Determinants of lipid clinic referral and attendance in a multi-ethnic adult population in south London: a cross-sectional study.

BACKGROUND: Primary dyslipidaemias, including familial hypercholesterolaemia, are underdiagnosed genetic disorders that substantially increase risk for premature coronary artery disease in adults. Early identification of primary dyslipidaemias via lipid clinic referral optimises patient management and enables cascade screening of relatives. Improving the identification of primary dyslipidaemias, and understanding disparities in ascertainment and management, is an NHS priority. We aimed to assess determinants of lipid clinic referral or attendance (LCR) in ethnically diverse adults. METHODS: We did a retrospective cross-sectional study using the Lambeth DataNet containing anonymised data from 41 general practitioner (GP) practices in south London. We looked at referral data for adult patients aged 18 years and older from Jan 1, 1995, until May 14, 2018. LCR was the main outcome. We used sequential multilevel logistic regression models adjusted for practice effects to estimate the odds of LCR assessed across six ethnic groups (reference group White) and patient-level factors (demographic, socioeconomic, lifestyle, comorbidities, total cholesterol [TC] >7·5mmol/L, statin prescription, and practice factors). The study was approved by NHS South East London Clinical Commissioning Group (CCG) and NHS Lambeth CCG. FINDINGS: 780 (0·23%) of 332 357 adult patients were coded as referred (n=538) or seen (n=252) in a lipid clinic. 164 487 (46·49%) were women (appendix). The fully adjusted model for odds of LCR showed the following significant associations for age (odds ratio [OR] 0·96, 95% CI 0·96-0·97, p<0·001); Black, African, Caribbean, or Black-British ethnicity (0·67, 0·53-0·84, p=0·001); ex-smoker status (1·29, 1·05-1·57, p=0·014); TC higher than 7·5 mmol/L (12·18, 9·60-15·45, p<0·001); statin prescription (14·01, 10·85-18·10, p<0·001); diabetes (0·72, 0·58-0·91, p=0·005); high-frequency GP attendance at seven or more GP consultations in the past year (1·49, 1·21-1·84, p<0·001); high GP-density (0·5-0·99 full-time equivalent GPs per 1000 patients; 2·70, 1·23-5·92, p=0·013). Sensitivity analyses for LCR restricted to familial hypercholesterolaemia-coded patients (n=581) found associations with TC higher than 7·5 mmol/L (4·26, 1·89-9·62, p<0·001), statin prescription (16·96, 2·19-131·36, p=0·007), and high GP-density (5·73, 1·27-25·93, p=0·023), with no significant associations with ethnicity. The relative contribution of GP practices to LCR was 6·32% of the total variance. There were no significant interactions between ethnicity and deprivation, age, or obesity. INTERPRETATION: While interpretation is limited by the accuracy and completeness of coded records, the study showed factors associated with a higher likelihood of LCR included individuals recorded as having TC higher than 7·5 mmol/L, statin prescription, ex-smoker status, high-frequency GP attendance, and registration at a GP practice with 0·5-0·99 GP density. Patients with increasing age; Black, African, Caribbean, or Black-British ethnicity patients; and patients with diabetes had lower odds of LCR. Finally, the difference in odds of LCR between Black and White patients highlights potential health inequalities. FUNDING: NHS Race & Health Observatory.

Triglycerides and cardiovascular disease.

PURPOSE OF REVIEW: Triglycerides (TGs) are measured as part of routine lipid profiles but their relationship to cardiovascular disease (CVD) risk has been controversial and overshadowed by high-density lipoprotein cholesterol (HDL-C). RECENT FINDINGS: Epidemiological studies show a clear relationship of TG-containing lipoproteins including remnant particles with CVD risk with the effect being most clearly demonstrated through the excess risk captured by non-HDL-C compared with low-density lipoprotein-cholesterol (LDL-C). Mendelian randomisation studies show a consistent relationship of gene variants linked to TG metabolism with rates of CVD. Furthermore, meta-analyses of intervention trials with statins and other nonstatin drugs also suggest that reducing TGs is associated with benefits on rates of CVD events. Historical subgroup data from fibrate trials suggest benefits in patients with high TG:HDL ratios but seem to add little to optimized statin therapy. Recent trials with omega-3 fatty acids (specifically eicosapentaenoic acid) have suggested that high-dose formulations in contrast to low dose formulations have benefits on CVD outcomes. SUMMARY: Further studies with newer agents are required to determine the place of TG-lowering drugs in therapeutic pathways. Trials with agents such as pemafibrate and vupanorsen may finally answer these questions.

