Porcine ear necrosis is associated with social behaviours in weaned piglets.

BACKGROUND: Porcine ear necrosis (PEN) is a worldwide health issue and its aetiology is still unclear. The aim of this study was to describe the prevalence and the severity of PEN in a commercial farm, associated with pig behaviour and health biomarkers measures. On two consecutive batches, PEN prevalence was determined at the pen level. PEN scores, blood haptoglobin concentration and oxidative status were measured on two pigs per pen (n = 48 pens) 9, 30 and 50 days (D) after arrival to the post-weaning unit. Social nosing, oral manipulation and aggression of pen mates and exploration of enrichment materials were observed on two to three pigs per pen twice a week from D9 to D50. RESULTS: At the pen level, the higher the time spent nosing pen mates, the lower the percentage of pigs affected by PEN during both the early and the late post-weaning periods (P < 0.002) and, in the opposite, the higher the time spent orally manipulating pen mates during the late post-weaning period, the higher the percentage of affected pigs (P = 0.03). At the pig level, the higher the increase in hydroperoxides and haptoglobin during the early post-weaning period, the higher the PEN scores on D30 (P < 0.001). CONCLUSIONS: This study suggests that a high incidence of social nosing, which can be an indicator of good social cohesion in a group, was significantly associated with less frequent lesions of PEN. In opposite, high incidence of oral manipulation of pen mates may increase the percentage of PEN-affected pigs. According to these observations, PEN is a multifactorial condition which may have social causes among others.

Alternative Samples for Porcine Reproductive and Respiratory Syndrome Surveillance in an Endemic PRRSV-1-Infected Breeding Herd: A Descriptive Study.

Knowing porcine reproductive and respiratory syndrome (PRRS) status is essential for designing herd management protocols. For this, weaning-age pigs are a key subpopulation. Recently, different alternatives to blood sampling have been introduced because they are easier, welfare-friendly and cost-saving tools. Moreover, most of them allow the testing of more animals and seem to be more sensitive in low-prevalence scenarios. However, these studies were implemented mainly in PRRSV-2-infected herds. The first objective of our study was to compare the rate of detection of PRRSV-1 by RT-qPCR in individual serum samples, family oral fluid samples (FOF) and udder wipes (UW) collected the day before weaning. The second objective was to evaluate the suitability of pooling. The study was performed on a 210-sow farrow-to-finish farm which was PRRSV-1 infected and unstable. A total of 119 litters were sampled. The rate of detection of PRRSV-1 in blood samples, FOF and UW was 10.9%, 7.6% and 0.8%, respectively. The agreement between sera and FOF was almost perfect even if the detection capacity of sera was numerically superior to FOF. The Ct values of positive sera were statistically lower than those of FOF. Two modalities of pooling (1:3 and 1:5) were tested for sera and FOF. For sera, both modalities did not impact the PRRSV-1 status either at the litter level or at the batch one. On the other hand, whatever the modality (pooled by 3 or 5), most of the pools of FOF gave negative results, misclassifying many litters and batches.

PRRSV-1 Stabilization Programs in French Farrow-to-Finish Farms: A Way to Reduce Antibiotic Usage.

Infection with the porcine reproductive and respiratory syndrome virus type 1 (PRRSV-1) has serious economic consequences for the pig industry. Swine practitioners and other agricultural advisors often describe an increase in antibiotic use when PRRSV-1 is circulating. Our objective was to assess the impact of PRRSV-1 stabilization programs on reducing antibiotic use in 19 French farrow-to-finish farms that successfully implemented such a protocol between 2007 and 2019. For each farm, we compared the global antibiotic consumption, including all physiological stages (expressed in mg/PCU and ALEA) one year before (P1) and one year after (P2) the implementation of the protocol, and the change between P1 and P2 was calculated in percentages. The data were also analyzed by level of consumption. We showed that antibiotic use decreased significantly between P1 and P2 if expressed in mg/PCU and showed a decreased tendency in terms of exposure (ALEA) after PRRSV-1 stabilization. Concerning the change from P1 to P2, depending on the level of consumption in P1, our results showed that the higher the consumption levels were in P1, the greater the antibiotic reduction in P2. This study highlights the ability of a stabilization protocol against PRRSV-1 to reduce antibiotic use, especially on farms that have high consumption rates. These hopeful results show that further investigations about the relationship between PRRSV-1 and antibiotic usage could be beneficial.

