Full exome sequencing of 11 families with Hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is not a well-studied or easily treated disease. Genetic information is essential for advances in the understanding and treatment of HS. This study aims to examine mutations in the gamma-secretase complex, the Notch signalling pathway and to perform a Mendelian analysis of genetic variants that segregated with disease in a full exome sequencing of 11 families with HS. METHOD: Whole-exome sequencing and Mendelian analysis of 11 families with HS from Denmark. Patients with a clinical diagnosis of active HS and a positive family history of HS were recruited. Consenting family members were enrolled and examined for HS as well. We included 11 families, with a total of 51 participants, 24 with HS and 27 without. Whole-exome sequencing using HiSeq platform as paired-end 2 × 150 bases was used. RESULTS: We found mutations in the Notch pathway for all families. We found mutations in the PSENEN and APH1B of the gamma-secretase genes. We also report 161 variants of unknown significance that segregated with the disease within these families. CONCLUSIONS: We did not find causative mutation for each family in this study, supporting the theory that HS is rarely caused by single-gene mutations. We suggest that future genetic studies should be focused on genome-wide association with thousands of cases, as this technique is better suited for suspected polygenic diseases.

Pain and inflammation in hidradenitis suppurativa correspond to morphological changes identified by high-frequency ultrasound.

BACKGROUND: Hidradenitis suppurativa (HS) is an inflammatory skin disease with a chronic intermittent course. The current classification systems used to categorize disease severity provide limited insight into the degree of inflammation and pain, which are key symptoms of the disease. OBJECTIVE: We sought to investigate the correlation and validity of simple patient- and investigator-assessed items related to inflammation with morphological changes identified by high-frequency ultrasound in HS. METHODS: Twenty patients with the clinical diagnosis of HS were enrolled in this study. All patients underwent clinical examinations during which one representative inflammatory nodule was selected in each patient based on the anamnestic information, patient experience and clinical presentation. Tenderness and flare activity of the representative nodule were graded by the patients and erythema by the investigator. Subsequently, all patients underwent high-resolution ultrasound scanning of their representative nodule. RESULTS: We found significant associations between the size of the representative nodule (the diameter in the transverse plane) and patient assessments of flare activity and tenderness. Moreover, we found a marked association between the size of the nodules and investigator assessment of erythema. CONCLUSION: Patient assessments of flare activity and pain, and investigator assessment of erythema are strongly associated with morphological changes identified using ultrasound, suggesting that these patient- and investigator-assessed items might be strong indicators of the degree of present inflammation in HS.

Do generalists and specialists agree on descriptive acne morphology?

BACKGROUND: Acne is a common skin disease, which is treated by many different specialities. Clinical guidelines for treatment are based on the recognition of acne morphology. The assessment of acne morphology is therefore an important element of the proper diagnosis and treatment of acne. OBJECTIVE: To evaluate the level of congruence in the assessment of acne morphology in General Practitioners (GPs) and Dermatologists compared to the assessment of an expert. METHODS: The study was conducted during 2008-2009. Randomly selected GP and Dermatologists Practitioners, (DPs) from Denmark were invited to complete an on-line questionnaire. The questionnaire was based on seven cases, each presented with digital photos and a short history. The respondents were asked to identify the morphology by marking their answer on a closed list. Congruence, variation and the participants' assessment were compared with a priori expert assessment using odds ratios, Fishers exact test and Index of Qualitative Variation. RESULTS: Of the 1700 GPs and 110 DPs invited, 355 GPs and 99 DPs participated. In all seven cases, DPs were more in accordance with expert opinion than were GPs. In addition, the GPs had a greater variation in the distribution of answers. CONCLUSION: GPs described acne morphology recognized clinical hallmarks of severity in acne less well than dermatologists and were far less consistent.

High platelet volume and increased risk of myocardial infarction: 39,531 participants from the general population.

BACKGROUND: Active platelets are large and contribute to development of myocardial infarction (MI). Platelet size is measured automatically as mean platelet volume (MPV) together with platelet count. OBJECTIVES: We tested the hypothesis that increased MPV is associated with risk of MI in the general population independent of known cardiovascular risk factors. METHODS: We examined 39,531 men and woman from the Danish general population (the Copenhagen General Population Study), of whom 1300 developed MI. RESULTS: After multifactorial adjustment for known cardiovascular risk factors, risk of MI was increased by 37% (95% CI, 18-59%) in the middle and 30% (12-52%) in the upper vs. the lower tertile of MPV. Compared with the 1st quintile of MPV, there was corresponding increased risk of MI of 13% (-7% to 39%), 35% (11-64%), 31% (8-59%) and 29% (6-57%) in the 2nd, 3rd, 4th and 5th quintile, respectively. Similar values for octiles were increases in MI risk of -3% (-25% to 26%), 15% (-10% to 46%), 31% (1- 69%), 32% (5-68%), 31% (2-67%), 27% (-1% to 62%) and 26% (-1% to 61%), respectively, in the 2nd through to the 8th octile vs. the 1st octile of MPV. Use of antiplatelet therapy did not modify these risk estimates. Finally, in prospective, multifactorially adjusted analyses, risk of MI increased by 38% (8-75%) in individuals with MPV ≥ 7.4 vs. < 7.4 fL. CONCLUSIONS: Increased MPV is associated with increased risk of MI independent of known cardiovascular risk factors.

