MRI Patterns Distinguish AQP4 Antibody Positive Neuromyelitis Optica Spectrum Disorder From Multiple Sclerosis.

Neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) are inflammatory diseases of the CNS. Overlap in the clinical and MRI features of NMOSD and MS means that distinguishing these conditions can be difficult. With the aim of evaluating the diagnostic utility of MRI features in distinguishing NMOSD from MS, we have conducted a cross-sectional analysis of imaging data and developed predictive models to distinguish the two conditions. NMOSD and MS MRI lesions were identified and defined through a literature search. Aquaporin-4 (AQP4) antibody positive NMOSD cases and age- and sex-matched MS cases were collected. MRI of orbits, brain and spine were reported by at least two blinded reviewers. MRI brain or spine was available for 166/168 (99%) of cases. Longitudinally extensive (OR = 203), "bright spotty" (OR = 93.8), whole (axial; OR = 57.8) or gadolinium (Gd) enhancing (OR = 28.6) spinal cord lesions, bilateral (OR = 31.3) or Gd-enhancing (OR = 15.4) optic nerve lesions, and nucleus tractus solitarius (OR = 19.2), periaqueductal (OR = 16.8) or hypothalamic (OR = 7.2) brain lesions were associated with NMOSD. Ovoid (OR = 0.029), Dawson's fingers (OR = 0.031), pyramidal corpus callosum (OR = 0.058), periventricular (OR = 0.136), temporal lobe (OR = 0.137) and T1 black holes (OR = 0.154) brain lesions were associated with MS. A score-based algorithm and a decision tree determined by machine learning accurately predicted more than 85% of both diagnoses using first available imaging alone. We have confirmed NMOSD and MS specific MRI features and combined these in predictive models that can accurately identify more than 85% of cases as either AQP4 seropositive NMOSD or MS.

Relapse Patterns in NMOSD: Evidence for Earlier Occurrence of Optic Neuritis and Possible Seasonal Variation.

Neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) show overlap in their clinical features. We performed an analysis of relapses with the aim of determining differences between the two conditions. Cases of NMOSD and age- and sex-matched MS controls were collected from across Australia and New Zealand. Demographic and clinical information, including relapse histories, were recorded using a standard questionnaire. There were 75 cases of NMOSD and 101 MS controls. There were 328 relapses in the NMOSD cases and 375 in MS controls. Spinal cord and optic neuritis attacks were the most common relapses in both NMOSD and MS. Optic neuritis (p < 0.001) and area postrema relapses (P = 0.002) were more common in NMOSD and other brainstem attacks were more common in MS (p < 0.001). Prior to age 30 years, attacks of optic neuritis were more common in NMOSD than transverse myelitis. After 30 this pattern was reversed. Relapses in NMOSD were more likely to be treated with acute immunotherapies and were less likely to recover completely. Analysis by month of relapse in NMOSD showed a trend toward reduced risk of relapse in February to April compared to a peak in November to January (P = 0.065). Optic neuritis and transverse myelitis are the most common types of relapse in NMOSD and MS. Optic neuritis tends to occur more frequently in NMOSD prior to the age of 30, with transverse myelitis being more common thereafter. Relapses in NMOSD were more severe. A seasonal bias for relapses in spring-summer may exist in NMOSD.

The clinical profile of NMOSD in Australia and New Zealand.

Neuromyelitis optica spectrum disorders (NMOSD) are an inflammation of the central nervous system associated with autoantibodies to aquaporin-4. We have undertaken a clinic-based survey of NMOSD in the Australia and New Zealand populations with the aim of characterising the clinical features and establishing the value of recently revised diagnostic criteria. Cases of possible NMOSD and age and sex-matched controls with multiple sclerosis (MS) were referred from centres across Australia and New Zealand. Cases were classified as NMOSD if they met the 2015 IPND criteria and remained as suspected NMOSD if they did not. Clinical and paraclinical data were compared across the three groups. NMOSD was confirmed in 75 cases and 89 had suspected NMOSD. There were 101 controls with MS. Age at onset, relapse rates and EDSS scores were significantly higher in NMOSD than in MS. Lesions and symptoms referable to the optic nerve were more common in NMOSD whereas brainstem, cerebellar and cerebral lesions were more common in MS. Longitudinally extensive spinal cord lesions were seen in 48/71 (68%) of cases with NMOSD. Elevations of CSF, white cell count and protein were more common in NMOSD. We have confirmed a clinical pattern of NMOSD that has been seen in several geographical regions. We have demonstrated the clinical utility of the current diagnostic criteria. Distinct patterns of disease are evident in NMOSD and MS, but there remains a large number of patients with NMOSD-like features who do not meet the current diagnostic criteria for NMOSD and remain a diagnostic challenge.

