Poser Sa Phenotypes
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IntroductionMultiple sclerosis is a chronic demyelinating disease of the centralnervous system. Contributing factors include a defect in immunological selftolerance resulting in a T helper cell type 1 mediated attack on myelinproteins. One ofthe most striking epidemiological features of multiple sclerosis is a gradientof increasing prevalence withlatitude. Aninverse association between solar radiation and prevalence of multiplesclerosis was first observed in1960. Recentphoto-immunological work has rekindled interest in this observation becauseultraviolet radiation can attenuate T helper cell type 1 mediated immuneresponses through severalmechanisms. Also,administration of ultraviolet radiation or 1,25-dihydroxycholecalciferol, theactive form of vitamin D 3, which is produced under the influence ofultravioletradiation, hasshown protective effects against the induction or progression of experimentalallergicencephalomyelitis.,In humans, ultraviolet radiation or vitamin D may also protect againstmultiple sclerosis.
A strong ecological association between regional levels ofultraviolet radiation and prevalence of multiple sclerosis is evident inAustralia (r =-0.91). In a deathcertificate based case-control study, high residential or occupationalexposure to sunlight was negatively associated with mortality from multiplesclerosis. Exposureto ultraviolet radiation early in life may alter immunological developmentduring a critical developmental phase.
However, the finding of a stronglatitudinal gradient of prevalence of multiple sclerosis in Australia evenamong immigrants from the United Kingdom and Ireland (70% who migrated afterage 15) suggests that cumulative exposure to ultraviolet radiation or exposurelater in life might also beimportant.Tasmania, the island state of Australia, is located at latitudes 41-3°Sand has a high prevalence of multiple sclerosis at 75.6 per 100 000population. Weconducted a case-control study in Tasmania to examine whether high past sunexposure was associated with a reduced risk of multiple sclerosis. CasesCases were members of the source population who had a diagnosis of multiplesclerosis. To recruit participants, information evenings were held for membersof the local multiple sclerosis societies, and information packs were sent outto neurologists, general physicians, general practitioners, and pharmacists,who were encouraged to publicise the posters and to inform people withmultiple sclerosis about the programme. Neurologists in the south of the statesent letters to eligible patients inviting them to participate and verballyencouraged newly diagnosed patients to participate. In total, 169 peopleresponded. We included 136 cases in the final sample: 30 people (18%) did notmeet the study criteria for diagnosis of multiple sclerosis, one personrefused a neurological assessment, one person died before interview, and oneperson deteriorated and was unable to take part.
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Respondents were interviewedand examined by one of the participating neurologists. Magnetic resonanceimages subsequently confirmed the diagnosis for 134 cases (99%), and for theother two cases we obtained the reports of previous scans.
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Eligible cases hadcerebral abnormalities on magnetic resonance imaging consistent with multiplesclerosis, as defined by Paty et al, and definite multiple sclerosis using thecriteria of Poser etal., Cases with aclassification of primary progressive multiple sclerosis had to exhibitprogressive neurological disability for at least one year, had to have noother better explanation for the clinical features, and had to have relevantspinal cord abnormalities and changes on cerebral magnetic resonance imagingconsistent with demyelination. The cases were also included in a geneticstudy, for which a haplotype analysis was conducted on the human leucocyteantigenregion. ControlsControls were selected from the source population using the roll ofregistered electors, a comprehensive listing of the population maintained bythe state electoral office of Tasmania. We randomly selected two controls foreach case and matched them to the index case on sex and year of birth.Overall, 272 of 359 eligible controls participated (response rate 76%). In anunmatched design, we required at least 100 cases and 200 controls to detect anodds ratio of 2.0 or 0.5 for the effect of a dichotomous exposure where 40% ofthe controls were exposed. Time in sunTwo research assistants conducted all interviews and measurements betweenMarch 1999 and June 2001.
Participants were asked about the amount of timethey would normally have spent in the sun during weekends and holidays inwinter and summer (“time in the sun” question), using questionsvalidated for teenagers in thisclimate. Answersto the time in the sun question for winter predict levels of serum25-hydroxycholecalciferol in 8 year old Tasmanianchildren. Thestandardised questionnaire included questions on measures to protect againstthe sun, use of vitamin D supplements at ages 10-15 years, medical history(including infections and immunisations), and other factors suggested by pastwork to be associated with multiple sclerosis. For the timing of exposures weobtained either the exact age or the five year age range in which the exposureoccurred. Beforeinterview, participants were asked to fill in a lifetime calendar for eachyear of their life. During the interview, participants answered the time inthe sun question for summer only for each year of their life, and from theinformation in the calendar we identified blocks of years where time in thesun was constant or not. The κ statistic (95% confidence interval)between the questionnaire based measure and the calendar measure (using themean value) for ages 6-10, 11-15, and 16-20 years was 0.54 (0.47 to 0.61),0.51 (0.44 to 0.58), and 0.44 (0.37 to 0.50), respectively.
