Large-scale whole-genome sequencing of the Icelandic population.

Here we describe the insights gained from sequencing the whole genomes of 2,636 Icelanders to a median depth of 20×. We found 20 million SNPs and 1.5 million insertions-deletions (indels). We describe the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway and conservation score. We demonstrate an excess of homozygosity and rare protein-coding variants in Iceland. We imputed these variants into 104,220 individuals down to a minor allele frequency of 0.1% and found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation, several mutations in ABCB4 that increase risk of liver diseases and an intronic variant in GNAS associating with increased thyroid-stimulating hormone levels when maternally inherited. These data provide a study design that can be used to determine how variation in the sequence of the human genome gives rise to human diversity.

CRP is associated with lung function decline in men but not women: a prospective study.

Systemic inflammation is associated with impaired lung function. Studies, most cross-sectional, report a stronger association between systemic inflammation and lung function impairment in men than women. The aim was to evaluate gender differences in the longitudinal association between systemic inflammation and lung function. We used data from randomly chosen residents of Reykjavík, born 1940-54, who were investigated in three stages: Baseline (1973-75; 1983-85) and follow-up (2001-03). The participants (n = 1049, 574 women) had a mean age of 28 ± 6 years at baseline and mean follow-up time of 27 ± 4 years. At each stage lung function (FEV(1) and FVC) and C-reactive protein (CRP) were evaluated. Change in FEV(1) (p = 0.04) and FVC (p = 0.01) was associated with baseline CRP in men but not in women. In the multiple variable analysis, CRP at baseline was associated with a decline in FEV(1) (-3.1 mL/year, 95% CI: -5.1, -0.99) and FVC (-2.5 mL/year, 95% CI: -4.4, -0.65) in men but not in women. Similarly during follow-up, change in CRP, standardised to 1SD, was associated with a decline in FEV(1) (-0.19 mL/year, 95% CI: -0.30, -0.07) and FVC (-0.11 mL/year, 95% CI: -0.22, -0.01)) in men but not in women. This prospective study confirms a stronger association between systemic inflammation and lung function decline in men than in women. This may indicate a gender difference in the mechanisms of lung function decline.

Irritable bowel syndrome: physicians' awareness and patients' experience.

AIM: To study if and how physicians use the irritable bowel syndrome (IBS) diagnostic criteria and to assess treatment strategies in IBS patients. METHODS: A questionnaire was sent to 191 physicians regarding IBS criteria, diagnostic methods and treatment. Furthermore, 94 patients who were diagnosed with IBS underwent telephone interview. RESULTS: A total of 80/191 (41.9%) physicians responded to the survey. Overall, 13 patients were diagnosed monthly with IBS by specialists in gastroenterology (SGs) and 2.5 patients by general practitioners (GPs). All the SGs knew of the criteria to diagnose IBS, as did 46/70 (65.7%) GPs. Seventy-nine percent used the patient's history, 38% used a physical examination, and 38% exclusion of other diseases to diagnose IBS. Only 18/80 (22.5%) physicians used specific IBS criteria. Of the patients interviewed, 59/94 (62.8%) knew they had experienced IBS. Two out of five patients knew IBS and had seen a physician because of IBS symptoms. Half of those received a diagnosis of IBS. A total of 13% were satisfied with treatment. IBS affected daily activities in 43% of cases. CONCLUSION: Half of the patients with IBS who consulted a physician received a diagnosis. Awareness and knowledge of diagnostic criteria for IBS differ between SGs and GPs.

Natural history of irritable bowel syndrome in women and dysmenorrhea: a 10-year follow-up study.