Incidence and prevalence of NMOSD in Australia and New Zealand.

OBJECTIVES: We have undertaken a clinic-based survey of neuromyelitis optica spectrum disorders (NMOSDs) in Australia and New Zealand to establish incidence and prevalence across the region and in populations of differing ancestry. BACKGROUND: NMOSD is a recently defined demyelinating disease of the central nervous system (CNS). The incidence and prevalence of NMOSD in Australia and New Zealand has not been established. METHODS: Centres managing patients with demyelinating disease of the CNS across Australia and New Zealand reported patients with clinical and laboratory features that were suspicious for NMOSD. Testing for aquaporin 4 antibodies was undertaken in all suspected cases. From this group, cases were identified who fulfilled the 2015 Wingerchuk diagnostic criteria for NMOSD. A capture-recapture methodology was used to estimate incidence and prevalence, based on additional laboratory identified cases. RESULTS: NMOSD was confirmed in 81/170 (48%) cases referred. Capture-recapture analysis gave an adjusted incidence estimate of 0.37 (95% CI 0.35 to 0.39) per million per year and a prevalence estimate for NMOSD of 0.70 (95% CI 0.61 to 0.78) per 100 000. NMOSD was three times more common in the Asian population (1.57 (95% CI 1.15 to 1.98) per 100 000) compared with the remainder of the population (0.57 (95% CI 0.50 to 0.65) per 100 000). The latitudinal gradient evident in multiple sclerosis was not seen in NMOSD. CONCLUSIONS: NMOSD incidence and prevalence in Australia and New Zealand are comparable with figures from other populations of largely European ancestry. We found NMOSD to be more common in the population with Asian ancestry.

Modelling genetic susceptibility to multiple sclerosis with family data.

A genetic contribution to susceptibility is well established in multiple sclerosis (MS) and 57 associated genetic loci have been identified. We have undertaken a meta-analysis of familial risk studies with the aims of providing definitive figures for risks to relatives, performing a segregation analysis and estimating the proportion of the overall genetic risk that currently identified genes represent. We have used standard methods of meta-analysis combined with novel approaches to age adjustment to provide directly comparable estimates of lifetime risk. The overall recurrence risk for monozygotic twins was 18.2% and for siblings 2.7%. The recurrence risk for dizygotic twins was significantly higher than for siblings. The overall estimate of sibling relative risk (λ(S)) was 16.8. Risks for older relatives (parents, siblings, aunts, uncles and cousins) show a latitudinal gradient, in line with population risk. No latitudinal gradient for λ(S) was seen. Segregation analysis supports a multiplicative model of one locus of moderate effect with many loci of small effect. The estimated contribution of the 57 known MS loci is 18-24% of λ(S). This meta-analysis supports the notion of MS being in part the result of multiple genetic susceptibility factors and environmental factors.

Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease.

Genetic heterogeneity is a difficulty frequently encountered in the search for genes conferring susceptibility to prostate cancer. To circumvent this issue, we selected a large prostate cancer pedigree for genome-wide linkage analysis from a population that is genetically homogeneous. Selected cases and first-degree relatives were genotyped with Affymetrix 10K SNP arrays, identifying a 14 Mb haplotype on chromosome 5 (5p13-q12) inherited identical-by-descent (IBD) by multiple cases. Microsatellite genotyping of additional deceased case samples confirmed that a total of eight cases inherited the common haplotype (P=0.0017). Re-sequencing of eight prioritised candidate genes in the region in six selected individuals identified 15 SNPs segregating with the IBD haplotype, located within the ITGA2 gene. Three of these polymorphisms were selected for genotyping in an independent Tasmanian data set comprising 127 cases with familial prostate cancer, 412 sporadic cases and 319 unaffected controls. Two were associated with prostate cancer risk: rs3212649 (OR=1.67 (1.07-2.6), P=0.0009) and rs1126643 (OR=1.52 (1.01-2.28), P=0.0088). Significant association was observed in both familial and sporadic prostate cancer. Although the functional SNP remains to be identified, considerable circumstantial evidence, provided by in vivo and in vitro studies, supports a role for ITGA2 in tumour development.

Sequence variants of alpha-methylacyl-CoA racemase are associated with prostate cancer risk: a replication study in an ethnically homogeneous population.