PRRSV Detection by qPCR on Serum Samples Collected in Due-to-Wean Piglets in Five Positive Stable Breeding Herds Following a Sow Mass Vaccination with a Modified Live Vaccine: A Descriptive Study.

Data concerning PRRSV-1 vaccine virus strains dissemination within vaccinated sow herds are scarce. However, it is a big concern for swine practitioners when designing the PRRSV diagnostics strategy in vaccinated farms. At the same time, the possibility of vaccine virus transmission from sows to their offspring is important to have in mind in order to limit the risk of recombination between different PPRSV-1 modified live virus vaccine (MLV1) when both sows and piglets have to be vaccinated. This study was conducted in five PRRSV-stable breeding herds. The selected farms presented different characteristics regarding production parameters and biosecurity management practices in order to be, as much as possible, representative of French swine production herds. In four different batches following a sow mass vaccination with a PRRSV-1 modified live virus vaccine (ReproCyc® PRRS EU, Boehringer Ingelheim, Ingelheim, Germany), we failed to detect the vaccine virus in due-to-wean piglets in all of the herds. This should mean that the dissemination of the vaccinal strain is a rare event, even just after a sow vaccination, at least for the vaccine tested in our study.

Microbiological Findings and Associated Histopathological Lesions in Neonatal Diarrhoea Cases between 2020 and 2022 in a French Veterinary Pig Practice.

This retrospective study described the aetiologies of neonatal diarrhoea cases and their associations with histological findings. A total of 106 diarrhoeic neonatal piglets were selected. Cultures, MALDI typings, PCRs and evaluation of intestinal lesions were performed. A total of 51 cases (48.1%) were positive for only one pathogen and 54 (50.9%) were positive for more than one pathogen. Clostridium perfringens type A was the most frequently detected pathogen (61.3%), followed by Enterococcus hirae (43.4%), rotavirus type A (38.7%), rotavirus type C (11.3%) and enterotoxigenic Escherichia coli (3.8%). Only lesions in the small intestine were correlated with detected pathogens. The detection of rotavirus was associated with an increased probability of observing villous atrophy (p < 0.001), crypt hyperplasia (p = 0.01) and leucocyte necrosis in the lamina propria (p = 0.05). The detection of Clostridium perfringens type A was associated with an increased probability of observing bacilli in close proximity to the mucosa (p < 0.001) and a decreased probability of observing epithelial necrosis (p = 0.04). Detection of Enterococcus hirae was associated with an increased probability of observing enteroadherent cocci (p < 0.001). Multivariate regression logistic models revealed that epithelial necrosis was more likely to occur in Enterococcus hirae-positive piglets (p < 0.02) and neutrophilic infiltrate was more likely to occur in Clostridium perfringens type A- and Enterococcus hirae-positive piglets (p = 0.04 and p = 0.02, respectively).

Microbial content of non-fermented liquid feed consumed by sows affects the occurrence of neonatal diarrhoea in their piglets: A case-control study.

