Evidence of gene-gene interaction in hidradenitis suppurativa: a nationwide registry study of Danish twins.

BACKGROUND: Hidradenitis suppurativa (HS) is a recurrent inflammatory skin disease that, apart from rare causative loss-of-function mutations, has a widely unknown genetic aetiology. OBJECTIVES: To estimate the relative importance of genetic and environmental factors underlying susceptibility to HS. METHODS: Via the Danish Twin Registry and the Danish National Patient Registry we pulled together information on zygosity with that of HS status. Cases of HS were identified by the International Classification of Diseases (ICD)-8 (705·91) and ICD-10 (L73·2). Heritability was assessed by the classic biometric model and the possibility of gene-gene interaction via the multilocus modelling approach. RESULTS: Among 100 044 registered twins, we found 170 twins (from 163 pairs) diagnosed with HS. The seven concordant pairs were all monozygotic. Monozygotic twins had a case-wise concordance rate of 28% [95% confidence interval (CI) 7-49], corresponding to a familial risk of 73 (95% CI 13-133) times that of the background population. The biometrical modelling suggested a heritability of 0·80 (95% CI 0·67-0·93), and the multilocus index estimate was 230 (95% CI 60-400). This is highly indicative of gene-gene interactions, with the possibility of up to six interacting loci. CONCLUSIONS: This twin study was substantially larger and employed a more valid phenotype than previous studies. Genetics account for the majority of HS susceptibility, and HS is most likely caused by gene-gene interactions rather than monogenetic mutations or solely additive genetic factors. New approaches aimed at assessing potential interactions at a single-nucleotide polymorphism (SNP)-SNP level should be implemented in future HS genome-wide association studies.

Effect of cryotherapy on dose of adjuvant paclitaxel in early-stage breast cancer.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of paclitaxel. Though no pharmacological agents have been identified to prevent CIPN, cryotherapy with frozen gloves and socks may reduce the risk of developing CIPN and thereby increase the likelihood of patients completing the planned dose of paclitaxel. PATIENTS AND METHODS: Among women with early-stage breast cancer who received at least one cycle of paclitaxel, 119 were included in the 2016 cohort who received cryotherapy when they developed symptoms of CIPN, and 96 patients in the 2017 cohort who received prophylactic cryotherapy. From electronic patient records, data were abstracted on dates and doses of adjuvant paclitaxel, dose reductions, cycle delays, symptoms of CIPN, and whether and when frozen gloves and socks were used. The outcome was the proportion of patients completing the planned 720 mg/m2 of paclitaxel cumulated over nine cycles. The hazard ratio (HR) of a dose-limiting event due to CIPN was estimated in a Cox proportional hazards model. RESULTS: In the 2016 cohort, cryotherapy was needed due to symptoms of CIPN in 54 (45%) patients. Significantly, more patients, 77% in the 2017 cohort, completed the planned dose of 720 mg/m² compared with 64% in the 2016 cohort, p = 0.017. The HR of a dose reduction or cessation due to CIPN, adjusted for age and HER-2 status, was 0.50 (95% confidence interval 0.30-0.84), p = 0.009, for the 2017 cohort compared with the 2016 cohort. CONCLUSIONS: The results of this study suggest that prophylactic cryotherapy may reduce the risk of a dose-limiting event due to CIPN and increase the proportion of patients completing the planned dose of paclitaxel in adjuvant treatment of early-stage breast cancer. Despite this, CIPN remains to be an important dose-limiting toxicity of paclitaxel.

The CODATwins Project: The Current Status and Recent Findings of COllaborative Project of Development of Anthropometrical Measures in Twins.

The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.

Heritability of the Number of Teeth in Middle-Aged and Older Danish Twins.

Tooth loss is a common health concern in older adults. We aimed to estimate the relative contributions of genetic and environmental factors to the variation in the number of teeth in middle-aged and older populations using a population-based cohort of Danish twins. The study included 5,269 Danish middle-aged or older twins who provided data on the number of teeth at baseline by structured interviews. The data were analyzed using univariate liability threshold modeling, stratified by sex and age, to estimate familial risk of tooth loss as well as estimates of heritability. In the whole cohorts, 23% of participants were edentate and 53% had retained 20 or more teeth. A statistical model including additive genetic factors and environmental factors partly shared by co-twins and partly unique to each individual twin gave the best statistical fit for the number of teeth in both age categories as well as in men and women. Overall, additive genetic factors explained 36% (95% confidence interval [CI]: 23% to 49%), common environmental factors 20% (95% CI: 9% to 31%), and unique environmental factors 44% (95% CI: 40% to 48%) of the total variation of the number of teeth. This study indicates that a substantial part of the variation in tooth loss is explained by genetic as well as environmental factors shared by co-twins. Our results implied that family background importantly affects tooth loss in both the middle-aged and the older populations. Family history is thus an important factor to take into account in dental health care.