BACKGROUND: Examination of variants of the alpha-methylacyl-CoA racemase (AMACR) gene, as genetic contributors to prostate cancer risk, has been of considerable interest given the gene's recently established role as a diagnostic biomarker for prostate cancer. METHODS: The AMACR gene variants, M9V and D175G, were genotyped in a familial dataset comprising 127 cases and in a second sporadic prostate cancer dataset comprising 414 cases and 319 controls. Genotype-disease associations were examined employing the M(QLS) test and unconditional logistic regression. Differences in allele frequencies were examined using the Fisher's exact test. Association between the AMACR haplotypes and prostate cancer risk was also investigated using haplo.score. RESULTS: Significant evidence for association with prostate cancer risk for both the M9V and D175G variants was observed in the Tasmanian prostate cancer dataset. Whilst this association remained significant, it was diminished when relatedness amongst the familial prostate cancer cases was considered. CONCLUSION: This study, performed in a relatively genetically homogenous Tasmanian population, provides further evidence for a significant association between variants within the AMACR gene and prostate cancer risk. Risk was found to be more significantly associated with AMACR gene variants in sporadic compared to familial prostate cancer cases. These findings again highlight that genetic heterogeneity in the study population should be considered when examining genetic risk factors in prostate cancer.

Familial, structural, and environmental correlates of MRI-defined bone marrow lesions: a sibpair study.

The aim of this study was to estimate the heritability and describe the correlates of bone marrow lesions in knee subchondral bone. A sibpair design was used. T2- and T1-weighted MRI scans were performed on the right knee to assess bone marrow lesions at lateral tibia and femora and medial tibia and femora, as well as chondral defects. A radiograph was taken on the same knee and scored for individual features of osteoarthritis (radiographic osteoarthritis; ROA) and alignment. Other variables measured included height, weight, knee pain, and lower-limb muscle strength. Heritability was estimated with the program SOLAR (Sequential Oligogenetic Linkage Analysis Routines). A total of 115 siblings (60 females and 55 males) from 48 families, representing 95 sib pairs, took part. The adjusted heritability estimates were 53 +/- 28% (mean +/- SEM; p = 0.03) and 65 +/- 32% (p = 0.03) for severity of bone marrow lesions at lateral and medial compartments, respectively. The estimates were reduced by 8 to 9% after adjustment for chondral defects and ROA (but not alignment). The adjusted heritability estimate was 99% for prevalent bone marrow lesions at both lateral and medial compartments. Both lateral and medial bone marrow lesions were significantly correlated with age, chondral defects, and ROA of the knee (all p < 0.05). Medial bone marrow lesions were also more common in males and were correlated with body mass index (BMI). Thus, bone marrow lesions have a significant genetic component. They commonly coexist with chondral defects and ROA but only share common genetic mechanisms to a limited degree. They are also more common with increasing age, male sex, and increasing BMI.

Confirmation of the adult-onset primary open angle glaucoma locus GLC1B at 2cen-q13 in an Australian family.

Primary open-angle glaucoma (POAG) is genetically heterogeneous, with 6 named POAG loci GLC1A-F mapped and genes myocilin (MYOC) and optineurin (OPTN) identified at 2 of the loci. Using penetrance-model-free methods, we screened the POAG loci GLC1A-F in an extended Australian pedigree, using 3-5 markers within each locus. p values of less than 0.05 were obtained empirically using SimWalk2 and exactly using Genehunter for 2 markers within the GLC1B region on chromosome 2. Fine mapping of this region produced p values of 0.01 or less at 5 markers flanked by D2S1897 and D2S2269. The 9 cM haplotype of interest overlaps the original GLC1B region. These results provide supportive evidence for the GLC1B locus on chromosome 2cen-q13 and verify the existence of POAG susceptibility gene in this region, increasing the likelihood of gene identification.

The genetic contribution and relevance of knee cartilage defects: case-control and sib-pair studies.