BACKGROUND: Microbial colonisation of piglets' intestines starts at birth, especially from contact with sow's faeces. Piglet microbiota could therefore be influenced by the sow's diet. The objective of this study was to evaluate whether the microbiological flora of liquid feed for sows can be associated with the development of neonatal diarrhoea. METHODS: This study was carried out on 10 case farms with neonatal diarrhoea and 10 control farms without neonatal diarrhoea. On each farm, a microbiological analysis of gestating and lactating liquid feed was performed. A generalised linear model was used to study the impact of the liquid feed microbiological counts and pH on the probability of neonatal diarrhoea developing. RESULTS: For thermotolerant coliforms, sulphite-reducing bacteria, heterotrophic bacteria and lactic-acid bacteria counts, there was no significant difference between case and control farms. The higher the count of total coliforms, enterococci and yeasts in sow non-fermented liquid feed, the greater the probability of observing neonatal diarrhoea. Moreover, taking into account total coliforms and yeasts counts together is highly predictive of neonatal diarrhoea risk. CONCLUSION: This study offers new perspectives of investigation and understanding of neonatal diarrhoea in breeding farms feeding sows with a non-fermented liquid feed.

Haematological reference intervals of sows at end gestation in ten French herds, the impact of parity on haematological parameters and the consequences on reproductive performance.

BACKGROUND: Changes in haematological values occur during the reproductive cycle. In veterinary swine practice, haematological reference intervals for this period are scarce. Over past decades, there has been a remarkable increase in reproductive prolificacy, possibly making previously established haematological reference intervals for sows outdated. OBJECTIVES: The aim of this study was to provide updated haematological reference intervals for sows at end-gestation, to study the influence of parity on those haematological parameters and to evaluate the impact of haemoglobin levels on production performance. METHODS: The data presented in this article were obtained using blood samples from 198 apparently healthy and conventionally managed group-housed sows at end-gestation from ten breeding herds located in France. The samples were analysed for haematological variables using impedance technique on Horiba ABX analyser (Horiba, Kyoto, Japan). The reference intervals were calculated according to the guidelines of The American Society for Veterinary Clinical Pathology using SUMMARY procedure in R Studio. Analysis of variance (ANOVA) models were used to evaluate the influence of parity on each haematological parameter and the impact of haemoglobin values on production performances at farrowing. Differences were considered as significant if p < 0.05. RESULTS: Reference intervals produced in this study were similar to previously published references but we noticed marked differences in white blood cell values. The study of the impact of parity revealed significant changes for gilts and parity 5 + sows regarding haematological values. Gilts had higher red and white blood cells counts, haemoglobin values and haematocrit values. Regarding haemoglobin values, the higher the number of liveborn and weaned piglets per litter, the lower the haemoglobin value at end-gestation. For sows of fifth or higher gestation, we found that the higher the percentage of stillborn piglets, the lower the haemoglobin value at end-gestation. CONCLUSIONS: This study provides haematological reference intervals for sows at end-gestation. These will be useful for swine veterinarians and researchers for a better understanding of the influence of parity on haematological parameters and haemoglobin values and their relation to reproductive performance.

Effectiveness of two intramuscular combined vaccines for the control of Mycoplasma hyopneumoniae and porcine circovirus type 2 in growing pigs: a randomized field trial.

BACKGROUND: Mycoplasma hyopneumoniae and Porcine circovirus type 2 are two economically important pathogens affecting growing pigs. Control and prevention of both diseases can be accomplished by vaccination, together with biosecurity and good management practices. Many commercial vaccines are available. The aim of this study was to assess the efficacy of Hyogen® and Circovac® administered mixed at weaning and to compare this protocol with a competitor ready-to-use (RTU) vaccine. CASE PRESENTATION: A randomised field trial was designed in a commercial farrow-to-finish farm located in France. A total of 641 pigs born from 54 different sows were included in this study. Piglets at weaning were allocated into three groups: the first one vaccinated with Hyogen® and Circovac® combined (group A), the second one vaccinated with a competitor RTU vaccine (group B) and the last one unvaccinated. Only minor local reactions for both vaccination groups could be observed which revealed a good safety of both protocols. Both vaccination schemes in this trial didn't improve wean-to-slaughter growth performances but significantly reduced lung lesions, lung fissures and pleurisy at slaughter, produced a seroconversion for both M. hyopneumoniae and PCV-2 and significantly reduced the PCV-2 viral load in blood. When we compared groups A and B, we observed no significant differences in growth performances, mortality, clinical signs, percentages of affected lungs at slaughter, lung fissures and pleurisy, and no difference in pathogens detection. However, two statistical differences were observed between both vaccines: the mean lung lesion score and the percentage of extensive lung lesions were lower in group A. This is consistent with lower M. hyopneumoniae loads in the lower respiratory tract in pigs from group A but this difference was not statistically significant. CONCLUSIONS: Results reported in this case study must be considered with caution since it was done in only one farm. In this trial, Hyogen® and Circovac® mixed together under field conditions offered a successful protection of growing pigs and significantly decreased the extension of lung lesions during a natural field challenge when compared with a competitor RTU vaccine.