Screening for patients with Gaucher's disease using routine pathology results: PATHFINDER (ferritin, alkaline phosphatase, platelets) study.

AIMS: Lysosomal ß-glucocerebrosidase A (GBA) deficiency causes Gaucher disease (GD), a recessive disorder caused by bi-allelic mutations in GBA. The prevalence of GD is associated with ethnicity but largely unknown and potentially underestimated in many countries. GD may manifest with organomegaly, bone involvement, and neurological symptoms as well as abnormal laboratory biomarkers. This study attempted to screen for GD in patients using abnormal platelet, alkaline phosphatase (ALP), and ferritin results from laboratory databases. METHODS: Electronic laboratory databases were interrogated using a 2- to 4-year time interval to identify from clinical biochemistry records patients with a phenotype of reduced platelets (<150 × 109 /L) and either elevated ALP (>130 iu/L) or ferritin [>150 (female) or >250 µg/L (male)]. The mean value over the screening window was used to reduce variability in results. A dried blood spot sample was collected for the determination of GBA activity in patients meeting these criteria. If low GBA activity was found, then the concentration of the GD-specific biomarker glucosyl-sphingosine (lyso-GB1) was assayed, and the GBA gene sequenced. RESULTS: Samples were obtained from 1058 patients; 232 patients had low GBA activity triggering further analysis. No new cases of GD with homozygosity for pathogenic variants were identified, but 12 patients (1%) were identified to be carriers of a pathogenic variant in GBA. CONCLUSIONS: Pathology databases hold routine information that can be used to screen for patients with inherited errors of metabolism. However, biochemical screening using mean platelets, ALP, and ferritin has a low yield for unidentified cases of GD.

Identification of patients with Fabry disease using routine pathology results: PATHFINDER (eGFR) study.

AIMS: Lysosomal α-galactosidase A deficiency (Fabry disease (FD)) was considered an X-linked recessive disorder but is now viewed as a variable penetrance dominant trait. The prevalence of FD is 1 in 40 000-117 000 but the ascertainment of late-onset cases and degree of female penetrance makes this unclear. Its prevalence in the general population, especially in patients with abnormal renal function is unclear. This study attempted to identify the prevalence of FD in patients with abnormal renal function results from laboratory databases. METHODS: Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of reduced estimated glomerular filtration rate categorised by age on one occasion or more over a 3-year time interval. Patients were recalled and a dried blood spot sample was collected for the determination of α-galactosidase A activity by fluorimetric enzyme assay in men and mass spectrometry assays of α-galactosidase A and lyso-globotriaosylceramide (lyso-GL-3) concentrations in women. RESULTS: Samples were obtained from 1084 patients identified with reduced renal function. No cases of FD were identified in 505 men. From 579 women, one subject with reduced α-galactosidase activity (1.5 µmol/L/h) and increased Lyso-GL-3 (5.5 ng/mL) was identified and shown to be heterozygous for a likely FD pathogenic variant (GLA c.898C>T; p.L300F; Leu300Phe). It was later confirmed that she was a relative of a known affected patient. CONCLUSIONS: Pathology databases hold routine information that can be used to identify patients with inherited errors of metabolism. Biochemical screening using reduced eGFR alone has a low yield for unidentified cases of Fabry Disease.

Reorganizing the treatment of cardiovascular disease in response to coronavirus disease 2019; time for the polypill?

PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID-19) pandemic has forced a redesign of healthcare services. Resource reallocation will have consequences on the routine management of chronic diseases, including cardiovascular disease (CVD). We consider how to mitigate potential adverse effects. RECENT FINDINGS: Combination therapy is well established in hypertension. Many guidelines recommend dual antihypertensive therapy as the initial treatment step as this results in faster blood pressure control, albeit with limited evidence of improved outcomes. Control of CVD risk factors through multiclass combination therapy (the polypill) was proposed many years ago. This approach has not been adopted by Western healthcare systems despite improving surrogate outcomes. Recently, the PolyIran trials have demonstrated improved CVD outcomes without increased adverse events, in both primary and secondary prevention. SUMMARY: The COVID-19 pandemic allows models of chronic healthcare to be rethought. Current practices are resource-intensive and there is a need to simplify titration and monitoring protocols in CVD. Moving toward the use of polypill combinations allied with telehealth consultations may be one solution.