OBJECTIVE: To describe the differences in knee cartilage defects between offspring of subjects with at least one parent with a total knee replacement for severe primary knee osteoarthritis (OA) and controls; and to estimate the heritability of knee cartilage defects in sib-pairs. METHODS: Population based, case-control study of 186 matched pairs (mean age 45 yrs, range 26-61) and sib-pair study of 128 subjects from 51 families (115 sib-pairs) within the case-control study. Knee cartilage defect scores (0-4) and prevalence (a cartilage defect score > or = 2) were assessed at the patellar, tibial, and femoral sites by processing images acquired using T1 weighted fat-saturated magnetic resonance imaging. Heritability was estimated using the SOLAR genetic analysis program. RESULTS: The prevalence of knee cartilage defects was surprisingly high (50% scored > or = 2 in any site). Compared to controls, offspring had higher knee cartilage defect scores and prevalence in tibiofemoral (4.39 vs 4.01, p = 0.003; 41% vs 28%, p = 0.009), patellar (1.32 vs 1.10, p = 0.031; 35% vs 26%, p = 0.075), and whole (5.71 vs 5.10, p = 0.002; 57% vs 42%, p = 0.007) compartments. These all became nonsignificant after adjustment for knee pain and radiographic OA. In the sib-pair component, knee cartilage defects had heritability for scores and prevalence, respectively, of 38% (p = 0.072) and 47% (p = 0.082) for tibiofemoral, 52% (p = 0.009) and 78% (p = 0.025) for patellar, and 43% (p = 0.038) and 68% (p = 0.072) for the whole compartments. These estimates became weaker at tibiofemoral and whole compartments after adjustment for bone size, knee pain, and radiographic OA. CONCLUSION: Knee cartilage defects are common, have a genetic component that is linked to the genetic contribution to knee pain and bone size, and may have a role in the genetic pathogenesis of knee OA.

The genetic contribution to longitudinal changes in knee structure and muscle strength: a sibpair study.

OBJECTIVE: To estimate the heritability of longitudinal changes in knee cartilage volume, chondral defects, subchondral bone size, and lower limb muscle strength. METHODS: A sibpair design was used. Longitudinal changes in lateral and medial tibial cartilage volume and bone size, as well as progression of chondral defects, were determined on serial magnetic resonance images. Radiographs were obtained and scored for individual features of radiographic osteoarthritis (OA) at baseline. Lower limb muscle strength was measured by dynamometry. Heritability was estimated using the SOLAR software package. RESULTS: A total of 115 subjects (55 men and 60 women, mean age 45 years) from 48 families representing 95 sibling pairs were successfully followed up for a mean of 2.4 years. The adjusted heritability estimates for changes in cartilage volume were 73% for the medial compartment (P < 0.01) and 40% for the lateral compartment (P = 0.10). The adjusted heritability estimates for changes in bone size were 62% for the lateral compartment (P = 0.03) and 20% for the medial compartment (P = 0.22). The adjusted heritability estimate for changes in muscle strength was 64% (P = 0.01). The adjusted heritability estimates for progression of chondral defects were 80% for the lateral compartment (P = 0.06) and 98% for the medial compartment (P = 0.03). These estimates changed little after adjusting for each other and for the predominantly mild radiographic OA, with the exception of progression of chondral defects in the lateral compartment. CONCLUSION: Early longitudinal changes in knee structures of relevance to later OA, such as changes in medial tibial cartilage volume, lateral tibial bone size, progression of chondral defects, and muscle strength, have high heritability, most likely reflecting a strong genetic component and suggesting their potential to be studied in quantitative trait linkage and association analysis.

Does the addition of information on genotype improve prediction of the risk of melanoma and nonmelanoma skin cancer beyond that obtained from skin phenotype?

The authors quantified improvement in predicting cutaneous malignant melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin made possible by information on common variants of the melanocortin-1 receptor gene (MC1R) in a 1998-1999 population-based case-control study of subjects aged 20-59 years of northern European ancestry in Tasmania, Australia. Melanin density at the upper inner arm was estimated by spectrophotometry. DNA samples were genotyped for five MC1R variants: Val60Leu, Asp84Glu, Arg151Cys, Arg160Trp, and Asp294His. Among controls (n = 267), variant carriers, versus noncarriers, had lower (p < 0.01) mean melanin concentrations. Increased risk conferred by genotype was restricted mainly to those with the darkest skins: for subjects with at least 2% melanin, the odds of carrying each additional variant were higher for cutaneous malignant melanoma (n = 39; odds ratio = 1.45, 95% confidence interval: 0.87, 2.44), basal cell carcinoma (n = 35; odds ratio = 1.86, 95% confidence interval: 1.14, 3.02), and squamous cell carcinoma (n = 42; odds ratio = 2.67, 95% confidence interval: 1.50, 4.74) cases than for controls (n = 135). Adding MC1R information to prediction based on age, sex, and cutaneous melanin increased the area under the receiver operating characteristic curve by 1.4% (cutaneous malignant melanoma), 3.2% (basal cell carcinoma), or 2.0% (squamous cell carcinoma). The improvement in prediction was probably too small to be valuable in a clinical setting.

