Bardur Sigurgeirsson

Risk of cancer in patients with dermatomyositis or polymyositis : a population-based study

BACKGROUND An association between polymyositis and cancer was first proposed in 1916, but the existence of the association has been disputed. An association between dermatomyositis and cancer is better accepted, but its magnitude is not known. METHODS We undertook a study to provide accurate estimates of the risk of cancer in patients with dermatomyositis or polymyositis. We studied the incidence of cancer and the rate of mortality from cancer in a population-based cohort of 788 patients with dermatomyositis or polymyositis in Sweden from 1963 through 1983. The results were compared with those for the general population. RESULTS Among the 396 patients with polymyositis, 42 cancers were diagnosed at the same time or after polymyositis was diagnosed in 37 patients (9 percent). The relative risk of cancer was 1.8 (95 percent confidence interval, 1.1 to 2.7) in the male patients and 1.7 (95 percent confidence interval, 1.0 to 2.5) in the female patients. Eighty-four males and 85 females died, and in 24 of these cases (14 percent) cancer was the principal cause of death. The mortality ratio (the rate of mortality from cancer in these patients as compared with that in the general population) was 0.90 (95 percent confidence interval, 0.6 to 1.4). Among the 392 patients with dermatomyositis, 61 cancers were diagnosed at the same time or after dermatomyositis was diagnosed in 59 patients (15 percent). The relative risk of cancer was 2.4 (95 percent confidence interval, 1.6 to 3.6) in the male patients and 3.4 (95 percent confidence interval, 2.4 to 4.7) in the female patients. Fifty-seven males and 110 females died, and in 67 of these cases (40 percent) cancer was the principal cause of death (mortality ratio, 3.8; 95 percent confidence interval, 2.9 to 4.8). CONCLUSIONS The risk of cancer is increased in patients with polymyositis or dermatomyositis. In patients with dermatomyositis there is also a higher rate of mortality from cancer.

Genetic determinants of hair, eye and skin pigmentation in Europeans

Hair, skin and eye colors are highly heritable and visible traits in humans. We carried out a genome-wide association scan for variants associated with hair and eye pigmentation, skin sensitivity to sun and freckling among 2,986 Icelanders. We then tested the most closely associated SNPs from six regions—four not previously implicated in the normal variation of human pigmentation—and replicated their association in a second sample of 2,718 Icelanders and a sample of 1,214 Dutch. The SNPs from all six regions met the criteria for genome-wide significance. A variant in SLC24A4 is associated with eye and hair color, a variant near KITLG is associated with hair color, two coding variants in TYR are associated with eye color and freckles, and a variant on 6p25.3 is associated with freckles. The fifth region provided refinements to a previously reported association in OCA2, and the sixth encompasses previously described variants in MC1R.

Sequence variants at the TERT-CLPTM1L locus associate with many cancer types

The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 × 10−12). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 × 10−8) and urinary bladder, prostate and cervix cancer (ORs = 1.07−1.31, all P < 4 × 10−4). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 × 10−4). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.

Parental origin of sequence variants associated with complex diseases.

Effects of susceptibility variants may depend on from which parent they are inherited. Although many associations between sequence variants and human traits have been discovered through genome-wide associations, the impact of parental origin has largely been ignored. Here we show that for 38,167 Icelanders genotyped using single nucleotide polymorphism (SNP) chips, the parental origin of most alleles can be determined. For this we used a combination of genealogy and long-range phasing. We then focused on SNPs that associate with diseases and are within 500 kilobases of known imprinted genes. Seven independent SNP associations were examined. Five—one with breast cancer, one with basal-cell carcinoma and three with type 2 diabetes—have parental-origin-specific associations. These variants are located in two genomic regions, 11p15 and 7q32, each harbouring a cluster of imprinted genes. Furthermore, we observed a novel association between the SNP rs2334499 at 11p15 and type 2 diabetes. Here the allele that confers risk when paternally inherited is protective when maternally transmitted. We identified a differentially methylated CTCF-binding site at 11p15 and demonstrated correlation of rs2334499 with decreased methylation of that site.

ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma

Fair color increases risk of cutaneous melanoma (CM) and basal cell carcinoma (BCC). Recent genome-wide association studies have identified variants affecting hair, eye and skin pigmentation in Europeans. Here, we assess the effect of these variants on risk of CM and BCC in European populations comprising 2,121 individuals with CM, 2,163 individuals with BCC and over 40,000 controls. A haplotype near ASIP, known to affect a similar spectrum of pigmentation traits as MC1R variants, conferred significant risk of CM (odds ratio (OR) = 1.45, P = 1.2 × 10−9) and BCC (OR = 1.35, P = 1.2 × 10−6). The variant in TYR encoding the R402Q amino acid substitution, previously shown to affect eye color and tanning response, conferred risk of CM (OR = 1.21, P = 2.8 × 10−7) and BCC (OR = 1.14, P = 6.1 × 10−4). An eye color variant in TYRP1 was associated with risk of CM (OR = 1.15, P = 4.3 × 10−4). The association of all three variants is robust with respect to adjustment for the effect of pigmentation.

