Devindri Perera

Past environmental sun exposure and risk of multiple sclerosis: a role for the Cdx-2 Vitamin D receptor variant in this interaction

Multiple studies have provided evidence for an association between reduced sun exposure and increased risk of multiple sclerosis (MS), an association likely to be mediated, at least in part, by the vitamin D hormonal pathway. Herein, we examine whether the vitamin D receptor (VDR), an integral component of this pathway, influences MS risk in a population-based sample where winter sun exposure in early childhood has been found to be an important determinant of MS risk. Three polymorphisms within the VDR gene were genotyped in 136 MS cases and 235 controls, and associations with MS and past sun exposure were examined by logistic regression. No significant univariate associations between the polymorphisms, rs11574010 (Cdx-2A > G), rs10735810 (Fok1T > C), or rs731236 (Taq1C > T) and MS risk were observed. However, a significant interaction was observed between winter sun exposure during childhood, genotype at rs11574010, and MS risk (P = 0.012), with the ‘G’ allele conferring an increased risk of MS in the low sun exposure group (≤2 h/day). No significant interactions were observed for either rs10735810 or rs731236, after stratification by sun exposure. These data provide support for the involvement of the VDR gene in determining MS risk, an interaction likely to be dependent on past sun exposure.

Fine mapping of multiple sclerosis susceptibility genes provides evidence of allelic heterogeneity at the IL2RA locus

Multiple sclerosis (MS) is a genetically complex autoimmune disease. To dissect further the involvement of four recent identified MS susceptibility genes (KIAA0350, IL2RA, RPL5 and CD58) in disease pathogenesis, we genotyped 94 haplotype-tagging single nucleotide polymorphisms (SNPs) from these loci in 1146 MS cases and 1309 controls. Seven newly-typed SNP variants were nominally associated with risk of MS, and one SNP (rs791589) in the first intron of the IL2RA gene remained associated after adjustment for rs2104286 genotype, a previously reported SNP association. These data provide further evidence of allelic heterogeneity at the IL2RA locus and point to the existence of at least two independent MS susceptibility alleles.

The association between exercise-induced pulmonary haemorrhage and race-day performance in Thoroughbred racehorses

BACKGROUND Exercise-induced pulmonary haemorrhage (EIPH) is commonly implicated as a cause of poor athletic performance but there is limited and conflicting evidence for this association. OBJECTIVES The aim of this study was to determine if EIPH, based on endoscopic examination after racing, is associated with a variety of novel and established performance parameters. STUDY DESIGN Prospective, observational cross-sectional study. METHODS Thoroughbred racehorses competing between 2012 and 2015 were examined on-course no earlier than 30 min after racing. Examinations were recorded and graded blindly by experienced veterinarians using a 0-4 scale. Linear mixed effect models were used for analysis of continuous response variables with horse name incorporated as a random effect to account for repeated sampling and horse variability. Generalised estimating equations were used for analysis of binary responses. Performance variables were examined in 2 models, comparing EIPH grade 0 to grades 1-4, and EIPH grade ≤2 compared with EIPH grades ≥3, controlling race factors that could influence performance. RESULTS There were 3794 observations collected from 1567 horses. EIPH was detected in 55.1% of observations. Horses with grade 4 EIPH were significantly more likely to have a lower finishing position and finish further behind the winner, less likely to place in the first 3 positions and collect race earnings, collected less earnings per race start and were slower over the last 600 m of the race than horses without EIPH (grade 0). Similar associations were seen in Model 2, with horses with EIPH grade ≥3 having inferior performance when compared to horses with EIPH ≤2. MAIN LIMITATIONS Enrolment was voluntary. CONCLUSION Mild to moderate haemorrhage was not associated with inferior race day performance in this population of Thoroughbred racehorses.

Saddlepoint approximation methods for testing of serial correlation in panel time series data

The saddlepoint method is used to approximate the tail probabilities of the lag one serial correlation coefficient α, of a zero mean, first-order auto-regressive process, for both large and small numbers of small samples, and to test for serial correlation in a first-order non-zero mean process. The formula for the tail probability due to Lugannani and Rice is extended to the current problem. In the case of the zero mean process, approximate tail probabilities are computed using our results, and are compared with the Edgeworth and normal approximations. Unlike the other two approximations, the saddlepoint approximation performs uniformly well over the whole range of tail probability values considered. For the testing of serial correlation in the non-zero mean process, the saddlepoint method used to obtain the P-values performs in a similar manner to the asymptotic normal approximation method used by Cox and Solomon [Cox, D.R. and Solomon, P.J. (1988). On testing for serial correlation in large numbers of small samples. Biometrika, 75, 145–148].

Circannual variability in adrenocorticotropic hormone responses to administration of thyrotropin-releasing hormone in clinically normal horses in Australia

Thyrotropin releasing hormone (TRH)-stimulation testing for pituitary pars intermedia dysfunction (PPID) in horses is only recommended at certain times of the year. Current diagnostic cut-off values reflect testing in the northern hemisphere during this time. The aims of this study were to evaluate TRH stimulation testing during two different phases of the circannual pituitary cycle and to determine whether diagnostic cut-off values developed in the northern hemisphere are appropriate in Australia. Thirteen clinically normal horses at Perth, Western Australia, and 23 horses at Townsville, Queensland, Australia, had TRH stimulation tests performed at two different time points during the circannual pituitary cycle. At both locations, post-TRH adrenocorticotropic hormone (ACTH) concentrations were significantly different between testing time points (Perth: P=0.001; Townsville: P<0.0001). In Perth, the mean ACTH concentrations 10min post-TRH in September and March were 51.4pg/mL (95% confidence interval, CI, 46.4-56.4pg/mL) and 248.5pg/mL (95% CI 170.2-326.9pg/mL), respectively. The median percentage change in ACTH concentrations in March was 361.9%. In Townsville, the mean ACTH concentrations 30min post-TRH in September and April were 35.3pg/mL (95% CI 29.6-40.9pg/mL) and 112.3pg/mL (95% CI 93.4-131.2pg/mL), respectively. The median percentage change in ACTH concentrations in April was 144.7%. The ACTH cut-off value after TRH stimulation in normal horses in September in Perth and Townsville was similar to the values established in the northern hemisphere. However, TRH stimulation testing in March/April was highly variable at both locations.