rs708272 — CETP TaqIB

The CETP TaqIB Variant — HDL Cholesterol, Longevity, and the Paradox of "Good" Cholesterol

The cholesterol ester transfer protein (CETP) is a liver-synthesized glycoprotein¹¹ liver-synthesized glycoprotein
CETP facilitates the bidirectional exchange of cholesteryl esters and triglycerides between lipoproteins in plasma that orchestrates cholesterol trafficking between lipoprotein particles. CETP transfers cholesteryl esters from HDL (high-density lipoprotein, the "good" cholesterol) to LDL and VLDL particles, while simultaneously shuttling triglycerides in the opposite direction. The rs708272 variant, known as TaqIB for the restriction enzyme site it creates or disrupts, sits in an intronic region²² intronic region
introns are non-coding sequences within genes that can still affect gene expression through regulatory elements of the CETP gene and modulates both CETP enzyme activity and concentration in plasma. People carrying the B2 allele (the A nucleotide) show 30-40% lower CETP activity, which translates to approximately 10% higher HDL cholesterol levels — yet the cardiovascular benefit of this seemingly favorable lipid shift remains one of genetics' most intriguing puzzles.

The Mechanism

The TaqIB polymorphism doesn't change the CETP protein sequence directly — it's located in intron 1, between coding regions — but it appears to affect gene expression through linkage disequilibrium³³ gene expression through linkage disequilibrium
linkage disequilibrium means this SNP tends to be inherited together with other functional variants in nearby regulatory regions with regulatory elements in the promoter and elsewhere in the gene. The B1 allele (G nucleotide) creates a restriction site for the TaqI enzyme and associates with higher CETP activity, while the B2 allele (A nucleotide) disrupts this site and correlates with reduced enzyme function. Lower CETP activity slows the transfer of cholesteryl esters out of HDL particles, allowing HDL to accumulate more cholesterol. The result: B2 carriers consistently show higher HDL-C concentrations, larger HDL particle sizes, and paradoxically, larger LDL particles as well — a pattern that resembles the lipid profile of people with genetic CETP deficiency⁴⁴ resembles the lipid profile of people with genetic CETP deficiency
complete CETP deficiency from loss-of-function mutations produces extremely high HDL-C (often >100 mg/dL) and has been linked to longevity in some populations, who can have HDL cholesterol levels twice the population average.

The Evidence

The relationship between this variant and cardiovascular disease defies simple categorization. A meta-analysis of 45 studies including over 42,000 participants⁵⁵ meta-analysis of 45 studies including over 42,000 participants
Guo et al. 2016. Associations of Cholesteryl Ester Transfer Protein TaqIB Polymorphism with the Composite Ischemic Cardiovascular Disease Risk and HDL-C Concentrations found that the B2 allele confers protection against ischemic cardiovascular disease in both Asian and Caucasian populations, with the protective effect scaling with allele dose. Yet a comprehensive pooled analysis⁶⁶ comprehensive pooled analysis
Dullaart and Sluiter. 2008. Common variation in the CETP gene and the implications for cardiovascular disease revealed a striking context dependency: in population-based studies of apparently healthy individuals, B2B2 homozygotes actually showed 45% higher cardiovascular risk compared to B1B1 carriers (OR 1.45), despite their elevated HDL. In contrast, among high-risk populations — people selected for existing cardiovascular disease or multiple risk factors — the B2B2 genotype was protective (OR 0.84). This apparent contradiction may reflect survivor bias⁷⁷ survivor bias
high-risk populations have already been selected for disease survival, potentially filtering out B2B2 individuals with poor outcomes or suggest that HDL cholesterol concentration alone doesn't capture HDL function, which may be more important for atheroprotection.