Feasibility of pooled oral fluid collection from pre-weaning piglets using cotton ropes.

Collection of pooled oral fluid (OF) by allowing pigs to chew on a cotton rope is an alternative to blood sampling. However, little is known about the applicability of this method to suckling piglets. The objectives of the present study were to describe the spontaneous interaction of suckling piglets with a rope and to investigate the influence of a rope pre-exposure on the success rate of sampling. We studied the interaction dynamics of 21 and 28 days-old suckling piglets with a cotton rope presented for 30 min. Ropes were manually wrung out inside plastic bags to release the oral fluid. A total of 49 litters were included. Percentages of success of pooled OF collection for 28-day-old, 21-day-old and 21-day-old pre-exposed litters were 82%, 62% and 100%, respectively. The mean volume collected did not differ between groups. Without pre-exposure, 84.7% and 95% of piglets interacted spontaneously with the rope at 21 and 28 days of age, respectively. The latency between rope presentation and interaction was highly variable between piglets within litters: from < 10 s to 30 min. Among piglets having interacted with the rope, the interaction lasted for at least 60 s for 90% and 91.4% of 21 and 28-day-old piglets, respectively. Pooled OF collection is achievable prior to weaning in piglets of at least 21 days of age. Pooled OF sampling is representative at litter level if collection is successful. In order to improve the success rate of collection, pre-exposing the piglets with a rope one day prior to sampling is effective.

Comparison of qPCR and blood smear microscopy for the diagnosis of Mycoplasma suis in a French veterinary practice.

Mycoplasma suis (M. suis) is an haemotropic Mycoplasma that adheres and invades erythrocytes and is responsible for infectious anaemia of pigs. Infections with M. suis have been reported worldwide. Clinical signs after M. suis infection can be significant particularly for the breeding herd in the period around farrowing but consequences are highly variable with some infected pigs never exhibiting clinical disease. The study aimed to determine the clinical relevance of Giemsa-stained blood smear for the diagnosis of M. suis compared with qPCR results. In our study, the comparison of qPCR results with microscopic investigation of Giemsa-stained blood smears revealed a lower sensitivity of the microscopic method: only 33 out of 102 qPCR positive blood samples were microscopically positive (M. suis visualised). No relationship between mean qPCR loads and microscopic observation was observed. Although more costly, qPCR is probably the best diagnostic tool available today for M. suis diagnosis.

Maternally-derived neutralizing antibodies reduce vaccine efficacy against porcine reproductive and respiratory syndrome virus infection.

