Trends and projections in the incidence of oesophageal cancer in the Netherlands: An age-period-cohort analysis from 1989 to 2041.

In Western populations, the incidence of oesophageal squamous cell carcinoma (OSCC) has been declining, whereas the incidence of oesophageal adenocarcinoma (OAC) has been increasing. Our study examines temporal trends in the incidence of oesophageal cancer in the Netherlands between 1989 and 2016, in addition to predicting future trends through 2041. Data from the Netherlands Cancer Registry and Statistics Netherlands were collected to obtain incidence trends of OSCC and OAC for the period 1989 to 2016. Age-period-cohort (APC) modelling was used to estimate the contribution of age, calendar period and birth cohort on the observed incidence trends. To predict the future numbers of new cases of both OSCC and OAC from 2017 to 2041, log-linear APC models were fitted to the trends of 1989 to 2016. The age-standardised incidence rates of OSCC have decreased slightly for men and increased slightly for women. In contrast, a marked increase in the incidence of OAC was observed, ranging from 2.8 per 100 000 persons in 1989 to 10.1 in 2016. This increase in OAC incidence was more prominent in men, and it will result in an increased risk of OAC for successive generations. Future projections indicate that the incidence of OAC will further increase to 13.1 per 100 000 persons in 2037 to 2041, meaning that there will be 13 259 cases of OAC in 2037 to 2041, as compared to 9386 diagnoses in 2017 to 2021. The changing epidemiologic trends in oesophageal cancer in the Netherlands should be reflected in the development of prevention, early detection and treatment strategies.

Research in Action-Students' Perspectives on the Integration of Research Activities in Undergraduate Biomedical Curricula.

We describe and evaluate our practice-based learning approach for research in undergraduate students studying Biomedical Sciences at Radboud University Nijmegen, the Netherlands. First-year students who started their study between 2015 and 2018 actively participated in data collection and measurements, including anthropometry, electrocardiogram findings, genetic variants, and lifestyle habits. All data were entered into one anonymous database, which was used by students to analyze their research questions. In 2019, 44 of the 87 students (50%) valued active measurements better than questionnaires. Most students (strongly) agreed that they have learned about data collection and were inspired to learn more about biomedical research.

High prevalence of impaired awareness of hypoglycemia and severe hypoglycemia among people with insulin-treated type 2 diabetes: The Dutch Diabetes Pearl Cohort.

OBJECTIVE: People with type 2 diabetes on insulin are at risk for hypoglycemia. Recurrent hypoglycemia can cause impaired awareness of hypoglycemia (IAH), and increase the risk for severe hypoglycemia. The aim of this study was to assess the prevalence and determinants of self-reported IAH and severe hypoglycemia in a Dutch nationwide cohort of people with insulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS: Observational study of The Dutch Diabetes Pearl, a cohort of people with type 2 diabetes treated in primary, secondary and tertiary diabetes care centers. The presence of IAH and the occurrence of severe hypoglycemia in the past year, defined as an event requiring external help to recover, were assessed using the validated Dutch version of the Clarke questionnaire. In addition, clinical variables were collected including age, diabetes duration, hemoglobin A1c, ethnicity and education. RESULTS: 2350 people with type 2 diabetes on insulin were included: 59.1% men, mean age 61.1±10.4 years, mean diabetes duration 14.8±9.2 years and 79.5% on basal-bolus therapy. A total of 229 patients (9.7%) were classified as having IAH and 742 patients (31.6%) reported severe hypoglycemia. Increased odds for IAH were found with complex insulin regimens and lower odds with having a partner and body mass index ≥30 kg/m2. Severe hypoglycemia was associated with complex insulin regimens, non-Caucasian ethnicity and use of psychoactive drugs, and inversely with metformin use. CONCLUSIONS: In this nationwide cohort, almost one out of ten people with type 2 diabetes on insulin had IAH and >30% had a history of severe hypoglycemia in the past year.

[The relationship between lifestyle and cancer; topic of conversation in the consultation room?] / Relatie tussen leefstijl en kanker.