The longevity connection strengthens the case for B2. The landmark Copenhagen City Heart Study⁸⁸ Copenhagen City Heart Study
Barzilai et al. 2021. Following 10,261 participants for up to 34 years followed over 10,000 people for three decades and found that CETP gene polymorphisms reducing enzyme activity — including TaqIB B2 — associated with significantly reduced risk of ischemic heart disease, myocardial infarction, and stroke, plus increased longevity, with no evidence of adverse effects. Meanwhile, a prospective study of 18,245 initially healthy American women⁹⁹ prospective study of 18,245 initially healthy American women
Voight et al. 2010. Polymorphism in the CETP Gene Region, HDL Cholesterol, and Risk of Future Myocardial Infarction over 10 years found that each copy of the B2 allele raised HDL-C by 3.1 mg/dL and lowered myocardial infarction risk by 24% (HR 0.76).

Intriguingly, the B2 allele shows a strong gene-diet interaction with alcohol consumption¹⁰¹⁰ strong gene-diet interaction with alcohol consumption
Mehlig et al. 2014. Studying 618 CHD patients. In a study of 618 coronary heart disease patients, B2B2 individuals consuming moderate amounts of alcohol (6.5-13 g ethanol daily for men) had a remarkable 79% reduction in CHD risk (OR 0.21) compared to low drinkers, while B1B1 carriers showed no such benefit. This interaction may reflect alcohol's effects on HDL particle remodeling, which could be amplified when CETP activity is already low.

Practical Implications

If you carry one or two copies of the B2 allele, your HDL cholesterol is likely 5-10% higher than if you carried B1B1, and your LDL and HDL particles tend to be larger and less atherogenic. The cardiovascular implications depend heavily on your broader risk profile. In the absence of other major risk factors, the B2 allele appears modestly protective, particularly if you're a moderate alcohol consumer. However, the variant doesn't eliminate cardiovascular risk — elevated HDL from reduced CETP activity may not confer the same protection as functionally robust HDL achieved through lifestyle. Focus on HDL function rather than HDL concentration¹¹¹¹ HDL function rather than HDL concentration
HDL's anti-inflammatory, antioxidant, and cholesterol efflux capacities matter more than the absolute number: exercise, omega-3 fatty acids, and avoiding oxidative stress all enhance HDL quality independent of CETP genotype.

For those with diabetes, the picture shifts. Several studies suggest the B2 allele's HDL-raising effects are most pronounced in individuals with lower insulin resistance¹²¹² HDL-raising effects are most pronounced in individuals with lower insulin resistance
Bini et al. 2010. Menopause and CETP TaqIB polymorphism effects in type 2 diabetes, BMI, and triglycerides. In type 2 diabetics, B2 carriers with better metabolic control show a more favorable HDL subpopulation profile (larger alpha-1 particles), while those with poor control lose this benefit. If you're B2B2 and managing diabetes or metabolic syndrome, optimizing insulin sensitivity and triglyceride levels may unlock your genotype's protective potential.

The alcohol interaction merits mention but not overinterpretation. While B2B2 individuals appear to derive cardiovascular benefit from light-to-moderate drinking, this doesn't constitute a prescription. Alcohol carries risks beyond cardiovascular disease, and the effect size, while striking, comes from observational data subject to confounding. If you already consume alcohol moderately and are B2B2, the data suggest you may be extracting more cardiovascular benefit than others — but this isn't a reason to start drinking if you don't currently.

Statin therapy appears equally effective across TaqIB genotypes, with no evidence that B1 or B2 status should influence treatment decisions for elevated LDL cholesterol. The variant's effect on HDL is independent of statin-mediated LDL lowering.

Interactions

The TaqIB variant's effects on lipid metabolism position it within a network of related genetic influences. Other CETP polymorphisms, including the promoter variant rs1800775 (-629C>A) and the missense variant rs5882 (I405V), show similar associations with HDL levels and often travel together in haplotype blocks. Compound effects with other HDL metabolism genes — particularly ABCA1, LIPC (hepatic lipase), and APOA1 — could amplify or dampen the TaqIB signal, though few studies have systematically evaluated multi-locus interactions. More broadly, the cardiovascular risk implications of elevated HDL from reduced CETP activity likely depend on LDL levels, triglyceride levels, and inflammatory markers — a reminder that single variants operate within complex, multifactorial disease pathways. Personalized cardiovascular risk assessment should integrate CETP genotype with conventional lipid panels, family history, and metabolic health markers rather than relying on any single genetic signal.