Background. Studies have shown that women are more likely to have irritable bowel syndrome (IBS) and more women seek healthcare because of IBS than men. Aim. We wanted to examine the natural history of IBS and dysmenorrhea in women over a 10-year period and to assess the change in IBS after menopause. Method. A population-based postal study. A questionnaire was mailed to the same age- and gender-stratified random sample of the Icelandic population aged 18-75 in 1996 and again in 2006. Results. 77% premenopausal women had dysmenorrhea in the year 1996 and 74% in 2006. 42% of women with dysmenorrhea had IBS according to Manning criteria in the year 2006 and 49% in 1996. 26% of women with dysmenorrhea had IBS according to Rome III 2006 and 11% in the year 1996. In 2006 30% women had severe or very severe dysmenorrhea pain severity. More women (27%) reported severe abdominal pain after menopause than before menopause 11%. Women without dysmenorrhea were twice more likely to remain asymptomatic than the women with dysmenorrhea. Women with dysmenorrhea were more likely to have stable symptoms and were twice more likely to have increased symptoms. Conclusion. Women with IBS are more likely to experience dysmenorrhea than women without IBS which seems to be a part of the symptomatology in most women with IBS. IBS symptom severity seems to increase after menopause.

Natural history of functional gastrointestinal disorders: comparison of two longitudinal population-based studies.

BACKGROUND: Functional gastrointestinal disorders are common but information on their natural history is limited. AIMS: To document the natural history of functional gastrointestinal disorders in a population based study and to compare with the Olmsted County study. METHOD: A questionnaire was mailed to the same age- and gender-stratified random sample of the Icelandic population aged 18-75 in 1996 and 2006. Results were compared to the Olmsted County study. RESULTS: Prevalence of functional gastrointestinal disorder symptoms was stable between these periods in time: 16.9% and 17.2% for irritable bowel syndrome, and 4.8% and 6.1% for functional dyspepsia. Onset of each disorder was more often higher in the Olmsted County study than in Iceland. Disappearance rates were similar for both studies. Transition probabilities varied across the different subgroups and were different between studies. The same proportion had the same symptoms in the initial and final studies. More subjects had no symptoms in Iceland (52% vs. 40%) and different symptoms at follow up (38% vs. 23%). CONCLUSION: Prevalence of functional gastrointestinal disorder symptoms was stable over time but the turnover in symptoms was high. A higher number of subjects had no symptoms in Iceland than in Olmsted County and there was a greater variation in subjects having different symptoms at follow up.

Natural history of heartburn: a 10-year population-based study.

AIM: To study the natural history and prevalence of heartburn at a 10-year interval, and to study the effect of heartburn on various symptoms and activities. METHODS: A population-based postal study was carried out. Questionnaires were mailed to the same age- and gender-stratified random sample of the Icelandic population (aged 18-75 years) in 1996 and again in 2006. Subjects were classified with heartburn if they reported heartburn in the preceding year and/or week, based on the definition of heartburn. RESULTS: Heartburn in the preceding year was reported in 42.8% (1996) and 44.2% (2006) of subjects, with a strong relationship between those who experienced heartburn in both years. Heartburn in the preceding week was diagnosed in 20.8%. There was a significant relationship between heartburn, dyspepsia and irritable bowel syndrome. Individuals with a body mass index (BMI) below or higher than normal weight were more likely to have heartburn. Heartburn caused by food or beverages was reported very often by 20.0% of subjects. CONCLUSION: Heartburn is a common and chronic condition. Subjects with a BMI below or higher than normal weight are more likely to experience heartburn. Heartburn has a great impact on daily activities, sleep and quality of life.

Persistent Chlamydia Pneumoniae serology is related to decline in lung function in women but not in men. Effect of persistent Chlamydia pneumoniae infection on lung function.

BACKGROUND: Chlamydia pneumoniae (C pn) infection causes an acute inflammation in the respiratory system that may become persistent, but little is known about the long-term respiratory effects of C pn infections. AIM: To estimate the long term respiratory effects of C pn with change in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) as a main outcome variable. METHODS: The study comprised of 1109 subjects (500 men and 609 women, mean age 28 ± 6 years) that participated in the Reykjavik Heart Study of the Young. Spirometry and blood samples for measurements of IgG antibodies for C pn were done at inclusion and at the end of the follow-up period (mean follow-up time 27 ± 4 years). RESULTS: Having IgG against C pn at both examinations was significantly associated to a larger decrease in FEV1 (6 mL/year) and FVC (7 mL/year) in women but not in men. In women the association between C pn and larger FEV1 decline was only found in women that smoked at baseline where having C pn IgG was associated with 10 mL/year decline compared to smokers without C pn IgG. These results were still significant after adjustment for age, smoking and change in body weight. CONCLUSION: Our results indicate that persistent C pn serology is related to increased decline in lung function in women but not in men. This effect was, however, primarily found in smoking women. This study is a further indication that the pathophysiological process leading to lung impairment may differ between men and women.