Modified live virus (MLV) vaccines are commonly used to reduce the impact of porcine reproductive and respiratory syndrome (PRRS) but limited efficacy is achieved in field conditions. Here, we evaluated the impact of maternally-derived neutralizing antibodies (MDNAs) on vaccine efficacy after PRRS virus (PRRSV) challenge. Piglets with low (A-) or high (A+) MDNA levels derived from a commercial pig herd were moved to experimental facilities to be vaccinated (V+) or not (V-) with a PRRSV-1 MLV vaccine at 3 weeks of age (woa). Because of unexpectedly low vaccine detection in A-V+ piglets post-vaccination (pv), all V+ piglets received a second vaccination at 4 woa. Five weeks (W5) pv, piglets were inoculated with a PRRSV-1 field strain to evaluate vaccine protection, and were mingled 24 h later with non-inoculated piglets of similar immune status to assess viral transmission. Vaccine strain was detected at W2 pv in 69% and 6% of A-V+ and A+V+ piglets, and at W5 pv in 50% and 25% of A-V+ and A+V+ piglets, respectively. At W5 pv, 94% of A-V+ and 44% of A+V+ piglets seroconverted, with a significant IFNg response induction in the A-V+ group only. After challenge, compared to the V- inoculated group, viremia was 100-fold lower at 10 days post-infection in A-V+ whereas viremia was not significantly reduced in A+V+ piglets. A lower transmission rate was estimated for the A-V+ group: 0.15 [0.07-0.29] versus 0.44 [0.18-1.76] and 0.32 [0.14-0.68] for the A+V+ and V- groups, respectively. Investigations about the low vaccine strain detection after the first vaccination suggested a relationship between IFNa levels and vaccine strain detection in A-V+ piglets. We showed that MDNAs impair vaccine efficacy against PRRSV both in inoculated and contact piglets, probably by reducing vaccine replication. IFNa may also interfere with PRRSV vaccination. These new data could help improving vaccination protocols.

A Field Recombinant Strain Derived from Two Type 1 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV-1) Modified Live Vaccines Shows Increased Viremia and Transmission in SPF Pigs.

In Europe, modified live vaccines (MLV) are commonly used to control porcine reproductive and respiratory syndrome virus (PRRSV) infection. However, they have been associated with safety issues such as reversion to virulence induced by mutation and/or recombination. On a French pig farm, we identified a field recombinant strain derived from two PRRSV-1 MLV (MLV1). As a result, we aimed to evaluate its clinical, virological, and transmission parameters in comparison with both parental strains. Three groups with six pigs in each were inoculated with either one of the two MLV1s or with the recombinant strain; six contact pigs were then added into each inoculated group. The animals were monitored daily for 35 days post-inoculation (dpi) for clinical symptoms; blood samples and nasal swabs were collected twice a week. PRRS viral load in inoculated pigs of recombinant group was higher in serum, nasal swabs, and tonsils in comparison with both vaccine groups. The first viremic contact pig was detected as soon as 2 dpi in the recombinant group compared to 10 and 17 dpi for vaccine groups. Estimation of transmission parameters revealed fastest transmission and longest duration of infectiousness for recombinant group. Our in vivo study showed that the field recombinant strain derived from two MLV1s demonstrated high viremia, shedding and transmission capacities.

Monitoring PRRSV-1 in suckling piglets in an endemic herd using reverse transcriptase quantitative real time polymerase chain reaction: comparison of the rate of detection in serum and oral fluid samples and evaluation of pooling.

BACKGROUND: Defining shedding and exposure status for PRRSV is essential in herd stabilisation protocols and weaning-age pigs is a key subpopulation. Oral fluid (OF) sampling is a welfare-friendly and cost saving promising alternative to blood sampling. The first objective of our study was to compare the rate of detection of PRRSV-1 in individual serum sample, individual OF sample, litter-based OF sample, collected the day before weaning. The second objective was to evaluate the interest of pooling samples. RESULTS: The study was performed on a 210-sows, PRRSV-1 exposed, with confirmed shedding, non-vaccinated against PRRSV, herd. 80 litters were sampled and 26 were viropositive and therefore included. The rate of detection of PRRSV-1 with RT-qrtPCR in blood samples, iOF and cOF was 67, 23 and 77%, respectively. The Ct values from RT-qrtPCR on collective OF were statistically lower if the serum of the piglet of the litter was positive. The lower the Cycle threshold (Ct) value of RT-qrtPCR on collective OF, the higher the probability that the serum sampled in the same litter was positive. Ability to detect PRRSV RNA after pooling was 67% for sera and 58% for cOF. CONCLUSIONS: The rate of detection of PRRSV-1 was about the same in cOF and blood samples. Virus sequencing, if required, should be performed on individual serum samples. The smaller the Ct of a cOF sample from a litter, the greater the likelihood that the serum sample from a piglet of that litter is positive.A cost-effective and representative sampling protocol to monitor sow herds stabilisation of a sow batch could be: to collect both cOF and one serum sample per litter; to perform firstly RT-qrtPCR on pooled cOF; in case of negative results to consider the batch negative; in case of positive results in a unvaccinated herd or a killed vaccine vaccinated one to consider the batch positive; in case of positive result in a herd vaccinated with a modified live vaccine serum samples of litters with positive cOF should be tested for sequencing (selecting the litters with the lowest Ct for cOF).