Hidradenitis suppurativa and Crohn's disease: two cases that support an association.

An association between Crohn's disease and hidradenitis suppurativa has been suggested. The presence of Crohn's disease generally precedes the diagnosis of hidradenitis suppurativa. We present two new cases in which hidradenitis lesions developed before Crohn's disease, suggesting an overlap and supporting an association. Furthermore, in one of these cases, treatment with infliximab resulted in marked improvement in both the Crohn's disease and hidradenitis suppurativa.

NOD2/CARD15 genotype, cardiovascular disease and cancer in 43,600 individuals from the general population.

OBJECTIVES: The NOD2/CARD15 gene is involved in the innate immune response, and thus in inflammation. Three polymorphisms in this gene (Arg702Trp rs2066844, Gly908Arg rs2066845 and Leu1007fsinsC rs5743293) have been associated with increased risk of the inflammatory bowel disease, the Crohn's disease. We tested whether these polymorphisms are also associated with increased risk of cardiovascular disease and cancer, in which the innate immune system and inflammation may influence pathogenesis. DESIGN, SETTING AND SUBJECTS: We genotyped 43,596 white individuals from two large Danish general population cohorts followed for 31 years: the Copenhagen City Heart Study (n = 10,597) and the Copenhagen General Population Study (n = 32,999). We examined the risk of cardiovascular disease (2743 and 3890, respectively, in the two studies) and cancer (2144 and 3241, respectively) by NOD2/CARD15 genotype using Cox and logistic regressions in both studies. To maximize statistical power, the three NOD2/CARD15 genetic variants were analysed together as follows: noncarriers for all three variants, heterozygotes for one of the three variants and homozygotes for one of the three variants pooled with compound heterozygotes for two variants. RESULTS: Multifactorially adjusted hazard ratios for cardiovascular disease and cancer in NOD2/CARD15 heterozygotes or homozygotes/compound heterozygotes versus noncarries did not differ from 1.0 in the Copenhagen City Heart Study or in the Copenhagen General Population Study. The corresponding multifactorially adjusted odds ratios likewise did not differ from 1.0 in either study. CONCLUSIONS: The NOD2/CARD15 Arg702Trp, Gly908Arg and Leu1007fsinsC polymorphisms were not associated with increased risk of cardiovascular disease or cancer in the Danish general population.

NOD2/CARD15 genotype and common gastrointestinal diseases in 43,600 individuals.

OBJECTIVES: NOD2/CARD15 is involved in the innate immune response and three polymorphisms in this gene (Arg702Trp rs2066844, Gly908Arg rs2066845 and Leu1007fsinsC rs5743293) have been associated with risk of the rare Crohn's disease. We tested the hypothesis that polymorphisms in NOD2/CARD15 associate with risk of nine common gastrointestinal diseases. DESIGN AND SETTING: We genotyped 43 596 white individuals from the Danish general population followed for 31 years, during which time 782 developed oesophagitis and reflux, 1395 ulcus ventriculi and duodeni, 1384 gastritis and dyspepsia, 1407 appendicitis, 646 irritable bowel syndrome, 1301 infectious diseases of the gastrointestinal tract, 681 anal fissure, fistula and abscess, 826 gastrointestinal cancer and 161 developed cancer in liver and pancreas. RESULTS: Some 89% were non-carriers, 11% heterozygotes, 0.15% homozygotes and 0.23% compound heterozygotes. Cumulative incidences differed by genotype for appendicitis (log-rank P = 0.02), anal fissure, fistula and abscess (P = 0.003) and gastrointestinal cancer (P = 0.004), but not for any of the other endpoints. Compared with non-carriers, age and sex adjusted hazard ratios were 2.7 (95%CI 1.4-5.5) for appendicitis amongst compound heterozygotes, 3.2 (1.3-7.8) for anal fissure, fistula and abscess amongst compound heterozygotes, and 3.8 (1.6-9.2) for gastrointestinal cancer amongst homozygotes, whilst other genotypes did not have increased risk. The increased risk of gastrointestinal cancer amongst homozygotes appeared to be similar amongst both men and women and amongst those below or above 60 years, and likely included both upper gastrointestinal cancer and colorectal cancer. CONCLUSIONS: NOD2/CARD15 polymorphisms are not major risk factors for common gastrointestinal diseases; however, we cannot completely exclude association with appendicitis, anal fissure, fistula and abscess, and gastrointestinal cancer.