Colonic adenomas found via colonoscopy: yield and risk factors for high-grade dysplasia.

BACKGROUND AND AIMS: The adenoma-carcinoma sequence is the model for colorectal carcinoma (CRC) developing through high-grade dysplasia (HGD) to CRC. The aim was to assess prevalence and location of adenomas found during colonoscopy and risk factors for HGD. MATERIAL AND METHODS: A population-based study using all colonoscopies and polyp specimens registered between 2000 and 2004 in Iceland. Multiple logistic regression analysis was used to assess independent risk factors for HGD. RESULTS: A total of 3,315 adenomas were removed from 2,385 patients. Only 14.0% were >1 cm in size. HGD was found in 135 (4.1%) of the adenomas and tubulovillous/villous histology in 15.0%. The prevalence of adenomas in the 50- to 69-year age group was 15.5%, and 21.5% in the >or=70-year group. 60.9% of them were located distal to the splenic flexure. Independent risk factors for HGD were in the order of importance: size; multiplicity; tubulovillous/villous histology; location in rectum, and age. The prevalence of HGD in the group with an adenoma size of 0.6-1.0 cm was 4.1% and in the 40- to 69-year age group it was 3.7%. CONCLUSION: The study suggests a potential 15% yield per colonoscopy of adenomas in 50- to 69-year-olds. There is an appreciable risk of HGD in diminutive polyps and in middle age.

Natural history of functional dyspepsia: a 10-year population-based study.

BACKGROUND: Functional dyspepsia (FD) is a common disorder, but information on its natural history is limited. AIM: To study the natural history of FD as assessed by 2 criteria over a 10-year period. METHOD: A population-based study conducted by mailing a questionnaire to the same age- and gender-stratified random sample of the Icelandic population aged 18-75 in 1996 and again in 2006. FD was estimated by the Functional Dyspepsia Score List and by dyspepsia subgroups categorized into 4 groups: (1) frequent upper pain, (2) meal-related, (3) nausea or vomiting, and (4) combinations of these groups. RESULTS: FD was diagnosed in 13.9% of the subjects in the 1996 sample (11.3% male, 15.8% female) and 16.7% in 2006 (12.3% male, 20.2% female) with a significant difference between males and females in 2006. Dyspepsia subgroup criteria showed a higher prevalence than conventional FD criteria. The proportion of FD subjects in one of the dyspepsia subgroups was low. There was a significant relationship between FD and heartburn and irritable bowel syndrome. A high proportion of subjects who seek medical care have FD. CONCLUSION: FD was stable over the 10-year period, but there was turnover in symptoms and increased intensity and frequency of gastrointestinal pain. Dyspepsia subgroup criteria showed a higher prevalence than FD, which was more common in young subjects and females. FD poses a heavy burden on the health care system.

Liver cirrhosis in Iceland and Sweden: incidence, aetiology and outcomes.

OBJECTIVE: The objectives of this study were to investigate the incidence, aetiology and mortality of liver cirrhosis in Iceland and in Gothenburg in Sweden. Further objectives were prognosis in relation to different aetiologies and to evaluate the relationship between alcohol consumption in these countries and the incidence of alcoholic cirrhosis in recent decades. The incidence and mortality of liver cirrhosis in Iceland has been reported to be the lowest in the Western world. There are very few data on aetiology, incidence and prognosis among cirrhotics in Sweden. MATERIAL AND METHODS: All patients diagnosed with liver cirrhosis in Gothenburg (600,000 inhabitants) and Iceland (300,000 inhabitants) during the period 1994-2003 were included. RESULTS: A total of 918 patients in Gothenburg and 98 in Iceland were identified. The annual incidence in Gothenburg was 15.3+/-2.4/100,000 compared to 3.3+/-1.2/100,000 in Iceland (p<0.0001). In Gothenburg, 69% were male and in Iceland 52% (p<0.001). In Gothenburg, 50% of the patients had alcoholic cirrhosis compared to 29% in Iceland (p<0.0001). In Gothenburg, the patients had a higher Child-Pugh score (9.0) (SD 2.5) compared to Iceland (7.3) (SD 2.7) (p<0.0001). There was no difference in survival between patients with alcoholic liver disease and those with other aetiologies. CONCLUSIONS: The incidence of liver cirrhosis is low in Iceland, i.e. 24% of the incidence in Gothenburg, due to the lower incidence of alcoholic and hepatitis C cirrhosis in Iceland. No increasing trends in the incidence of cirrhosis in these two countries were observed during the study period.