The genetic contribution to muscle strength, knee pain, cartilage volume, bone size, and radiographic osteoarthritis: a sibpair study.

OBJECTIVE: To estimate the heritability of muscle strength, knee pain, cartilage volume, bone size, and radiographic osteoarthritis (ROA), and to assess whether heritability of the knee structural components is independent of ROA. METHODS: A sibpair design was utilized. Sagittal T1-weighted fat-suppressed magnetic resonance imaging (MRI) of the right knee was performed to determine cartilage volume and bone size. Standing semiflexed radiographs of the same knee were obtained to assess the presence of ROA. Knee pain was assessed by questionnaire and muscle strength by dynamometry. Heritability was estimated using the genetic analysis program SOLAR. RESULTS: A total of 128 subjects (61 men, 67 women; mean age 45 years) from 51 families representing 115 sibpairs were studied. Lower limb muscle strength had high heritability (42%; P = 0.02), as did knee pain (44%; P = 0.07). Heritability estimates for cartilage volume were 65% for medial tibial cartilage, 77% for lateral tibial cartilage, and 84% for patellar cartilage, and heritability estimates for bone size were 85% for medial tibial bone area, 57% for lateral tibial bone area, and 70% for patella bone volume (all P < or = 0.004). For ROA, heritability was 61% for presence (with a large standard error) (P = 0.16) and 61% for severity (P = 0.02). The estimates for tibial bone areas were the only ones markedly reduced after adjustment for body size, while all estimates with the exception of knee pain were independent of ROA. Cartilage and, to a lesser extent, bone sites investigated by MRI were largely under independent genetic control, with a lesser shared genetic component. CONCLUSION: With the exception of prevalent ROA, all knee modalities assessed had high heritability, most likely reflecting a strong genetic component. Cartilage volume, bone size, and muscle strength all have the potential to be studied in quantitative trait linkage analyses, but their exact relevance with regard to OA remains uncertain at this time.

Investigation of albinism genes in congenital esotropia.

PURPOSE: Esotropia is a feature of albinism. Amongst esotropic patients there may be mild unrecognised albinos. Oculocutaneous albinism shares several clinical features with congenital esotropia. It is well known that mammals with oculocutaneous albinism have misrouted retinal ganglion cell axons, most likely caused by the absence of melanin or DOPA during development. We investigated the hypothesis that mutations in the albinism genes Tyrosinase, the P Gene, and TYRP1 may also be responsible for congenital esotropia via a similar mechanism. METHODS: We screened these three genes in 21 families with congenital esotropia using single stranded conformational polymorphism analysis. RESULTS: No rare sequence variants segregating with esoptopia were detected. A novel silent mutation of the TYRP1 gene was identified in one pedigree but is not likely to be causative. Several previously reported common polymorphisms were detected but do not segregate with disease in this population. CONCLUSIONS: Rare mutations of these genes do not appear to be responsible for congenital esotropia. Although we found no evidence for segregation of common variants with disease, these require further investigation for a possible contribution to a complex threshold model. Several lines of evidence indicate a genetic componenet of congenital esotropia, however, this is the first investigation of candidate genes for this disorder.

Mutations in a novel gene, NHS, cause the pleiotropic effects of Nance-Horan syndrome, including severe congenital cataract, dental anomalies, and mental retardation.

Nance-Horan syndrome (NHS) is an X-linked disorder characterized by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental retardation. NHS has been mapped to a 1.3-Mb interval on Xp22.13. We have confirmed the same localization in the original, extended Australian family with NHS and have identified protein-truncating mutations in a novel gene, which we have called "NHS," in five families. The NHS gene encompasses approximately 650 kb of genomic DNA, coding for a 1,630-amino acid putative nuclear protein. NHS orthologs were found in other vertebrates, but no sequence similarity to known genes was identified. The murine developmental expression profile of the NHS gene was studied using in situ hybridization and a mouse line containing a lacZ reporter-gene insertion in the Nhs locus. We found a complex pattern of temporally and spatially regulated expression, which, together with the pleiotropic features of NHS, suggests that this gene has key functions in the regulation of eye, tooth, brain, and craniofacial development.

The association between hormonal and reproductive factors and hand osteoarthritis.