First demonstration of the circulation of a pneumovirus in French pigs by detection of anti-swine orthopneumovirus nucleoprotein antibodies.

The presence of pneumoviruses in pigs is poorly documented. In this study, we used the published sequence of the nucleoprotein (N) of the recently identified Swine Orthopneumovirus (SOV) to express and purify SOV N as a recombinant protein in Escherichia coli. This protein was purified as nanorings and used to set up an enzyme-linked immunosorbent assay, which was used to analyse the presence of anti-pneumovirus N antibodies in swine sera. Sera collected from different pig farms in the West of France and from specific pathogen free piglets before colostrum uptake showed indirectly that a pneumovirus is circulating in pig populations with some variations between animals. Piglets before colostrum uptake were sero-negative for anti-pneumovirus antibodies while most of the other pigs showed positivity. Interestingly, in two farms presenting respiratory clinical signs and negative or under control for some common respiratory pathogens, pigs were detected positive for anti-pneumovirus antibodies. Globally, anti-pneumovirus N antibody concentrations were variable between and within farms. Further studies will aim to isolate the circulating virus and determine its potential pathogenicity. SOV could potentially become a new member of the porcine respiratory complex, important on its own or in association with other viral and bacterial micro-organisms.

A prospective study of the impact of AGTR1 A1166C on the effects of candesartan in patients with heart failure.

AIM: To evaluate the impact of AGTR1 A1166C (rs5186) on the response to candesartan in patients with heart failure. MATERIALS & METHODS: Prospective, multicentre, open-label study. We studied 299 symptomatic patients with heart failure presenting a left ventricular ejection fraction ≤40%. RESULTS: Reductions in the primary end points of natriuretic peptides were not significantly associated with AGTR1 A1166C. Nevertheless, carrying the 1166C allele was associated with a greater compensatory increase in renin activity (p = 0.037) after 16 weeks of treatment with candesartan and a more modest effect on aldosterone concentrations (p = 0.022). CONCLUSION: AGTR1 1166C carriers may experience a greater long-term compensatory renin-angiotensin-aldosterone system activation following treatment with candesartan. Whether these associations ultimately influence clinical outcomes requires investigation. Clinicaltrials.gov : NCT00400582.

Complete Genome Sequence of a Recombinant Porcine Reproductive and Respiratory Syndrome Virus Strain from Two Genotype 1 Modified Live Virus Vaccine Strains.

This paper provides information on the complete genome sequence of a porcine reproductive and respiratory syndrome virus (PRRSV) strain isolated on a French pig farm which was identified as a recombinant strain from two commercial modified live virus vaccine strains of genotype 1 (VP-046BIS and DV strains).

Evaluation of porcine reproductive and respiratory syndrome stabilization protocols in 23 French Farrow-to-finish farms located in a high-density swine area.

BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is responsible for reproductive disorders in sows and respiratory problems in pigs, and has a major economic impact. Controlling PRRSV is therefore a priority for the swine industry. Stabilization of a herd, defined as the production of PRRSV-negative pigs at weaning from seropositive sows, is a common method of control, and different protocols have been described in the literature to achieve this stabilization. CONTEXT AND PURPOSE: The objective of this study was to evaluate wether the combination of mass vaccination of sows and their piglets with a Genotype I modified live virus (MLV) vaccine, with temporal closure to the introduction of replacement animals and unidirectional pig and human flow can result in the production of PRRSV-negative pigs at weaning. The study took place in French farrow-to-finish farms located in a high-density swine area where the disease concerns over 60% of farms and only closely related strains of genotype I have been reported. Twenty-three 100-to-700 sow farrow-to-finish farms were selected prospectively between 2005 and 2014, regardless of their biosecurity level. Those farms adopted a stabilization protocol characterized by the following standardized measures: vaccination of sows, gilts, and piglets with the Genotype I MLV vaccine PORCILIS®PRRS, temporary herd closure, and strict internal biosecurity measures. Monitoring of herd status was then performed using a combination of 3 diagnostic tools: Real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and Open reading frame (ORF) 5 and ORF7 sequencing. The status of finishing units (either active or inactive, meaning PRRSV-positive or PRRSV-negative, respectively) was not considered in this study. RESULTS AND CONCLUSIONS: At the end of the monitoring period, considering the results of all the analyses, clinical signs, and epidemiology, 19 farms were considered stable and 1 remained unstable. In 3 farms it was commonly agreed to extend the number of vaccinated batches of piglets, which enabled them to be considered stable at the end of a second round of monitoring. The combination of vaccination of sows and their piglets with a Genotype I MLV vaccine, together with the closure of the farm and a unidirectional pig and human flow, seems to be effective for farrow-to-finish farms even in high-density swine area, even with French PRRSV strains closely related to one another. This research is the first European study examining such a large number of farms, and increased confidence in the results stems from the added value of using the ORF7 and ORF5 sequencing tool.

Genetic markers associated with cutaneous adverse drug reactions to allopurinol: a systematic review.

Pharmacogenomic markers in the HLA coding genes have been associated with drug hypersensitivity of multiple drugs, including allopurinol. In this systematic review, we summarize the pharmacogenomic evidence available regarding allopurinol-induced cutaneous adverse drug reactions (cADRs). We found that the HLA-B*5801 allele was significantly associated with the risk of severe cADRs in the Han Chinese, Korean, Thai, Japanese and European populations. The association between less severe cADRs and HLA-B*5801 was less consistent. All SNPs identified in genome-wide association studies of common variants were also located in or nearby HLA-B*5801. Future studies should focus on more common but less severe allopurinol-induced cADRs, as well as the potential role of rare variants as predictors of these cADRs.

CKM and LILRB5 are associated with serum levels of creatine kinase.

BACKGROUND: Statins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs for the treatment and prevention of cardiovascular disease. Creatine kinase (CK) is a commonly used biomarker to assist in the diagnosis of statin-induced myotoxicity but the normal range of CK concentrations is wide, which limits its use as a diagnostic biomarker. METHODS AND RESULTS: We conducted a genome-wide association study of serum CK levels in 3412 statin users. Patients were recruited in Quebec, Canada, and genotyped on Illumina Human610-Quad and an iSelect panel enriched for lipid homeostasis, hypertension, and drug metabolism genes. We found a strong association signal between serum levels of CK and the muscle CK (CKM) gene (rs11559024: P=3.69×10(-16); R(2)=0.02) and with the leukocyte immunoglobulin-like receptor subfamily B member 5 (LILRB5) gene (rs2361797: P=1.96×10(-10); R(2)=0.01). Genetic variants in those 2 genes were independently associated with CK levels in statin users. Results were successfully replicated in 5330 participants from the Montreal Heart Institute Biobank in statin users for CKM (rs11559024: P=4.32×10(-16); R(2)=0.02) and LILRB5 (rs12975366 P=4.45×10(-10); R(2)=0.01) and statin nonusers (P=4.08×10(-7), R(2)=0.01; P=3.17×10(-9), R(2)=0.02, respectively). CONCLUSIONS: This is the first genome-wide study to report on the underlying genetic determinants of CK variation in a population of statin users. We found statistically significant association for variants in the CKM and LILRB5 genes.