Low cholesterol syndrome and drug development.

PURPOSE OF REVIEW: Low cholesterol syndromes were considered curiosities. The present article reviews some hypolipidaemic disorders and the drugs developed from the insights they provided. RECENT FINDINGS: Abetalipopoproteinaemia and hypobetalipoproteinaemia are associated with low cholesterol concentrations and caused by mutations in apolipoprotein (apo) B or microsomal transfer protein. This led to the development of mipomersen and lomitapide which are used to treat homozygous familial hypercholesterolaemia. Mutations in proprotein convertase subtilisin kexin-9 (PCSK9) can cause either high or low cholesterol. Loss of function PCSK9 mutations prompted the development of antibody therapies to PCSK9 which are now widely used to treat hypercholesterolaemia. Mutations in apolipoprotein C-3 and angiopoietin-like protein 3 (ANGPTL3) cause hypolipoproteinaemia and reduced triglycerides. Antisense therapies to apolipoprotein C-3 and antibodies to ANGPTL3 are in development to treat familial chylomicronaemia syndrome. Activating mutations in apoA-1 result in hyper-functioning high-density lipoprotein (HDL) and suggest that modifying HDL turnover may reduce cardiovascular disease (CVD) risk. SUMMARY: Orphan lipid disorders have provided insights into mechanisms involved in lowering cholesterol levels and the potential safety and efficacy of interventional processes. They have been not only enabled development of drugs to treat rare lipid disorders but also those finding wider use in general lowering of CVD risk.

Genetic risk scores in lipid disorders.

PURPOSE OF REVIEW: Extensive work has gone into understanding the genetics of cardiovascular disease (CVD) and implicating genes involved in hyperlipidaemia. Translation into routine practise involves using genetic risk scores (GRS) to identify high-risk individuals in the general population. Some of these risk scores are beginning to disentangle the complex nature of CVD and inherited dyslipidaemias. RECENT FINDINGS: GRS of varying complexity have been used to identify high-risk groups of patients with polygenic CVD including some individuals with risk equivalent to monogenic disease. In phenotypic familial hypercholesterolaemia a six or 12 gene lipid GRS may identify polygenic cases that comprise up to 50% of cases. In high triglyceride syndromes including even cases of familial chylomicronaemia syndrome more than 80% of cases are polygenic and not even associated with rare variants. In both familial hypercholesterolaemia and familial chylomicronaemia syndrome individuals with polygenic disease have a lower risk than those with monogenic disease. SUMMARY: GRS show promise in identifying individuals with high risks of CVD. They have a close relationship with imaging markers. It is unclear whether GRS, imaging or both will be used to identify individuals at high risk of future events.

An update on trials of novel lipid-lowering drugs.

PURPOSE OF REVIEW: A number of novel trials have assessed the efficacy of new lipid-lowering therapies in cardiovascular disease (CVD). RECENT FINDINGS: Proprotein convertase subtilisin kexin-9 inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 50-55%. A CVD outcome trial in patients with acute coronary syndromes with evolocumab achieved a LDL-C of 0.8 mmol/l (31 mg/dl) and a 20% relative risk reduction in CVD events in 2.2 years. Cholesterol ester transfer protein inhibitors raise high-density lipoprotein cholesterol and can lower LDL-C. Anacetrapib reduced coronary artery disease events by 7%, but not wider composite CVD outcomes, in a population with chronic CVD with pretreatment LDL-C of 1.6 mmol/l (62 mg/dl). The conflicting outcomes of cholesterol ester transfer protein inhibitor trials means these compounds are not being developed further. Trials using lipid drugs targeting inflammation have previously been generally unsuccessful, but recent data on the interleukin-1B receptor antagonist canakinumab has proven the concept of intervention on inflammation in atherosclerosis by showing a reduction in acute coronary interventions, but at the predictable cost of increased infections. SUMMARY: Despite the success of proprotein convertase subtilisin kexin-9 inhibition, the ability to achieve low LDL-C with off-patent medications and the costs of novel therapies will limit their use even in high-risk patients and confine them to the highest-risk sub-groups of patients.