No difference inagreement was found between cases and controls. Actinic damageSilicone casts of the skin surface of the hand, measuring actinic damage,were used as an objective marker of cumulative lifetime sun exposure. Thismeasure has been associated with living in a location with high ultravioletradiation, lifetime exposure to sun, outdoor occupations and leisureactivities, solar keratosis, and basal and squamous cellcancer. Silicone liquid was mixed with catalyst and applied to the dorsum of theparticipant's left hand.
Phenotype identification with PhenoDissim. One major goal in image-based screens is to identify perturbations that show significantly different phenotypes when compared to negative controls. Applying the PhenoDissim method, we computed the phenotypic dissimilarity between each perturbation and the negative controls.
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After seven minutes, the cast was removed. The lineson the underside of the cast were examined under a low power dissectingmicroscope and graded by one observer from 1 (undamaged skin) to 6 (severedeterioration). By age 14 up to 70% of Australians show detectable skin damage caused by thesun. In Nambour(latitude 27°S), Queensland, 72% of men and 47% of women had moderate tosevere deterioration of the skin by their30s.
Age and sexhave also been shown to be strong predictors of the amount of actinic damage,and we controlled for these two factors through our matcheddesign. Skin phenotypeSkin phenotype was assessed with a spectrophotometer at the upper inner armand buttock-body sites usually not exposed to sunlight. Products.
Cutaneous melanindensity was estimated from the skin reflectance of light centred at 400 nm and420 nm. Skincolour at the upper inner arm was also assessed visually by the researchassistants. The standardised questionnaire included a question on lifetimesunburns where the pain lasted more than two days, a measure that reflectsboth skin phenotype and sun exposure behaviour. The research assistant alsorecorded the number of naevi greater than 5 mm on the left arm, hair and eyecolour, height, and weight. Data analysisPearson correlations were calculated as measures of linear association.Odds ratios and 95% confidence intervals were estimated by conditionallogistic regression (STATA 7.0). Tests for trend of categorical variables wereundertaken by replacing the binary predictors with a single predictor, takingcategory rank scores. The scaled variables for melanin and naevi weredichotomised at previously used cut-offpoints.
Analysisof actinic damage was restricted to 323 high quality casts. The recording ofyear by year exposure by the lifetime calendar allowed an estimation ofaverage exposure at any age. We did this for ages 6-10, 11-15, and 16-20 andfor ages 6-10, 6-15, 6-20, and so on. To aggregate and then average annualexposure, the categories were assigned rank scores.
For each age span in thefigure the average sun exposure was dichotomised at 2-3 hours a day. Fortable 4 and the figure, thesample was limited to cases and their matched controls who had not experiencedany symptoms of multiple sclerosis before or during the age span. To takeaccount of duration of disease, we stratified by time elapsed since the firstsymptom of multiple sclerosis: 0-5, 6-10, 11-15, 16-20, and 20 years. Atest of interaction was conducted using the coefficient and standard error ofa product term of exposure to sun and duration of disease. In analysis,controls were given the years of duration or the age at onset (age at firstsymptom) of their case pair. Proportional hazard regression was used amongcases to assess the effect of sun exposure and skin phenotype on the age atonset of disease. ResultsOverall, 68% (n = 92) of the cases were female, and most of the cases andcontrols were born in Tasmania and living there at age 10.
Sixty five per centof the cases had relapsing remitting multiple sclerosis Although only ofborderline significance, the odds of having light skin colour (. Childhood sun exposurePeople with multiple sclerosis were less likely to report severe sunburnepisodes during their lifetime, despite their fairer skin. We observed a stronginverse association between sun exposure in childhood and adolescence andmultiple sclerosis.For example, cases were less likely than controls to report higher levels( 1 hour a day) of exposure during winter at age 6-10 years (odds ratio0.47, 95% confidence interval 0.26 to 0.84). This inverse association wasobserved for exposure both in winter and in summer (see). Compared to bivariateanalysis, including both summer and winter questionnaire based measures forexposure as dichotomised terms in the model left the estimated effect ofexposure in winter almost unchanged (adjusted odds ratio 0.52, 0.28 to 0.95 atage 6-10 years), but greatly reduced the effect of exposure in summer (0.63,0.30 to 1.35 at age 6-10 years). This was found irrespective of the age atexposure.