OBJECTIVE: This survey explores the degree of consensus amongst healthcare professionals for the support of cancer patients' lifestyle management, based on three questions posed to them: a) what do they know about the relation between lifestyle and cancer?; b) do they consider lifestyle support for cancer patients part of their professional role?; c) does their own lifestyle influence the lifestyle management consultations they may have with cancer patients? Design Survey study. METHOD: A digital questionnaire with questions concerning lifestyle and cancer was sent to 1550 healthcare professionals in and around Nijmegen. The questionnaire was filled out by 562 healthcare professionals (36% response rate), of whom 404 (72%) were involved in cancer patient care. This cohort of responders consisted of 170 medical specialists, 62 general practitioners, and 172 nurses and allied health professionals. RESULTS: Healthcare professionals acknowledge the influence of lifestyle on the development of cancer. Almost all healthcare professionals (98%) agree on the positive effects of a healthy lifestyle on the well-being of cancer patients. Approximately two-thirds of all responders believe that lifestyle support should 'usually' or 'always' form part of cancer care; about fifty percent report to implement this in clinical practice. Healthcare professionals require evidence-based knowledge concerning the relationship between lifestyle and cancer, patient information materials, and additional consultation time to support lifestyle management involving cancer patients. The healthcare professionals' own lifestyle appears to have an influence: in those responders who do not adhere to a healthy lifestyle themselves, lifestyle was also covered less in consultations. CONCLUSION: This explorative survey shows that lifestyle support of cancer patients is deemed an important topic amongst healthcare professionals.

[Patients on the move: validated methods to quantify physical activity]. / Patiënten in beweging: gevalideerde methoden om lichamelijke activiteit te kwantificeren.

Physical activity is an important component in the maintenance and improvement of general health; physical inactivity is, however, an increasing problem in the Netherlands. Requests for advice on physical activity are increasing within the healthcare. Assessment of an individual's physical activity pattern is required to provide tailored advice. There are a number of methods for measuring physical activity; these are divided into subjective and objective methods. Subjective measures include physical activity questionnaires and diaries. Objective measures include indirect calorimetry, measurement with doubly labelled water, heart-rate monitoring and the use of an accelerometer or pedometer. The choice of method depends predominantly on the aim of the measurement, and the availability of personnel, time and financial resources. In clinical practice a validated questionnaire is usually the preferred method, but when measuring effects this should be combined with an objective measurement instrument.

Entering a new era of body indices: the feasibility of a body shape index and body roundness index to identify cardiovascular health status.

BACKGROUND: The Body Mass Index (BMI) and Waist Circumference (WC) are well-used anthropometric predictors for cardiovascular diseases (CVD), but their validity is regularly questioned. Recently, A Body Shape Index (ABSI) and Body Roundness Index (BRI) were introduced as alternative anthropometric indices that may better reflect health status. OBJECTIVE: This study assessed the capacity of ABSI and BRI in identifying cardiovascular diseases and cardiovascular disease risk factors and determined whether they are superior to BMI and WC. DESIGN AND METHODS: 4627 Participants (54±12 years) of the Nijmegen Exercise Study completed an online questionnaire concerning CVD health status (defined as history of CVD or CVD risk factors) and anthropometric characteristics. Quintiles of ABSI, BRI, BMI, and WC were used regarding CVD prevalence. Odds ratios (OR), adjusted for age, sex, and smoking, were calculated per anthropometric index. RESULTS: 1332 participants (27.7%) reported presence of CVD or CVD risk factors. The prevalence of CVD increased across quintiles for BMI, ABSI, BRI, and WC. Comparing the lowest with the highest quintile, adjusted OR (95% CI) for CVD were significantly different for BRI 3.2 (1.4-7.2), BMI 2.4 (1.9-3.1), and WC 3.0 (1.6-5.6). The adjusted OR (95% CI) for CVD risk factors was for BRI 2.5 (2.0-3.3), BMI 3.3 (1.6-6.8), and WC 2.0 (1.6-2.5). No association was observed for ABSI in both groups. CONCLUSIONS: BRI, BMI, and WC are able to determine CVD presence, while ABSI is not capable. Nevertheless, the capacity of BRI as a novel body index to identify CVD was not superior compared to established anthropometric indices like BMI and WC.

Associations between thyroid function and mortality: the influence of age.