Demand management of weekend haematology and clinical biochemistry requests.

BACKGROUND: Increasing demand for laboratory testing at weekends is common but little is known about its appropriateness. METHODS: An audit was conducted in a large district hospital of routine haematology and clinical biochemistry requests ordered over two weekends. Appropriateness was assessed by review of ordered tests compared with clinical records by a qualified chemical pathologist. RESULTS: Profiles requested on phlebotomy included full blood count (76%), renal profile (91%), C-reactive protein (41%), liver function tests (18%) and another test in 18%. Phlebotomy was likely unnecessary in 47.5% of episodes while 60.8% of requested assays were graded probably unnecessary or unnecessary. At ward level the number of requests averaged 37 (median 32; range 2-76) totalling 446 separate profiles or assays. There was no difference in phlebotomy requests by ward (P = 0.19). Differences were observed in ordered tests (P = 0.005) which were caused by one outlier ward with a low request rate. CONCLUSIONS: A large number of unnecessary common tests seem to be carried out at weekends as part of the routine care. Implementation of demand management through education and if necessary electronic limitation of requests may be useful to control laboratory workloads.

Review of referral criteria to lipid clinics and outcomes of treatment in four UK centres.

BACKGROUND: Little data exist on the referral patterns and effectiveness of lipid clinics. METHODS: An audit was conducted in four clinics of 100 consecutive referrals each. Data were recorded on referral criteria, cardiovascular disease (CVD) risk factors, drug history, investigations, diagnoses, therapies, results and referrals. RESULTS: Patients were aged 56 ± 14 years, 47% were male and 87% were primary prevention. Risk factors included smoking (16%), type 2 diabetes (13%) and hypertension (13%). Referrals were made for hypercholesterolaemia (68%), diagnosis of FH (31%), statin intolerance (23%) and hypertriglyceridaemia (23%). Initial total cholesterol (TC) was 7.65 ± 2.64 mmol/L, triglycerides (TG) 2.17 (0.41-76.9 mmol/L) mmol/L, HDL-C 1.53 ± 0.71 mmol/L, LDL-C 4.57 ± 1.66 mmol/L with non-HDL-C 5.90 ± 2.09 mmol/L. Criteria for FH were met in 21% with genetic testing in 13% and lipid cascade testing in 30% of index cases. Triglycerides >20 mmol/L were present in 4%. The diagnosis was changed in 21%: hypercholesterolaemia (7%), mixed hyperlipidaemia (7%) and hypertriglyceridaemia (7%). Hepatic steatosis was identified in 14.5%. Lipoprotein(a) levels >125 nmol/L occurred in 41% in one clinic. Therapy changes included altered statins (40%), addition of a fibrate (11%) or ezetimibe (8%). These reduced TC by 1.92 mmol/L (19%; P = 0.0001), LDL-C 1.07 mmol/L (15%; P = 0.02), non-HDL-C 1.50 mmol/L (16%; P < 0.001), and TG 2.3 (-4 to 38) mmol/L (16%; P < 0.001) with 11% extra achieving TG <5 mmol/L while HDL-C increased by 7% (P = 0.37). CONCLUSIONS: Lipid clinics have diverse functions including diagnosis of FH, managing severe hypercholesterolaemia, mixed hyperlipidaemia and statin intolerance. Effectiveness criteria of average reductions of 1.5 mmol/L in TC or non-HDL-C, 1 mmol/L in LDL-C and 2 mmol/L in TG would be reasonable for newly referred patients.

The challenges of proprotein convertase subtilisin-kexin-9 inhibitors for lipid guidelines and models of care.

PURPOSE OF REVIEW: The article reviews the challenges facing cardiovascular disease (CVD) guidelines committees. RECENT FINDINGS: Clinical trials in high-risk populations have shown additional CVD event reduction with ezetimibe and proprotein convertase subtilisin-kexin-9 inhibitors. These trials recruit middle-aged secondary prevention populations, whereas increasingly the population at risk of CVD comprises the elderly in primary prevention. Some major guidelines have moved from a lipid-target to a risk-based approach. Some guidelines wish to preserve treatment targets to optimize the risk profile of individual patients as opposed to using population-based approaches. A numbers needed to treat approach has been suggested as a way of prioritizing patients for treatment, while retaining an individual's LDL cholesterol risk. However, the main barrier to implementation of some novel therapies in medicine is not their efficacy or safety but their cost. Health economic approaches that consider both benefits and costs can help guideline committees to define populations mostly likely to benefit. SUMMARY: The efficacy and expense of novel treatments is challenging traditional guideline development. Previously guideline committees used only to review clinical efficacy and safety endpoints but now they also have to consider costs to derive recommendations that are practical to implement.

