rs6994076 — TTPA -980T>A

TTPA -980T>A --- Your Vitamin E Set Point

Vitamin E is the body's primary fat-soluble antioxidant¹¹ fat-soluble antioxidant
A molecule that protects cell membranes from oxidative damage by neutralizing lipid peroxyl radicals, protecting every cell membrane from oxidative damage. But absorbing vitamin E from food is only the first step --- your liver must actively select and redistribute it to the rest of your body. That job falls to a single protein: alpha-tocopherol transfer protein²² alpha-tocopherol transfer protein
A liver protein encoded by the TTPA gene that binds alpha-tocopherol and loads it onto VLDL particles for systemic distribution (alpha-TTP), encoded by the TTPA gene on chromosome 8.

The rs6994076 variant sits in the promoter region of TTPA, approximately 980 base pairs upstream of the gene's transcription start site. It determines how much alpha-TTP your liver produces, which in turn sets your baseline circulating vitamin E level and how effectively you respond to supplementation.

The Mechanism

Alpha-TTP is expressed primarily in the liver, where it binds alpha-tocopherol with high selectivity and loads it onto VLDL particles³³ VLDL particles
Very low-density lipoproteins --- the transport vehicles that carry fat-soluble vitamins and lipids from the liver to peripheral tissues for distribution throughout the body. Without this protein, dietary vitamin E would be rapidly excreted in bile rather than retained in circulation.

The T allele at position -980 creates a new binding site for the transcriptional repressor BCL6⁴⁴ BCL6
B-cell lymphoma 6 protein --- a zinc-finger transcription factor that suppresses target gene expression when bound to DNA. When BCL6 occupies this site, it suppresses TTPA promoter activity, reducing the amount of alpha-TTP protein produced. Less alpha-TTP means less efficient vitamin E retention and distribution.

Notably, TTPA expression is itself regulated by oxidative stress --- a feedback loop where the need for antioxidant protection upregulates the protein that delivers it. The -980T variant blunts this response, potentially limiting the body's ability to mobilize vitamin E during periods of increased oxidative demand.

The Evidence

The Wright et al. 2009 study⁵⁵ Wright et al. 2009 study
Wright ME et al. Association of variants in two vitamin E transport genes with circulating vitamin E concentrations and prostate cancer risk. Cancer Epidemiol Biomarkers Prev, 2009 examined TTPA polymorphisms in 847 controls from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The TT genotype had 3.1% lower baseline serum alpha-tocopherol compared to AA (p = 0.03). More strikingly, TT carriers showed a 25.4% lower serum response to three years of daily vitamin E supplementation (50 mg/day) compared to AA homozygotes (p = 0.002), with heterozygotes intermediate at 16.4% lower response (p = 0.005).

Ulatowski et al. 2012⁶⁶ Ulatowski et al. 2012
Ulatowski L et al. Expression of the alpha tocopherol transfer protein gene is regulated by oxidative stress and common single nucleotide polymorphisms. Free Radic Biol Med, 2012 confirmed the functional mechanism using luciferase reporter assays in human hepatocytes. The -980T variant significantly repressed promoter activity by creating a putative BCL6 binding site, providing a molecular explanation for the observed differences in vitamin E levels.

A Mediterranean cohort study⁷⁷ Mediterranean cohort study
Zanon-Moreno V et al. Effects of polymorphisms in vitamin E-, vitamin C-, and glutathione peroxidase-related genes on serum biomarkers and associations with glaucoma. Mol Vis, 2013 of 500 individuals independently confirmed the significant association between rs6994076 and plasma vitamin E levels (p < 0.001).

The T allele frequency varies substantially across populations: approximately 48% in Europeans, 73% in East Asians and Africans, and 70% in South Asians. This means TT homozygosity is far more common in non-European populations, where baseline vitamin E levels may be more often influenced by this variant.

Practical Implications

The effect of rs6994076 on baseline vitamin E is modest (~3%) but the impact on supplementation response is substantial (~25%). This has two practical consequences:

First, TT carriers may need higher doses of vitamin E supplements to achieve the same serum increase as AA carriers. Standard supplement doses may be less effective for them.

Second, the preferred form matters. Natural d-alpha-tocopherol⁸⁸ d-alpha-tocopherol
Also labeled as RRR-alpha-tocopherol; the naturally occurring stereoisomer that alpha-TTP binds most efficiently (RRR-alpha-tocopherol) is bound by alpha-TTP with far greater affinity than the synthetic dl-alpha-tocopherol mixture. When alpha-TTP availability is already reduced by the T allele, using the natural form maximizes what the protein can deliver.

Dietary sources of alpha-tocopherol include sunflower seeds, almonds, hazelnuts, wheat germ oil, and spinach. These provide vitamin E in its natural form and are the first-line approach to maintaining adequate levels regardless of genotype.

The AVED Connection

Loss-of-function mutations in TTPA cause the rare autosomal recessive disorder ataxia with vitamin E deficiency⁹⁹ ataxia with vitamin E deficiency
AVED (OMIM #277460) --- a progressive neurodegenerative condition caused by inability to retain dietary vitamin E, treatable with high-dose supplementation (AVED), characterized by progressive cerebellar ataxia and peripheral neuropathy. While rs6994076 is a common regulatory variant with mild effects --- not a disease-causing mutation --- it illustrates the same biological principle: alpha-TTP is the bottleneck for vitamin E retention, and any reduction in its function shifts circulating levels downward.