OBJECTIVE: The aim of this study was to investigate the influence of age on the association between thyroid function and mortality. DESIGN: The Nijmegen Biomedical Study is a population-based study, comprising 5816 randomly selected adults of all age groups without previously known thyroid disease. METHODS: TSH, free thyroxine (FT4) and peroxidase antibodies were measured in 2002-2003. The number of deaths were established in 2012 (median follow-up time 9.4 years). RESULTS: Subclinical thyrotoxicosis was associated with mortality in subjects aged <65 years (hazard ratio (HR) 2.5, 95% CI 1.1-5.7), but not in subjects aged >65 years. As for thyroid function within the normal range: in the 493 participants aged 80 years or older, an FT4 level in the high-normal range (18.5-22 pmol/l) was associated with a higher mortality in comparison with FT4 levels in the middle range (11.5-15.0 pmol/l): HR 1.7 (95% CI 1.0-2.9). In these elderly, TSH levels within the high-normal range (3.0-4.0 mIU/l) were also associated with a higher mortality in comparison with TSH levels within the middle range (1.0-2.0 mIU/l): HR 1.8 (95% CI 1.0-3.1). CONCLUSIONS: The relationship between thyroid function and mortality differs according to age. This finding might (partially) explain the discrepant results of previous studies examining the relationship between thyroid function and mortality in different age groups.

Pattern of follow-up care and early relapse detection in breast cancer patients.

Routine breast cancer follow-up aims at detecting second primary breast cancers and loco regional recurrences preclinically. We studied breast cancer follow-up practice and mode of relapse detection during the first 5 years of follow-up to determine the efficiency of the follow-up schedule. The Netherlands Cancer Registry provided data of 6,509 women, operated for invasive non-metastatic breast cancer in 2003-2004. In a random sample including 144 patients, adherence to follow-up guideline recommendations was studied. Mode of relapse detection was studied in 124 patients with a second primary breast cancer and 160 patients with a loco regional recurrence. On average 13 visits were performed during the first 5 years of the follow-up, whereas nine were recommended. With one, two and three medical disciplines involved, the number of visits was 9, 14 and 18, respectively. Seventy-five percent (93/124) of patients with a second primary breast cancer, 42 % (31/74) of patients with a loco regional recurrence after breast conserving surgery and 28 % (24/86) of patients with a loco regional recurrence after mastectomy had no symptoms at detection. To detect one loco regional recurrence or second primary breast cancer preclinically, 1,349 physical examinations versus 262 mammography and/or MRI tests were performed. Follow-up provided by only one discipline may decrease the number of unnecessary follow-up visits. Breast imaging plays a major and physical examination a minor role in the early detection of second primary breast cancers and loco regional recurrences. The yield of physical examination to detect relapses early is low and should therefore be minimised.

Is there a relationship between fatigue perception and the serum levels of thyrotropin and free thyroxine in euthyroid subjects?

BACKGROUND: Thyrotoxicosis and hypothyroidism are associated with fatigue. Here we studied euthyroid subjects to determine if there was a relationship between serum thyrotropin (TSH), free thyroxine (FT(4)) and thyroperoxidase antibodies and fatigue. METHODS: A total of 5897 participants of the Nijmegen Biomedical Study received a questionnaire and serum TSH (normal range 0.4-4.0 mIU/L) and FT(4) (normal range 8-22 pmol/L) were measured. Fatigue was evaluated by the RAND-36 and the shortened fatigue questionnaire (SFQ). RESULTS: Euthyroid subjects with a serum TSH level of 0.4-1.0 mIU/L had a lower RAND-36 vitality score (65.2 vs. 66.8; regression coefficient (RC) -1.6 [95% confidence interval (CI) -2.6 to -0.5]; p=0.005) and a higher SFQ score (11.7 vs. 11.0; RC 0.6 [CI 0.2-1.0]; p=0.004) than those with a TSH of 1.0-2.0 mIU/L. Those with a serum FT(4) of 18.5-22 pmol/L reported fatigue more often (52.5% vs. 33.3%; relative risk (RR) 1.4 [CI 1.0-1.9]; p=0.03), had a lower RAND-36 vitality score (61.7 vs. 66.6; RC -4.4 [CI -8.1 to -0.6]; p=0.02) and a higher SFQ score (13.2 vs. 11.0; RC 1.9 [CI 0.4-3.3]; p=0.01) than subjects with a FT(4) level of 11.5-15 pmol/L. In comparison to euthyroid subjects without known thyroid disease, euthyroid subjects with previously known thyroid disease reported fatigue more often (52.3% vs. 34.0%; RR 1.3 [CI 1.0-1.5]; p=0.025), had a lower RAND-36 vitality score (61.4 vs. 66.3; RC -2.9 [CI -5.3 to -0.6]; p=0.015) and a higher SFQ score (13.7 vs. 11.1; RC 1.4 [CI 0.5-2.3]; p=0.002). CONCLUSION: In euthyroid individuals without a history of thyroid disease, there is a modest relationship between thyroid function and fatigue with subjects having an apparently higher production of T(4) experiencing more fatigue. Subjects with a history of thyroid disease, but with normal TSH and FT(4) concentrations, experience more fatigue than the general population. The reasons for this are unclear, but subtle abnormalities in the dynamics of thyroid hormone secretion should be considered.

