SLCO1B1 Genotype (rs4149015)

Statins are among the most commonly prescribed medicines in the world, and pravastatin is one of them. To do their job, statins have to get from your blood into your liver, and a transporter protein called OATP1B1, made by the SLCO1B1 gene, helps carry every statin in. This test reads one letter, rs4149015, in the stretch of DNA just in front of SLCO1B1 on chromosome 12.

Your genetics report may list this letter under pravastatin and describe it as part of the SLCO1B117 haplotype (a set of changes inherited together). That description comes from research published in 2004 and 2005. Since then, the official naming system has retired 17, the evidence for this letter has stayed small and mixed, and CPIC, the expert group that writes gene-based prescribing guidelines, does not use it. The SLCO1B1 change CPIC says every test must include, c.521T>C (Val174Ala), is read by a separate test.

What SLCO1B1 Does

OATP1B1 sits on the surface of liver cells and pulls statins and several other commonly prescribed medicines in from the blood. When the transporter works less well, more of a statin stays in the bloodstream. CPIC notes that this can raise the risk of statin-associated muscle symptoms, such as muscle aches.

The best-studied change in SLCO1B1 is c.521T>C (rs4149056), which swaps one building block of the protein (Val174Ala). Its C version lowers the transporter's activity in lab studies and raises blood levels of several medicines. In the 2008 SEARCH study of people taking a high dose (80 mg) of simvastatin, the only strong genetic signal for statin muscle damage (myopathy) pointed to this change, through a neighboring marker inherited with it almost every time. Each C copy raised the odds about 4.5-fold. This is the change the SLCO1B1 Genotype (Val174Ala) test reads.

What This Variant Is

rs4149015 is a change from G to A about 800 DNA letters before the point where the SLCO1B1 gene starts being read. It sits in the gene's promoter region, the stretch of DNA that helps control how much of the transporter is made, and it does not change the transporter protein itself. G is the usual letter and A is the less common one. Older papers call this change -11187G>A and newer ones c.-910G>A; they are the same letter counted in two different ways.

Does it change how much transporter is made? The limited evidence suggests it does not. In a 2007 study of 31 Japanese liver samples, the amount of the gene's working copy (messenger RNA) did not differ by this variant, and the variant did not change the gene's activity in a lab test. When PharmVar, the international group that names gene versions, reviewed SLCO1B1, it noted that none of the variants this far in front of the gene had been found to change the transporter's activity.

What the *17 Label Means

Scientists name common versions of a gene with star alleles, short labels for a set of changes inherited together on one copy of the gene. In 2004, researchers named SLCO1B117 for a combination of three changes on the same copy: this A letter, a change called c.388A>G, and c.521T>C. So 17 always carried the C version of c.521T>C, the change the Val174Ala test reads.

The naming has since changed. PharmVar now ignores changes more than about 500 letters in front of the gene when it defines SLCO1B1 star alleles, so it dropped this letter and merged 17 into 15, a version defined by c.388A>G and c.521T>C. CPIC's 2022 guideline states that the 17 name no longer exists, and rs4149015 is not one of the letters CPIC uses to work out SLCO1B1 function. A report that still says 17 is using the older naming.

Carrying an A here also cannot tell you for certain whether you carry c.521C. In a 2006 study of 468 people in Finland, the A letter was found on 9.7 percent of gene copies and the full old *17 combination on 6.9 percent. So about 7 in 10 copies with A also carried c.521C, and about 3 in 10 did not. How often the two travel together also differs between populations.

What this means for you: this letter alone cannot tell you your SLCO1B1 function. The Val174Ala result is the one CPIC says every SLCO1B1 test should include.

What the Pravastatin Studies Found

The link to pravastatin rests mainly on three small studies published between 2004 and 2006. In the first, researchers measured pravastatin blood levels in 41 healthy adults of European ancestry. The group included six people picked out for unusually high pravastatin levels, and three of the six A carriers were among them. The six people with one A copy had average pravastatin levels about twice as high (98 percent higher over 12 hours) as people with G/G. The three people who carried the full *17 combination, including c.521C, had levels 130 percent higher. The authors concluded that combinations of changes on one copy predicted the transporter's behavior better than single letters.

A 2005 follow-up in the same volunteers looked at lathosterol, a blood marker of how much cholesterol the body is making, over the 12 hours after one 40 mg dose. Pravastatin lowered it less in the three 17 carriers. The authors suggested that less pravastatin may reach the liver in 17 carriers and that their cholesterol-lowering response may be weaker, but the study did not measure LDL cholesterol over weeks or months of treatment.

