Leucocyte immunoglobulin-like receptor subfamily-B5 (LILRB5) genetic variation and statin-associated muscle symptoms: another piece in a puzzling puzzle

This editorial refers to ‘A common missense variant of LILRB5 is associated with statin intolerance and myalgia’†, by M.K. Siddiqui et al., on page 3569. Treatment with HMG-CoA reductase inhibitors (statins) is a cornerstone of pimary and secondary prevention of atherosclerotic vascular disease.1–3 In clinical practice, muscle problems occurring upon regular use of statins [statin-associated muscle symptoms (SAMS)] frequently lead to the discontinuation of statins.4–7 On the other hand, registry experience indicates that long-term adherence to statins is crucial to exploit fully the potential clinical benefit of statins.5–8 It has been a matter of debate whether or not statin treatment can in fact cause clinically relevant muscle complaints. This discussion has been fuelled by the observation that the incidence rates of SAMS in open-label registries4–7 , 9 markedly exceed the corresponding rates in very large randomized clinical trials.4–7 , 9 Randomized trials, however, may incompletely reflect clinical practice. They may exclude elderly and frail individuals, and patients with previous muscle symptoms, multiple co-morbidites, or risk factors for muscle symptoms such as alcohol consumption or a history of poor statin tolerance prior to enrolment. Further, mild muscle symptoms may not have been adjudicated as SAMS in trials. The only study specifically addressing skeletal muscle function and performance (STOMP) during statin treatment prospectively evaluated the occurrence of muscle symptoms in 420 statin-naive individuals: the incidence of myalgia was 9.4% with atorvastatin 80 mg per day for 6 months compared with 4.6% with placebo. There was a slight, but significant rate increase of average creatine kinase (CK; by 21 U/L), but no alteration of muscle strength or exercise performance.10 Hence, accounting for nocebo bias, the rate of actual statin-related muscle complications may be ∼5% overall. While nocebo effects seem to account for the majority of SAMS, the pathophysiology of the true ones appears heterogeneous and is poorly understood. Evidently, interindividual differences in the metabolism of statins along with fatcors compromising muscle integrity are contributing. For example, polymorphisms in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene are associated with the incidence of SAMS under simvastatin treatment.11 , 12 SLCO1B1 is a transporter that is responsible for the uptake of statins into hepatocytes. The SLCO1B1 polymporphism (c.521T>C, p.V174A) is associated with increased statin levels in the blood. Heterozygous carriers of the genetic variant exhibit a 4.5-fold and homozygous carriers a 17-fold increased risk of myopathy with simvastatin. In the current issue of the journal, Siddiqui and colleagues13 bring to light the missense variant rs 12975366 at the LILRB5 locus (leucocyte immunoglobulin-like receptor subfamily B5), changing Asp247 into glyine, as a new genetic modifier of the risk of SAMS. For discovery, they used two different definitions of ‘statin intolerance’, namely general statin intolerance including CK elevations as a criterion, and lowest approved daily starting dose statin intolerance, disregarding CK activity. Individuals who were on long-standing, complication-free statin treatment served as controls. This nested, extreme end strategy identified 588 and 591 cases and similar numbers of respective controls out of 11 947 statin users in the GoDARTS cohort. The LILRB5 wild-type allele Asp247 was associated with both statin intolerance phenotypes, at odds ratios of 1.81 [95% confidence interval (CI) 1.34–2.45] and 1.36 (95% CI 1.07–1.73), respectively, in a dominant model. These findings were by and large replicated using the phenotype ‘statin-induced myopathy’ in groups of 129 cases and 2501 population-based controls (CPRD-STAGE/WTCCC) and of 229 cases and 432 controls (PREDICTION-ADR), respectively. While Asp247 predisposed to the development of any myalgia in the JUPITER study, a clear effect of Asp247 on treatment limiting myalgia could not be delineated from the JUPITER study. The power and quality of genetic association studies crucially depend on the precision with which the clinical phenotype is defined. During the past few years, a multitude of definitions of ‘statin intolerance’ or ‘statin myopathy’ have been suggested, but a global consensus has not been reached.5–7 Hence, the authors did well to use two different definitions for ‘statin intolerance’ tentatively and validated their definitions against the established SLCO1B1 polymorphism. Both their approaches produced fairly consistent results. Due to the lack of a global consensus, the phenotype definitions in the three replication cohorts were different from those of the discovery cohort and heterogenous amongst each other. The numbers of cases and controls in Siddiqui’s study are still small. However, recognition should be given to the authors13 for making this effort in the best conceivable fashion, especially on the foil of the