rs4841132 — PPP1R3B

PPP1R3B rs4841132 — The Hepatic Glycogen Switch

Most people associate liver disease with fat. Yet for carriers of the minor A allele at rs4841132, the primary problem begins one step earlier in liver metabolism: the regulation of glycogen¹¹ glycogen
The body's main short-term glucose storage molecule. The liver stores glycogen and releases glucose into the blood between meals to maintain stable blood sugar levels synthesis and breakdown. This variant is in complete linkage disequilibrium²² linkage disequilibrium
LD: the tendency of nearby genetic variants to be inherited together. Two SNPs in complete LD are interchangeable genetic markers for the same underlying biological signal with rs4240624, and the two positions tag the same PPP1R3B signal. The landmark Stender 2018 study (n=112,428) used rs4841132 as the primary tagging SNP, making it the most directly-cited variant for this locus in the literature.

PPP1R3B encodes a regulatory subunit of protein phosphatase 1 (PP1), a master switch that governs glycogen synthesis and breakdown in the liver. The A allele at rs4841132 — carried by roughly 9% of Europeans and up to 20% of people of Latino ancestry — influences how much glycogen the liver stores, pushing the balance toward accumulation. The downstream effects extend beyond glycogen: elevated liver enzymes, increased hepatic glycogenosis susceptibility, and a meaningful increase in gallstone risk have all been documented across large population studies.

The Mechanism

Protein phosphatase 1³³ Protein phosphatase 1
PP1: one of the most abundant phosphatases in the body, involved in glycogen metabolism, muscle contraction, protein synthesis, and many other processes. Its activity is tightly regulated by dozens of binding proteins (PP1) is a central regulator of glycogen metabolism. PPP1R3B acts as a glycogen-targeting subunit that directs PP1 to two key enzymes: glycogen synthase (which builds glycogen) and glycogen phosphorylase (which breaks it down). By activating glycogen synthase and inhibiting glycogen phosphorylase, PPP1R3B tips the liver toward glycogen storage.

The rs4841132 A allele is a near-gene regulatory variant — annotated as a non-coding transcript variant affecting the LOC157273 lncRNA locus adjacent to PPP1R3B — that increases PPP1R3B activity or expression. Mouse studies confirm the mechanism directly: overexpression of PPP1R3B causes hepatic glycogen accumulation and elevated plasma ALT, while knockouts produce glycogen-deficient livers. In humans, the minor A allele is associated with increased hepatic X-ray attenuation — a hallmark of glycogen loading — and elevated liver enzymes across the large Stender 2018 cohort.

Importantly, the excess glycogen from this variant does not appear to directly increase hepatic triglyceride content. This distinguishes the PPP1R3B signal from the well-known PNPLA3 rs738409 variant, which directly promotes liver fat accumulation. Instead, the effect reflects hepatic glycogenosis⁴⁴ hepatic glycogenosis
Abnormal glycogen accumulation in the liver. Can cause hepatomegaly and elevated liver enzymes, and is associated with metabolic syndrome even in the absence of excess fat, a condition independently harmful even without steatosis.

Because rs4841132 and rs4240624 are in complete LD, they measure the same biological effect. Individuals genotyped at either position carry the same functional risk information. rs4841132 is included in the GeneOps database because it is the primary rsid analyzed in the Stender 2018 landmark study and is present on chip platforms where rs4240624 may not be represented.

The Evidence

The foundational work comes from Stender et al. 2018⁵⁵ Stender et al. 2018
Stender S, Smagris E, et al. "Relationship between genetic variation at PPP1R3B and levels of liver glycogen and triglyceride." Hepatology, 2018, which analyzed 112,428 participants across three large cohorts. The minor A allele at rs4841132 showed consistent ALT elevation (P = 3×10⁻⁴ in the Copenhagen cohort; P = 0.004 in the Dallas Heart Study), and liver disease odds ratios of 1.13–1.23. Crucially, no association was found with hepatic triglyceride content, pointing specifically at glycogen as the culprit. This study explicitly identifies rs4841132 as being in complete LD with rs4240624 and uses both rsids to describe the same locus.

Hernaez et al. 2013⁶⁶ Hernaez et al. 2013
Hernaez R, McLean J, et al. "Association between variants in or near PNPLA3, GCKR, and PPP1R3B with ultrasound-defined steatosis." Clin Gastroenterol Hepatol, 2013 used NHANES III data (n=4,804) and found an OR of 1.28 (P=.03) for ultrasound-defined hepatic steatosis in non-Hispanic white adults — suggesting that glycogen accumulation in the liver may mimic the appearance of steatosis on standard ultrasound, even when triglycerides are not elevated.

The 2021 Männistö study (n=242 bariatric surgery patients) found that risk-allele carriers produced dramatically different bile acid profiles and that 13 of 17 bile lipid classes were elevated in carriers — a pattern that mirrors bile composition in gallstone patients.

Practical Actions

The primary lever for managing hepatic glycogen burden is dietary carbohydrate quality and quantity. The liver processes dietary carbohydrates — and especially fructose — almost exclusively, making this the highest-impact dietary modification for A-allele carriers. Prioritize low-glycemic carbohydrate sources (vegetables, legumes, lentils, barley) over refined carbohydrates and added sugars. Minimize fructose from sugary beverages, fruit juice, and high-fructose sweeteners.

Annual liver enzyme monitoring (ALT/AST) is warranted for heterozygous carriers; homozygous AA carriers should pursue a more thorough evaluation including discussion of hepatic imaging. Mildly elevated ALT in the absence of alcohol use or obesity should be flagged as potentially related to hepatic glycogen accumulation.

Gallstone risk is elevated for A-allele carriers, particularly in the context of obesity or planned rapid weight loss, which can mobilize bile cholesterol and precipitate stone formation.

Interactions

rs4841132 and rs4240624 are in complete LD and represent the same functional signal at the PPP1R3B locus. Carrying risk alleles at this locus is expected to have additive effects with PNPLA3 rs738409 (hepatic fat accumulation via a distinct lipid pathway) and GCKR rs780094 (impaired hepatic glucose sensing and elevated triglycerides). Individuals with risk alleles across these three genes face compounding liver stress through glycogen overload (PPP1R3B), lipid dysregulation (PNPLA3), and altered glucose metabolism (GCKR).