Infections and obesity: A multinational epidemiological study.

Viral infections have been associated with the aetiology of obesity in animal models. This study investigates the association between 7 serological markers of infections and body mass index (BMI) in a population based sample. Individuals (n=985, mean age 42+/-97 (28-55) y, mean BMI 25.594.2) from Iceland, Sweden and Estonia underwent a structured interview and blood sampling. IgG antibodies were measured against Helicobacter pylori and the cagA protein, hepatitis A virus, Toxoplasma gondii, herpes simplex virus 1, Chlamydia pneumoniae, Epstein-Barr virus and cytomegalovirus. High-sensitive C-reactive protein (CRP) was measured as a marker of systemic inflammation. A significant positive association between being overweight (BMI25 kg/m2) and IgG antibodies was found for Helicobacter pylori (OR 1.86, CI 1.34-2.60) and Chlamydia pneumoniae (OR 1.39, CI 1.03-1.88) and combined seropositivity had synergistic effect (OR 2.54 (1.62-3.97)). CRP was positively related to BMI (pB0.0001), whereas no significant association was found between CRP and IgG antibodies against Helicobacter pylori and/or Chlamydia pneumoniae and CRP. The results suggest that infections with Chlamydia pneumoniae and Helicobacter pylori are both significantly and synergistically associated with overweight and this association is not related to indicators of systemic inflammation.

A common genetic background for inflammatory bowel disease and ankylosing spondylitis: a genealogic study in Iceland.

OBJECTIVE: Patients with ankylosing spondylitis (AS) and approximately 50% of their first-degree relatives may have a genetic abnormality that results in subclinical intestinal inflammation. This study was undertaken to examine the familial occurrence and cosegregation of AS and inflammatory bowel disease (IBD) in order to determine whether there is a shared genetic risk factor in families. METHODS: The Icelandic genealogy database and population-wide data on all living Icelanders diagnosed as having AS (n = 205) and/or IBD (n = 1,352) were used to estimate the risk ratios of AS for relatives of patients with AS, the risk ratios of IBD for relatives of patients with IBD, and the cross-risk ratios of AS for relatives of patients with IBD or of IBD for relatives of patients with AS. The mean kinship coefficients for each disease were calculated. The control population for disease risk calculations comprised 10,000-100,000 sets of matched Icelandic subjects. RESULTS: First-, second-, and third-degree relatives of patients with AS had risk ratios of 94, 25, and 3.5, respectively, indicating an increased risk of developing AS (each P < 0.0005), while first-, second-, and third-degree relatives of patients with IBD had risk ratios for IBD of 4.4, 2.2, and 1.4, respectively (each P < 0.0001). The cross-risk ratios of IBD were 3.0 and 2.1 in first- and second-degree relatives of patients with AS, respectively, and were the same for AS in first- and second-degree relatives of patients with IBD. With the exception of Crohn's disease, the risk of having AS, ulcerative colitis, or IBD in spouses of patients with these diseases did not differ significantly from that in controls. Calculation of the kinship coefficients confirmed these patterns of familial risk. CONCLUSION: Patients with AS or IBD in Iceland are significantly more related to each other than are randomly sampled control subjects, in terms of an increased risk of either or both conditions developing in third-degree relatives. These findings suggest that one or more undiscovered genetic variants may underlie the risk of both diseases.

Long-term effects of nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective agents on the small bowel: a cross-sectional capsule enteroscopy study.

BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drug (NSAID) gastropathy is sufficiently important as to warrant co-administration of misoprostol or proton pump inhibitors or a switch to selective cyclooxygenase (COX)-2 inhibitors. However, the serious ulcer outcome studies suggested that 40% of the clinically significant gastrointestinal bleeding originated more distally, presumably from NSAID enteropathy. We used capsule enteroscopy to study small-bowel damage in patients on long-term NSAIDs and COX-2-selective agents. METHODS: Sixty healthy volunteers acted as controls. One hundred twenty and 40 patients on long-term NSAIDs and COX-2 selective agents, respectively, underwent a capsule enteroscopy study. Small-bowel damage was categorized and quantitated. RESULTS: Sixty-two percent of patients on conventional NSAIDs were abnormal, which differed significantly (P < .001) from controls. The main pathology related to reddened folds (13%), denuded areas (39%), and mucosal breaks (29%). Two percent had diaphragm-like strictures and 3% had bleeding without an identifiable lesion. The damage, seen in 50% of patients on selective COX-2 inhibitors (reddened folds, 8%; denuded areas, 18%; and mucosal breaks, 22%), did not differ significantly (P > .5) from that seen with NSAIDs. CONCLUSIONS: Long-term NSAIDs and COX-2-selective agents cause comparable small-bowel damage. This suggests an important role for COX-2 in the maintenance of small-bowel integrity. The results have implications for strategies that aim to minimize the gastrointestinal damage in patients requiring anti-inflammatory analgesics.

Seroprevalence of Helicobacter pylori and cagA antibodies in Iceland, Estonia and Sweden.

The public health implications from H. pylori infection are considerable but the transmission routes are largely unknown. In this study, the prevalence, patient characteristics and risk factors for Helicobacter pylori infection were comparatively investigated in Iceland, Sweden and Estonia. Blood samples were collected from 1046 subjects aged approximately 25-50 y (447 in Reykjavik, 359 in Uppsala and 240 in Tartu) for determination of antibodies to H. pylori and its cagA protein. The prevalence of H. pylori antibodies was 69% in Tartu, 36% in Reykjavik and 11% in Uppsala (p<0.0001). There was an increase in prevalence with age in Iceland and Sweden but not in Estonia. The prevalence of antibodies to the cagA protein in subjects seroreactive to H. pylori was lower in Reykjavik (36%) than in Uppsala (69%) and Tartu (62%) (p<0.0001). H. pylori infection, as determined by seroreactivity, was positively associated with smoking and BMI. Overall, socioeconomic development during the childhood period seems to be the most important factor for the prevalence of H. pylori infection. In adults, smoking may be a contributory factor.

Granulomatous ileitis in a patient with ankylosing spondylitis.

BACKGROUND: A 21-year-old white male with a 3-year history of back pain presented with a 6-month history of weight loss (without significant gastrointestinal symptoms), lethargy and left hip pain, and diarrhea that had lasted 4 days. INVESTIGATIONS: Barium follow-through, upper and lower gastrointestinal endoscopy and biopsies, capsule enteroscopy, CT of the chest and abdomen, measurement of the concentration of fecal calprotectin, intestinal absorption permeability test and wireless capsule endoscopy. DIAGNOSIS: Ankylosing spondylitis associated with ileitis of spondylarthropathy. MANAGEMENT: Sulfasalazine and elemental diet, steroids, physiotherapy and bilateral hip replacement.

The effect of infectious burden on the prevalence of atopy and respiratory allergies in Iceland, Estonia, and Sweden.

BACKGROUND: Epidemiologic reports on the effect of microbe exposure on the development of atopy and allergic asthma are inconsistent. OBJECTIVES: The study investigates the association between serologic markers of infections and occurrence of atopy, allergic asthma, and rhinitis among adults in Iceland, Sweden, and Estonia. METHODS: Individuals (n = 1249; mean age, 42 years) from Iceland, Sweden, and Estonia underwent a structured interview and blood sampling. Specific IgE was measured against 4 allergens, and IgG antibodies were measured against Helicobacter pylori, Toxoplasmosis gondii, hepatitis A virus, herpes simplex virus 1, Chlamydia pneumoniae, EBV, and cytomegalovirus. RESULTS: Nonatopic subjects more often had positive serology for Helicobacter pylori, herpes simplex virus 1, Chlamydia pneumoniae, and cytomegalovirus. Having a low number (

Gender differences in the association between C-reactive protein, lung function impairment, and COPD.