Heritability assessment of cartilage metabolism. A twin study on circulating procollagen IIA N-terminal propeptide (PIIANP).

OBJECTIVE: The aim of this investigation was to estimate the heritability of circulating collagen IIA N-terminal propeptide (PIIANP) by studying mono- and dizygotic healthy twin pairs at different age and both genders. DESIGN: 598 monozygotic (MZ) and dizygotic (DZ) twin individuals aged 18-59 years were recruited from the Danish Twin Registry. PIIANP was measured by competitive ELISA. The similarity of circulating PIIANP among MZ and DZ twins was assessed by intraclass correlations according to traits. The heritability was estimated by variance component analysis accounting for additive and dominant genetic factors as well as shared and non-shared environment but ignoring epistasis (genetic inter-locus interaction) and gene-environment interaction. RESULTS: The intraclass correlation of PIIANP in MZ and DZ twins was 0.69 (0.60-0.76) and 0.46 (0.34-0.58) respectively indicating a significant genetic impact on PIIANP in serum. Additive genetic effects explained 45% (21-70%), shared environment 24% (7-53%) and non-shared environment 31% (24-39%) of the total variance. The heritability estimate did not differ across ages and between genders. CONCLUSIONS: The study shows that approximately 45% of the collagen IIA synthesis as assessed by the collagen IIA N-terminal propeptide in serum is attributable to genetic effectors while individual and shared environment account for 24% and 31% respectively. The heritability does not differ between genders or according to age.

Surfactant protein D of the innate immune defence is inversely associated with human obesity and SP-D deficiency infers increased body weight in mice.

Surfactant protein D (SP-D) is a key regulator of pathogen-induced inflammation. SP-D is further involved in lipid homeostasis in mouse lung and circulation and recent data have demonstrated that the body mass index (BMI; in kg/m(2)) is influenced by genes in common with SP-D. The objective of the present study was to describe the association between serum SP-D and weight, waist circumference or BMI, and furthermore to observe body weight development in SP-D-deficient (Spd-/-) mice. As a part of the Danish population-based twin study (GEMINAKAR) on the metabolic syndrome, we analysed 1476 Danish twins for serum SP-D and investigated associations with weight, waist circumference and BMI by multiple regression analysis. Serum SP-D was significantly and inversely associated with weight (P = 0.001) and waist circumference in men (P < 0.001) and to BMI in both genders (P = 0.039 women, P < 0.001 men). The age-dependent increase in serum SP-D was most prominent in lean persons (BMI < 20). Spd-/- mice and wild-type mice were subjected to a feeding study and body weights were recorded in a time course over 24 weeks. Spd-/- mouse weight gain was significantly increased, with 90 mg/week (P < 0.0001) in males on normal chow. Fat percentage was significantly increased by 17% in the Spd-/- male mice (P = 0.003). We conclude, that there is an association between low levels or absent SP-D and obesity.

Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells.

The purpose of this study was to clarify whether HLA-DR expression of colorectal tumour cells or the CD4+/CD8+ ratio of the tumour infiltrating lymphocytes is significantly associated with the prognosis of colorectal cancer. Using flow cytometry, we studied the tumour cell expression of the HLA class II in 70 enzymatically dissociated colorectal cancers and the phenotype of tumour infiltrating lymphocytes (TILs) in 41 cases. There was no trend in 5-year survival between three levels (low, medium, high) of HLA-DR expression on the tumour cells. Patients with low CD4+/CD8+ ratios had a better clinical course, with significantly higher 5-year survival, p=0.046, independent of the Dukes stage and age. Our results have implications for tumour immunology; colorectal cancer cells might be a target for cytotoxic T-lymphocytes, however the tumour cells are not able to initiate an immune response. Stimulation of the immune system could possible be obtained using dendritic cells cultured in vitro and loaded with tumour antigens.