A 2006 study in 20 children with inherited high cholesterol (familial hypercholesterolemia) found the opposite pattern. The two children with one A copy had pravastatin levels about 74 percent lower than children with G/G, and a bigger rise in HDL cholesterol after two months of treatment. The authors said the reasons were unclear and needed more study.

Other statins have been looked at in small studies too. In a 2017 study of 50 healthy Korean men given atorvastatin, carriers of the old *17 combination had higher atorvastatin blood levels than non-carriers.

PharmGKB, a public database that grades evidence on genes and medicines, rates the rs4149015 and pravastatin link at level 3, its grade for a low level of evidence. It flags the adult and child studies as conflicting, and notes that its summary covers blood levels only, not clinical outcomes. Its summary sentence follows the children's study (lower levels in A carriers) and lists the adult study as conflicting.

What this means for you: the pravastatin findings come from a handful of people (six adults with one A copy, three of whom carried the full *17 combination, and two children) and point in different directions. They are not enough to predict how pravastatin will work for you.

Statin Muscle Side Effects

SLCO1B1 is best known for its link to statin muscle side effects, and that link comes from c.521T>C. In the SEARCH study, people with two C copies had about 17 times the odds of myopathy on 80 mg of simvastatin compared with people with two T copies, and the researchers estimated that more than 60 percent of the myopathy cases could be put down to the C version.

This letter is different. CPIC's 2022 guideline, which reviewed the evidence on SLCO1B1 and statin muscle symptoms, does not use rs4149015, and PharmGKB lists no muscle side-effect findings for it. An A here often, but not always, sits on the same copy as c.521C, so on its own this result cannot reliably tell you your risk of statin muscle side effects, whichever letters you have. The Val174Ala result answers that question directly.

What Guidelines Say

CPIC's 2022 guideline covers three genes and statin muscle symptoms: SLCO1B1, ABCG2 and CYP2C9. For SLCO1B1, it works out a person's transporter function (for example normal, decreased or poor) from their two star alleles, and it says every SLCO1B1 test should include c.521T>C. CPIC does give pravastatin recommendations for people with decreased or poor SLCO1B1 function, but that function comes from star alleles, and those no longer include rs4149015.

What this means for you: under CPIC, your rs4149015 result on its own does not place you in any SLCO1B1 function group. Statin choices are decisions for your prescriber, and nobody should start, stop or change a medicine because of this result.

How Common It Is

In the gnomAD v4.1 genome data, about 5 percent of all SLCO1B1 gene copies carry A. It is about 6 percent in people of non-Finnish European ancestry, which works out to roughly 1 in 8 people carrying at least one copy and about 1 in 270 carrying two. It is more common in people of East Asian ancestry (about 13 percent of copies, so roughly 1 in 4 people carry it) and Finnish ancestry (about 11 percent), and less common in people of South Asian (about 4.5 percent), Latin American (about 3.7 percent) and African ancestry (about 1.4 percent).

How Results Are Reported

This result is the pair of letters at position 12:g.21130388 on the current GRCh38 reference genome (position 21283322 on the older GRCh37 build), read on the forward strand of chromosome 12, the same strand the SLCO1B1 gene is read from. G is the usual letter and A is the less common one. G/G means no copies, A/G or G/A means one copy (the order does not matter), and A/A means two. Some reports print the pair without a slash, so AG is the same result as A/G.

This variant is studied as a possible influence on how medicines are handled. It is not known to cause disease, and ClinVar, the US public database of variant classifications, has no entry for it.

Why You Only Need This Test Once

Your DNA does not change, so your rs4149015 result at 30 will be the same at 70. What is worth tracking over time is your cholesterol, such as LDL cholesterol and apoB, especially if you take a cholesterol medicine.

What to Do With Your Result

Whatever your genotype, the practical steps are the same:

• Share it with your prescriber and pharmacist: keep it with your other genetic results, knowing that CPIC does not use this letter to guide statin choices.
• Look at your SLCO1B1 Val174Ala result: c.521T>C is the SLCO1B1 change CPIC says every test should include, and the main change behind its statin recommendations.
• Do not start, stop or change a medicine on this result alone: if you take pravastatin or another statin, talk to your prescriber before any change.
• Keep your cholesterol results in view: your LDL cholesterol and apoB show how a cholesterol medicine is actually working for you, which this genotype cannot predict.

Carrying A here is fairly common and is not a reason for worry. It is a small, uncertain piece of your medicine genetics, and your SLCO1B1 Val174Ala result tells you much more.