fuzziness of clinical definitions and the low frequency of statin-related myalgia, and replication is surely warranted. While CK activity is neither sensitive nor specific for SAMS, the discovery that circulating CK is related to LILRB5 genetic variation has paved the way for the study of Siddiqui et al. In this sense, the work is a classical candidate gene study with a biochemical rationale. Yet, it is an open question how closely CK itself is involed in the mechanism behind the the LILRB5 variant. Previous knowledge about the biology of LILRB5 is limited. LILR5B is part of the family of leucocyte immunoglobulin-like receptors which are cell surface immunoregulatory receptors residing on cells of the mononuclear/phagocyte system (MPS). LILR5B may assume the role of a scavenger receptor involved in the clearance of circulating enyzmes which then explained the effect of LILRB5 variants on CK activity.14 However, a link of the Asp247Gly variant to statin-induced muscle damage is not straightforward. The finding that the LILR5B genotype predicted statin intolerance independent of CK activity and also when the statin intolerance phenotype was defined independently of CK would point to mechanisms not specifically involving the CK molecule. Rather, LILR5B might directly be implicated in muscle integrity. The genotyping of some of the other 13 loci recognized to drive circulating CK14 in patients presenting with SAMS might help to distinguish between these two possibilities. Impairment of tissue repair mechanisms through LILR5B Asp247 lowering the function of CD4+Foxp3+ regulatory T cells must surely have a role. There are, however, additional mechanisms of SAMS including the statin-mediated inhibition of the mevalonate pathway potentially leading to increased catabolism of muscular proteins and decreased glucose uptake.5–7 Genetically low production of creatine (which serves to store energy as creatine phosphate) caused by variants of glycine amidinotransferase (GATM)15 and mitochondrial dysfunction due to coenzyme Q10 depletion may also predispose to SAMS. Importantly, pre-existing, asymptomatic, and rare inherited disorders of skeletal muscle can be unmasked by statin administration (Take home figure). This includes conditions such as malignant hyperthermia, carnitine palmitoyltransferase II deficiency, McArdle disease, and myoadenylate deaminase deficiency. For instance, of 110 patients with drug-induced myopathies who underwent mutation testing, 10% were heterozygous or homozygous for mutations causing one of these myopathies, and others will probably be linked to statin-induced myalgia in the future, once they are considered for the diagnostic work-up.16 Conceptual framework of factors implicated in the occurrence of statin-associated muscle symptoms (SAMS). The pathophysiology of SAMS is multifactorial. SAMS may become clinically manifest as a consequence of the interactions of frequent genetic polymorphisms at susceptibility loci, rare homozygous or heterozygous mutations causal for myopathies, and not primarily genetic factors like other morbidities or concomitant drugs. LILR5B, leucocyte immunoglobulin-like receptor subfamily-B5; SLCO1B1, solute carrier organic anion transporter family member 1B1; RYR1, ryanodine receptor 1; CPT2, carnitine palmitoyltransferase 2; PGYM, glycogen phosphorylase, muscle associated; AMPD1, adenosine monophosphate deaminase 1. Two non-genetic, yet significant groups of risk factors still need to be considered (Take home figure). First, concomitant use of drugs that interfere with statin metabolism, such as macrolides or azole antifungals, alcohol, or grapefruit juice, are well known triggers of statin-related myopathy. Secondly, there is a range of clinical factors strongly affecting risk, for instance age, sex, ethnicity, hypothyroidism, and kidney or liver disease.5–7 Taken together, statin-induced muslce symptoms appear as a multifactorial entity (Take home figure) which become manifest clinically if genetic predispositions (rare mutations and frequent polymorphisms) and non-genetic triggers exceed a certain threshold in an individual. Beyond Siddiqui’s work, future studies need to address this complexity, including, for example, rare monogenic causes of myopathy, thyroid status, alcohol consumption, or physical activity. Will testing for the LILR5B gene will be of value in the management of patients requiring statin treatment? In analogy to the SLCO1B1 polymorphism, which has a very limited specificity and a low positive predictive value, the answer is certainly ‘no’—at least as long as the LILR5B genotype is tested in isolation. However, once it is incorporated into an informative clinical algorithm also accounting for other genetic and relevant non-genetic conditions (Take home figure), the LILR5B genotype has the potential to enhance predisposition testing or diagnosis of statin-induced myopathy. Along this line, Siddiqui and colleagues13 have significantly contributed to the concept of personalized vascular medicine which holds the potential to individualize treatments and to facilitate adherence to cholesterol lowering for cardiovascular prevention.