738409 (I148M): PNPLA3 governs triglyceride hydrolysis inside hepatocytes, generating substrates for MTTP to load onto VLDL. G/G carriers at rs1800591 who also carry PNPLA3 GG (I148M homozygous — impaired hydrolysis) face both impaired substrate mobilization (PNPLA3) and impaired export (MTTP), a convergent hepatic triglyceride retention risk that exceeds either variant alone.

Nutrient Interactions

fat (dietary) altered_metabolism
triglycerides altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

GG Common Promoter Form Normal

Common MTTP promoter genotype — modestly reduced hepatic fat export efficiency

The -493G allele travels in linkage with a promoter haplotype that shows approximately two-fold lower MTTP transcriptional activity than the -493T haplotype in hepatic cells (Rubin et al. 2008). This means your hepatocytes produce less MTTP protein per cell than T-allele carriers, reducing the efficiency of triglyceride loading onto nascent VLDL particles. The clinical consequence is modest at the population level: meta-analyses of general NAFLD show no significant association (OR 1.08), but biopsy-confirmed NASH studies show the G allele is enriched in more severe disease (OR ~3 in dominant models). This suggests the variant does not dramatically increase simple steatosis risk but may accelerate progression when hepatic fat accumulation is already under way from dietary or metabolic factors.

TT Higher-Expression Promoter Beneficial

Two high-activity MTTP promoter alleles — most efficient hepatic fat export

The T allele at -493 is the promoter-active variant — it supports higher MTTP transcription through a haplotype configuration that binds transcriptional activators more efficiently at the nearby -164 position (Rubin et al. 2008). With two T alleles, your hepatocytes express the highest levels of MTTP among the three genotypes, enabling the most efficient triglyceride loading onto VLDL particles and the most rapid clearance of hepatic fat. Meta-analysis data placing T/T as the reference (lowest risk) group in NAFLD/NASH analyses, combined with functional promoter data showing approximately two-fold higher activity, provide coherent mechanistic and clinical support for this protective phenotype. One important caveat from the HCV literature: in the presence of HCV genotype 3 infection, the T-allele's protection is reversed — the GT/TT group showed dramatically elevated steatosis risk in one cohort, possibly because HCV genotype 3 exerts direct steatogenic effects through pathways that override MTTP expression differences (Prata et al. 2022).

GT Intermediate Expression Intermediate

One low-activity and one higher-activity MTTP promoter allele — intermediate fat export

In hepatic cells, the G and T promoter alleles compete for transcription factor binding. G/T heterozygotes produce a mixed pool of MTTP protein from both promoter variants — functionally intermediate between G/G and T/T homozygotes. The Tan et al. 2020 meta-analysis found the heterozygote model (GT vs TT) showed OR = 3.16 (95% CI 1.13–8.83) for NASH, driven largely by the lower MTTP expression contributed by the G allele. Cohort studies in specific populations (Egyptian children, Japanese adults) have consistently found G-allele carriers are overrepresented among NASH diagnoses relative to their population frequency. The finding that G/G homozygotes show more advanced NASH histology than G/T heterozygotes (Namikawa 2004) confirms a dose-response relationship with allele count.