Radiotherapy, chemotherapy and atherosclerosis.

PURPOSE OF REVIEW: This article reviews the effects of radiotherapy and chemotherapy in promoting the progression of atherosclerosis in patients with cancer. RECENT FINDINGS: Radiotherapy is associated with an increase in the incidence of atherosclerosis with the effects being related to the site of irradiation and dose of radiotherapy. Cranial irradiation is associated with dyslipidaemia and the metabolic syndrome secondary to effect on growth hormone secretion. Chemotherapeutic oncological therapies are associated with numerous cardiac diseases including valve disease, pericarditis and cardiomyopathy but can also promote atherosclerosis. Therapies directed against vascular endothelial growth factor including tyrosine kinase inhibitors have a direct effect in raising blood pressure and increase rates of cardiovascular disease (CVD) events. Antimetabolites such as 5-fluorouraciland capecitabine cause chest pain and increase CVD events. Anthracyclines cause heart failure and may increase CVD risk. SUMMARY: There is increasing evidence that radiotherapy and some chemotherapeutic agents are associated with increased rates of CVD. Patients who have received treatment for cancer should be considered at higher risk of developing atherosclerosis and require increased monitoring, further investigation and earlier treatment than would be suggested by classical risk factor management strategies.

Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres.

BACKGROUND: Prescribing criteria have been suggested for proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors but few studies exist of their real-world effectiveness. METHODS: This study audited PCSK-9 inhibitor therapy in 105 consecutive patients from two hospital centres-a university hospital (UH; n = 70) and a district general hospital (DGH; n = 35). Baseline characteristics including cardiovascular disease risk factors, NICE qualification criteria, efficacy and side effects were assessed. RESULTS: Baseline LDL-C levels were similar in both centres. NICE criteria were met for 2.05 items in the whole study (UH patients 1.7 and DGH patients 2.7). District general hospital patients were more likely to have familial hypercholesterolaemia (89 vs 69%; P = .02); intolerance to statins (94 vs 52%; P < .001) and polyvascular disease (42% vs 17%; P = .005). Prescriptions (evolocumab 73%; alirocumab 23%) were collected by 76% of patients (UH 64% vs DGH 100%). Therapy was discontinued by time of review in 15% of patients (UH 7% vs DGH 25%; P = .02). In adherent patients PCSK-9 inhibitor treatment reduced TC by 28% (2.24 ± 2.39 mmol/L; P < .001) and LDL-C by 49% (2.10 ± 1.33 mmol/L; P < .001). A LDL-C < 2.5 mmol/L was achieved in 30% of patients and <2.0 mmol/L in 20%. PCSK-9 therapy was effective and safe in patients with increased lipoprotein (a), diagnosed muscle diseases (including myopathies and muscular dystrophy) or poststatin rhabdomyolysis, nephrotic syndrome or HIV disease. Mixed results were obtained in patients with significant mixed hyperlipidaemia. CONCLUSIONS: This study suggests that PCSK-9 inhibitors are effective but that prescriptions should not be changed to long-term delivery until patients have been reviewed and shown to be adherent.

Statin myopathy: over-rated and under-treated?

PURPOSE OF REVIEW: Statins are recommended as first-line therapy for cardiovascular disease. Unfortunately, a proportion of patients cannot tolerate these drugs because of muscle-related side-effects. This review summarizes the definition of statin-related muscle disorders, aetiological factors, and recommended management strategies. RECENT FINDINGS: A number of consensus groups have defined and classified statin-related muscle disorders, whereas others have suggested diagnostic and management strategies. Mechanisms behind statin-related muscle toxicity have been identified. Therapeutic and clinical investigation pathways have been reviewed and algorithms defined. New drugs have become available to reduce low-density lipoprotein cholesterol levels that are not associated with causing muscle side-effects. SUMMARY: Statin-related muscle side-effects are common. Secondary causes of muscle disease unmasked by statin therapy should be identified. Most patients can be managed by adjustment of standard treatment protocols.

