CELSR2 Genotype

Two people can eat the same food, exercise the same way, and end up with very different cholesterol numbers. A meaningful part of that gap is written into your genes, and one of the most consistently studied spots sits in a small cluster on chromosome 1 that includes CELSR2 (cadherin EGF LAG seven-pass G-type receptor 2). The variants here have been tied to LDL cholesterol, coronary artery disease, and the early stiffening of arteries that leads to heart attacks.

This test reads which version of the CELSR2 region you inherited from your parents. It is a once-in-a-lifetime answer to a useful question: does your DNA push your cholesterol and coronary risk upward, downward, or sit roughly in the middle? The number on a single lipid panel can be moved by last week's diet. Your CELSR2 result cannot.

What CELSR2 Actually Is

CELSR2 sits in a tightly linked cluster of genes on chromosome 1p13.3 that also includes PSRC1, MYBPHL, and SORT1. The gene itself codes for a cell-surface protein involved in how cells stick to and signal each other. The more important point for your health is what happens nearby. Common DNA differences in this region change how active these genes are in the liver, and the liver is where the body decides how much LDL cholesterol stays in your bloodstream.

That is why this single stretch of DNA has shown up again and again in genome-wide studies of cholesterol, heart attacks, and vascular inflammation. The variants do not change CELSR2 alone. They tune the whole neighborhood, and that neighborhood has a measurable grip on your lipid profile.

Heart Disease Risk

The strongest signal from CELSR2-region genetics is for coronary artery disease, the slow buildup of plaque in the arteries feeding your heart. In a meta-analysis pooling many human studies, one common variant in this region (rs599839) raised cardiovascular disease risk by about 19% per copy of the risk version (allelic odds ratio 1.19, 95% confidence interval 1.13 to 1.26). In plain terms, inheriting one or two copies of the risk variant tilts your lifetime odds of coronary disease upward in a measurable, repeatable way.

A separate study of 2,429 Italian adults looked at a different variant in the same gene (rs629301). People carrying two copies of the risk version had more severe narrowing of their coronary arteries on angiography, and the size of that risk was roughly the same as being ten years older. That is a striking number. A genetic variant essentially aging your coronary arteries by a decade is the kind of information a standard cholesterol panel cannot give you.

The mechanism makes sense. The same Italian study found the TT (two risk copies) genotype came with higher LDL cholesterol, higher non-HDL cholesterol, higher apoB (the protein on every artery-clogging particle), higher apoE and apoCIII, and lower HDL cholesterol. The genetic signal acts on the lipid system, and the lipid system acts on the arteries.

Cholesterol and Lipid Patterns

In a study of about 2,000 European adults with replication in additional cohorts, each copy of the coronary-risk version of rs599839 raised total cholesterol by about 0.17 mmol/L (roughly 6.6 mg/dL), with a related effect on LDL cholesterol. That sounds small. Spread across decades of life, those small per-copy shifts are exactly what large genetic studies have shown drives lifetime heart attack risk.

Population matters here. The same rs629301 variant that strongly tracked with LDL and coronary disease in Italians showed no detectable effect on serum lipids in a 459-person Thai cohort. Genetic risk is not uniform across ancestries, and a CELSR2 result needs to be interpreted with that in mind. If your family ancestry is non-European, the effect size attached to a given variant may be smaller, larger, or different in pattern from what European-ancestry studies report.

A Counterintuitive Finding in Fatty Liver Disease

In people with non-alcoholic fatty liver disease (NAFLD), one of the same CELSR2-region variants behaves in a way that initially looks contradictory. A study of NAFLD patients found that the minor G allele of rs599839 was tied to lower LDL cholesterol and lower risk of dyslipidemia and carotid plaque, which sounds good, but also to a higher risk of hepatocellular carcinoma (liver cancer).

This is not actually a paradox. The variant changes how active CELSR2, PSRC1, and SORT1 are in the liver. Turning those genes up shifts more cholesterol out of the bloodstream and into the liver. That is protective for your arteries and harmful for an already-stressed liver. The same DNA change pulls two different organs in opposite directions. It is a reminder that a genetic risk variant is rarely simply good or simply bad. The right read depends on which organ you are most worried about.