Individuals with COPD have systemic inflammation that can be assessed by measuring C-reactive protein (CRP). In this paper we evaluated whether CRP is related to COPD, lung function and rate of lung function decline. We included 1237 randomly selected subjects (mean age 42, range 28-56 years) from three centers in the European Community Respiratory Health Survey: Reykjavik, Uppsala and Tartu. CRP was measured at the end of the follow-up (mean 8.3 years) and the values were divided into 4 quartiles. Fifty-three non-asthmatic subjects fulfilled spirometric criteria for COPD (FEV1/FVC < 70%). COPD occurred more often in the 4th CRP quartile (OR (95% CI) 3.21 (1.13-9.08)) after adjustment for age, gender, body weight and smoking. High CRP levels were related to lower FEV1 values in both men (-437 (-596, -279) mL) and women (-144 (-243, -44) mL). The negative association between CRP and FEV1 was significantly larger in men than women (p = 0.04). The decline in FEV1 was larger (16 (5, 27) mL) in men with high CRP levels whereas no significant association between CRP and FEV1 decline was found in women. Higher CRP values are significantly associated with COPD and lower lung function in men and women. In men higher CRP values are related to a larger decline in FEV1.

Seroprevalence of Toxoplasma gondii in Sweden, Estonia and Iceland.

Toxoplasmosis is a disease caused by the intracellular protozoan parasite, Toxoplasma gondii which infects up to one-third of the world human population. Toxoplasmosis in neonates and immunocompromised patients can lead to severe disease and death. We investigated the prevalence and risk factors for T. gondii infection in Iceland, Sweden and Estonia, and tested the hypothesis that T. gondii infection causes systemic inflammation and protects against atopy. Blood samples were collected from 1277 randomly selected subjects. The presence of T. gondii IgG antibodies was determined by an ELISA method and levels of Hs-CRP by immunoturbidimetric assay. The prevalence of T. gondii antibodies was 54.9% in Tartu, 23% in Uppsala and 9.8% in Reykjavik (p<0.0001). The risk of positive T. gondii antibodies increased with the number of siblings and with age in Sweden. T. gondii infection was associated with asthma related symptoms and increased Hs-CRP (p = 0.02). No association was found with IgE-sensitization and lung function. We concluded that risk factors for T. gondii infection suggested that soil exposure was 1 of the mechanisms in all 3 countries and a meat-associated infection route is a risk in Sweden.

Prevalence and mechanism of nonsteroidal anti-inflammatory drug-induced clinical relapse in patients with inflammatory bowel disease.

BACKGROUND & AIMS: It has been variably suggested that nonselective NSAIDs and cyclooxygenase (COX)-2 selective inhibitors aggravate or ameliorate clinical disease activity in patients with inflammatory bowel disease. We assessed the effect of these drugs in patients with inflammatory bowel disease (n = 209) and the possible mechanisms. METHODS: First, patients with quiescent Crohn's disease and ulcerative colitis received the non-NSAID analgesic acetaminophen (n = 26) and the conventional NSAIDs naproxen (n = 32), diclofenac (n = 29), and indomethacin (n = 22) for 4 weeks. The Harvey-Bradshaw index was used to define relapse. Second, to assess the mechanism of relapse, intestinal inflammation was quantitated (fecal calprotectin) before and during treatment (20 patients/group) with acetaminophen, naproxen (topical effect, COX-1 and -2 inhibitor), nabumetone (COX-1 and -2 inhibitor), nimesulide (selective COX-2 inhibitor), and low-dose aspirin (selective COX-1 inhibition). RESULTS: Nonselective NSAIDs were associated with a 17%-28% relapse rate within 9 days of ingestion. No patient had an early relapse on acetaminophen, nimesulide, or aspirin, whereas those on naproxen and nabumetone (20%) experienced relapse. These clinical relapses were associated with escalating intestinal inflammatory activity. CONCLUSIONS: NSAID ingestion is associated with frequent and early clinical relapse of quiescent inflammatory bowel disease, and the mechanism appears to be due to dual inhibition of the COX enzymes. Selective COX-2 inhibition with nimesulide and COX-1 inhibition with low-dose aspirin appear to be well-tolerated in the short-term.