The hinterland of familial hypercholesterolaemia: what do we not know?

PURPOSE OF REVIEW: Familial hypercholesterolaemia is the commonest autosomal dominant disorder in man, but many questions about familial hypercholesterolaemia remain to be answered. Guidelines are increasing in importance as healthcare becomes standardized. The review suggests areas that require more investigation or where pertinent guidelines may need to be reviewed. RECENT FINDINGS: Familial hypercholesterolaemia is commoner than previously thought, but its epidemiology needs further investigation against a background of changing environmental and lifestyle factors that may bear on its phenotypic expression. Screening for familial hypercholesterolaemia may be more difficult than might be thought as cascade testing may not capture all cases effectively and universal screening appears compelling, but requires testing and evaluation. Cardiovascular disease guidelines are moving to being risk based, but familial hypercholesterolaemia stands alone as defined by large database of lipids-cholesterol criteria. A risk-based approach may need to be considered for familial hypercholesterolaemia, but a good evidence base is required. The effects of older therapies on prognosis in familial hypercholesterolaemia are based on surrogate as opposed to cardiovascular disease outcomes. Novel efficacious but expensive therapies are on the horizon, but no specific outcome trials in familial hypercholesterolaemia are planned and they may not be cost-effective outside very severe familial hypercholesterolaemia. Further research is also required to trial and test different models of care for familial hypercholesterolaemia. SUMMARY: Despite familial hypercholesterolaemia being a common genetic condition, aspects of basic epidemiology, risk assessment, treatment, and models of care remain uncertain.

Prioritizing health outcomes in a limited world: writing lipid guidelines.

PURPOSE OF REVIEW: Guidelines are increasing in importance as healthcare becomes standardized. This article examines the processes by which the new US American College of Cardiology-American Heart Association and UK National Institute of Health and Care Excellence lipid guidelines came to their conclusions and how the nature of the evidence base and health economics contributed to the recommendations made. RECENT FINDINGS: The writing of guidelines is becoming a systematic formal process with increasing emphasis on maintaining integrity, minimizing conflicts of interest and using consistent systematic methods to define the evidence base, grade its quality and then make recommendations. These processes are illustrated by showing why new cardiovascular disease risk assessment tools were required, what recommendations could be made about diet and lifestyle, why a fixed-dose drug treatment protocol as opposed to a target-based approach was recommended for the management of patients in secondary prevention, diabetes and primary prevention and how these would impact clinical practice. SUMMARY: Modern systematic evidence assessment and economic appraisal convincingly favour the use of lipid-lowering drugs especially statins at higher doses than currently prescribed in secondary prevention and at lower risk thresholds in primary care than previously imagined. As long-term adherence to treatment is required patient choice is key to realizing the benefits of these interventions.

The origin, global distribution, and functional impact of the human 8p23 inversion polymorphism.

Genomic inversions are an increasingly recognized source of genetic variation. However, a lack of reliable high-throughput genotyping assays for these structures has precluded a full understanding of an inversion's phylogenetic, phenotypic, and population genetic properties. We characterize these properties for one of the largest polymorphic inversions in man (the ∼4.5-Mb 8p23.1 inversion), a structure that encompasses numerous signals of natural selection and disease association. We developed and validated a flexible bioinformatics tool that utilizes SNP data to enable accurate, high-throughput genotyping of the 8p23.1 inversion. This tool was applied retrospectively to diverse genome-wide data sets, revealing significant population stratification that largely follows a clinal "serial founder effect" distribution model. Phylogenetic analyses establish the inversion's ancestral origin within the Homo lineage, indicating that 8p23.1 inversion has occurred independently in the Pan lineage. The human inversion breakpoint was localized to an inverted pair of human endogenous retrovirus elements within the large, flanking low-copy repeats; experimental validation of this breakpoint confirmed these elements as the likely intermediary substrates that sponsored inversion formation. In five data sets, mRNA levels of disease-associated genes were robustly associated with inversion genotype. Moreover, a haplotype associated with systemic lupus erythematosus was restricted to the derived inversion state. We conclude that the 8p23.1 inversion is an evolutionarily dynamic structure that can now be accommodated into the understanding of human genetic and phenotypic diversity.