OBJECTIVE: To describe the association of reproductive and hormonal factors with the presence and severity of hand osteoarthritis (OA) in Tasmanian women. METHODS: Cross-sectional study of 348 women from 76 families. A structured questionnaire collected information regarding reproductive history and the use of estrogen containing medications. Hand OA was assessed by two observers using the Altman atlas for joint space narrowing and osteophytes at distal interphalangeal (DIP) and carpometacarpal (CMC) joints, as well as Heberden's nodes (HN) based on hand photography. RESULTS: The prevalence of hand OA was high in this sample at 65-70%. Parity, increasing age at menopause and years of menstruation were associated with both symptomatic hand OA and a more severe DIP score (but not presence of radiographic disease) while both current and ever use of hormone replacement therapy (HRT) were significantly associated with increased prevalence of HN and severity of HN and DIP OA (all P<0.05). HRT usage less than 5 years was associated with increased severity of both DIP disease and HN. No factors were associated with CMC disease apart from ever breast-feeding which was protective (OR 0.37, 95% CI 0.18-0.79). CONCLUSIONS: These results require confirmation in clinical trials or carefully controlled longitudinal studies but suggest that estrogen exposure around the time of disease onset (either endogenous or exogenous) may have a "priming" effect on the severity of DIP OA while breast-feeding in earlier life may be protective for CMC OA.

A cross sectional study of the association between sex, smoking, and other lifestyle factors and osteoarthritis of the hand.

OBJECTIVE: To describe the association between sex, smoking, physical activity, occupation, and previous digit fracture and hand osteoarthritis (OA). METHODS: Cross sectional study of 522 subjects from 101 Tasmanian families (348 women, 174 men). Hand OA was assessed by 2 observers using the OARSI atlas for joint space narrowing and osteophytes at distal interphalangeal (DIP) and carpometacarpal joints as well as a score for Heberden's nodes based on hand photography. A structured questionnaire collected information regarding physical activity, sport participation, occupation, and smoking history. RESULTS: Women had a higher prevalence of hand OA and the increase with age was significantly higher for women at all sites (all p < 0.05). Ever smoking was associated with less frequent (OR 0.59, 95% CI 0.38, 0.92) and less severe Heberden's nodes (beta -0.60, 95% CI -1.03, -0.17), but not radiological disease. Recall of occupation, physical activity, and sport participation between the ages of 20 and 40 years had no association with the prevalence or severity of hand OA, while self-reported digital fracture was significantly associated with more common (OR 2.42, 95% CI 1.22, 4.83) and severe DIP joint disease (beta +3.92, 95% CI +1.50, +6.36). No factors were associated with carpometacarpal disease. CONCLUSION: In this sample, women had a higher prevalence of hand OA at all sites as well as greater severity and a steeper age gradient (implying higher incidence rates). Smoking may decrease the risk of Heberden's nodes while having no effect on radiological hand OA, suggesting a differential effect possibly at the time of disease onset. With the exception of digital fracture, these data do not support a causal role for occupation or activity in earlier life with regard to hand OA.

Cutaneous melanin density of Caucasians measured by spectrophotometry and risk of malignant melanoma, basal cell carcinoma, and squamous cell carcinoma of the skin.

Recent advances have enabled quite accurate estimation by spectrophotometry of the density of cutaneous melanin. The relation between skin cancers and this objective measure of skin phenotype is examined here. For this purpose, a population-based case-control study of subjects aged 20-59 years of northern European ancestry was conducted in Tasmania, Australia. Cases (n = 244) of cutaneous malignant melanoma during 1998-1999, and a sample of cases of basal cell carcinoma (n = 220) and squamous cell carcinoma (n = 195) of the skin were identified from cancer registrations. Controls (n = 483) were selected from a comprehensive population listing. Melanin at the upper inner arm was estimated from skin reflectance of light of 400 and 420 nm wavelengths. For melanoma, basal cell carcinoma, and squamous cell carcinoma, respectively, the odds ratios comparing the least with the highest of four melanin categories were 6.2 (95% confidence interval (CI): 2.3, 16.6), 6.3 (95% CI: 2.6, 15.1), and 4.2 (95% CI: 1.7, 10.8) for men and 1.9 (95% CI: 1.0, 3.7), 1.4 (95% CI: 0.7, 3.0), and 0.7 (95% CI: 0.3, 1.7) for women. The gender differences were not due to disparities in site of occurrence or (for melanoma) in thickness of the lesion. The authors conclude that, particularly for men, cutaneous melanin density at the upper inner arm is a strong predictor of risk of skin cancer.