New common variants affecting susceptibility to basal cell carcinoma

In a follow-up to our previously reported genome-wide association study of cutaneous basal cell carcinoma (BCC), we describe here several new susceptibility variants. SNP rs11170164, encoding a G138E substitution in the keratin 5 (KRT5) gene, affects risk of BCC (OR = 1.35, P = 2.1 × 10−9). A variant at 9p21 near CDKN2A and CDKN2B also confers susceptibility to BCC (rs2151280[C]; OR = 1.19, P = 6.9 × 10−9), as does rs157935[T] at 7q32 near the imprinted gene KLF14 (OR = 1.23, P = 5.7 × 10−10). The effect of rs157935[T] is dependent on the parental origin of the risk allele. None of these variants were found to be associated with melanoma or fair-pigmentation traits. A melanoma- and pigmentation-associated variant in the SLC45A2 gene, L374F, is associated with risk of both BCC and squamous cell carcinoma. Finally, we report conclusive evidence that rs401681[C] in the TERT-CLPTM1L locus confers susceptibility to BCC but protects against melanoma.

Two newly identified genetic determinants of pigmentation in Europeans.

We present results from a genome-wide association study for variants associated with human pigmentation characteristics among 5,130 Icelanders, with follow-up analyses in 2,116 Icelanders and 1,214 Dutch individuals. Two coding variants in TPCN2 are associated with hair color, and a variant at the ASIP locus shows strong association with skin sensitivity to sun, freckling and red hair, phenotypic characteristics similar to those affected by well-known mutations in MC1R.

Quality of Life and Prevalence of Arthritis Reported by 5,795 Members of the Nordic Psoriasis Associations Data from the Nordic Quality of Life Study

Quality of life measures are widely used in dermatology as well as in rheumatology, but there are no large studies taking arthritis into consideration when studying quality of life in psoriasis. The aim of this study was to investigate psoriasis-related quality of life in a large sample of members of the psoriasis associations from the Nordic countries including an arthritis-related evaluation. The prevalence of reported arthritis within the groups was also estimated. An Arthritis Disability Index suitable for parallel use together with Finlays Psoriasis Disability Index was constructed. A total of 5,795 members and 702 patients seen by Nordic dermatologists rated the severity of their disease and completed the Psoriasis Disability Index formula and a Psoriasis Life Stress Inventory, and if arthritis had been diagnosed, the Arthritis Disability Index formula. Approximately 30% of all psoriatic patients, irrespective of group, received a diagnosis of arthritis either by their dermatologist or a rheumatologist. Members previously hospitalized for their disease had a higher frequency of arthritis (41%) than those without a history of hospitalization (23%). The highest prevalence of arthritis was found in Norway (33.8%). Members with arthritis exhibited greater impairment of psoriasis-related quality of life, longer disease duration, and greater self-reported disease severity for psoriasis. Important predictors for impairment of arthritis-related quality of life were pain, number of affected joints, and restriction of joint mobility. These data show, that the prevalence of arthritis in psoriasis may be significantly higher than the previously accepted average of 7%. The results demonstrate that when studying quality of life in psoriasis, arthritis and arthralgia are important independent factors to be included in the evaluation.

Common variants on 1p36 and 1q42 are associated with cutaneous basal cell carcinoma but not with melanoma or pigmentation traits

To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide SNP association study of 930 Icelanders with BCC and 33,117 controls. After analyzing 304,083 SNPs, we observed signals from loci at 1p36 and 1q42, and replicated these associations in additional sample sets from Iceland and Eastern Europe. Overall, the most significant signals were from rs7538876 on 1p36 (OR = 1.28, P = 4.4 × 10−12) and rs801114 on 1q42 (OR = 1.28, P = 5.9 × 10−12). The 1p36 locus contains the candidate genes PADI4, PADI6, RCC2 and ARHGEF10L, and the gene nearest to the 1q42 locus is the ras-homolog RHOU. Neither locus was associated with fair pigmentation traits that are known risk factors for BCC, and no risk was observed for melanoma. Approximately 1.6% of individuals of European ancestry are homozygous for both variants, and their estimated risk of BCC is 2.68 times that of noncarriers.

A Melanoma Epidemic in Iceland: Possible Influence of Sunbed Use

Since 1980, sunbed use and travel abroad have dramatically increased in Iceland (64°-66°N). The authors assessed temporal trends in melanoma incidence by body site in Iceland in relation to sunbed use and travel abroad. Using joinpoint analysis, they calculated estimated annual percent changes (EAPCs) and identified the years during which statistically significant changes in EAPC occurred. Between 1954 and 2006, the largest increase in incidence in men was observed on the trunk (EAPC = 4.6%, 95% confidence interval: 3.2, 6.0). In women, the slow increase in trunk melanoma incidence before 1995 was followed by a significantly sharper increase in incidence, mainly among women aged less than 50 years, resembling an epidemic incidence curve (1995-2002: EAPC = 20.4%, 95% confidence interval: 9.3, 32.8). In 2002, the melanoma incidence on the trunk was higher than the incidence on the lower limbs for women. Sunbed use in Iceland expanded rapidly after 1985, mainly among young women, and in 2000, it was approximately 2 and 3 times the levels recorded in Sweden and in the United Kingdom, respectively. Travels abroad were more prevalent among older Icelanders. The high prevalence of sunbed use probably contributed to the sharp increase in the incidence of melanoma in Iceland.