Other Cardiometabolic Links

Variants in this region have also been associated with Lp-PLA2 activity, a blood marker of vascular inflammation that tracks with heart disease risk. Coding variation in CELSR2 has been tied to IGFBP1 (insulin-like growth factor binding protein 1) levels and to type 2 diabetes risk, with some evidence of sex-specific effects. A separate study linked a CELSR2-region eQTL (expression quantitative trait locus, a DNA spot that controls how much of a gene gets made) to LDL cholesterol and resting metabolic rate, with effects acting partly through muscle.

Treat these as supporting evidence rather than the headline. The most reliable, replicated signal from this region remains LDL cholesterol and coronary artery disease.

Statin Response

A pharmacogenetic meta-analysis found that one variant in the CELSR2-PSRC1-SORT1 cluster (rs646776) was tied to a modest extra LDL drop on statins, about 1.3% beyond the typical response. That is not a reason to start or stop a statin. It is one of many small genetic inputs that explain why two people on the same statin dose end up at slightly different LDL levels.

Your Result Is For Life

Unlike a cholesterol or blood sugar reading, your CELSR2 genotype does not change. You inherited it at conception and you will have the same result if you test today, in five years, or in twenty. There is no retest cadence to follow for the genotype itself.

The action is on the downstream side. If you carry a higher-risk version, your lipid panel and apoB should be tracked more aggressively, ideally annually or every six months if you are actively making changes. A coronary calcium score in your 40s or 50s becomes more valuable, because your genetic baseline tells you that plaque, if it is forming, is forming on top of an inherited push toward higher LDL. The genetic test is the one-time setup. The lipid tracking is the ongoing work.

When the Result Can Be Misleading

Genetic tests carry their own confounders that differ from blood-based markers:

• Variant panel coverage: this assay only reads the specific CELSR2-region variants it is designed to detect. A result that does not flag risk does not rule out other rare variants in or near the gene that the panel was not built to find.
• Ancestry-specific effects: the size of the effect attached to a given CELSR2 variant differs across populations. A risk variant tightly tied to LDL in European cohorts had no detectable lipid effect in a Thai cohort. Your ancestry shapes how to read your result.
• Variant of uncertain significance: the lab may report a variant in this region whose clinical meaning is still being worked out. An unfamiliar finding is not automatically a warning.
• Polygenic context: CELSR2 is one of many genes that nudge your cholesterol and heart risk. Other loci such as 9p21 and LPA carry signals of similar or larger size. A high-risk CELSR2 result combined with otherwise protective genetics looks different from the same result on top of a high polygenic risk score for LDL.

What To Do With An Unexpected Result

If your CELSR2 result points to higher inherited risk, the next moves are about translating that genetic information into a concrete monitoring and prevention plan, not about retesting the gene. The questions to ask are: what is your apoB right now, what is your Lp(a) (a separate inherited risk marker not covered by this test), what does a coronary calcium scan show, and what is the lipid trajectory of your siblings and parents?

If you have a family history of early heart attack, this result is most useful when paired with a lipidologist or preventive cardiologist who can weigh your CELSR2 status alongside the rest of your inherited and acquired risk. If you have non-alcoholic fatty liver disease, the picture is more complex because of the divergent liver and heart effects, and a hepatologist may want to weigh in. If your result is benign and your other risk factors are low, that is genuine reassurance about one piece of your inherited cardiovascular risk, though it does not replace standard lipid tracking.

What This Result Means For Your Family

Because this is a germline variant, your siblings have a 50% chance of carrying the same risk version on at least one chromosome, and your children inherit half of your DNA. A clear-cut CELSR2 result is useful information to share with first-degree relatives, especially if there is a family pattern of high cholesterol or early heart attacks. It does not guarantee they share your result, but it raises the value of them getting tested earlier than they otherwise would.