Impact of routine follow-up examinations on life expectancy in ovarian cancer patients: a simulation study.

OBJECTIVE: The clinical benefit of routine follow-up in patients treated for ovarian cancer is subject to debate. In this study, the magnitude of the potential survival benefit of routine examinations was evaluated by Markov modeling. METHODS: The clinical course of ovarian cancer was simulated using a 4-state nonstationary Markov model. Risk of recurrence and mortality probabilities were derived from individual patient data and Statistics Netherlands. The life expectancy was simulated for 3 follow-up scenarios: a current, withholding (all recurrences detected symptomatically), and perfect follow-up program (all recurrences detected asymptomatically). The impact of effective recurrence treatment in the future was modeled by varying the mortality ratio between patients with asymptomatically versus symptomatically detected recurrences. The model was validated using empirical data. RESULTS: The mean life expectancy of patients, aged 58 years and in complete clinical remission after primary treatment, was 10.8 years. Varying the transition probabilities with ±25% changed the life expectancy by up to 1.1 years. The modeled life expectancy for the withholding and perfect follow-up scenarios was also 10.8 years and insensitive to model assumptions. In patients with stages IIB to IV, the life expectancy was 7.0 years, irrespective of follow-up strategy. A mortality ratio of 0.8 for patients with asymptomatically versus symptomatically detected recurrences resulted in a gain in life expectancy of 5 months for withholding versus perfect follow-up. CONCLUSIONS: Routine follow-up in ovarian cancer patients is not expected to improve the life expectancy. The timing of detection of recurrent ovarian cancer is immaterial until markedly improved treatment options become available.

Hepcidin and hemoglobin content parameters in the diagnosis of iron deficiency in rheumatoid arthritis patients with anemia.

OBJECTIVE: To explore the utility of the novel iron indices hepcidin, reticulocyte hemoglobin content (Ret-Hgb), and erythrocyte (red blood cell) hemoglobin content (RBC-Hgb) for detection of iron deficiency in rheumatoid arthritis (RA) patients with anemia and active inflammation and to compare these indices with conventional parameters of iron deficiency. METHODS: Blood samples from 106 outpatients with RA were analyzed in a cross-sectional exploratory study. Forty patients were classified as having either iron deficiency anemia (IDA), anemia of chronic disease (ACD), their combination (IDA/ACD), or "other anemia" based on biochemical parameters for inflammation and iron deficiency. The ability of serum and urine hepcidin, Ret-Hgb, and RBC-Hgb measurement to discriminate among these states was evaluated. RESULTS: Hepcidin content in serum from patients in the IDA group as well as that from patients in the combined IDA/ACD group differed significantly from that in serum from patients in the ACD group. This difference was also observed with hepcidin in urine, Ret-Hgb, and RBC-Hgb, although with less significance. The area under the receiver operating characteristic curve for serum hepcidin was 0.88 for the comparison of IDA/ACD patients with ACD patients and 0.92 for the comparison of the combined IDA group and IDA/ACD group to all other patients with anemia. Hepcidin at <2.4 nmoles/liter had a sensitivity of 89% and a specificity of 88% to distinguish IDA/ACD from ACD. Both Ret-Hgb and RBC-Hgb measurements also allowed differentiation between these latter groups, with a sensitivity of 67% and 89%, respectively, and a specificity of 100% and 75%, respectively. CONCLUSION: Serum hepcidin and, to a lesser extent, urine hepcidin, Ret-Hgb, and RBC-Hgb, are potential useful indicators for detecting iron deficiency in RA patients with anemia and active inflammation.

[Aftercare in oncology--greater role for the general practitioner]. / Nacontrole oncologie--grotere rol voor de huisarts.

Patients who undergo curative treatment for cancer continue to be medically monitored for a number of years. Scheduled aftercare, mainly aimed at early detection of locoregional cancer recurrences, distant metastases and secondary primary tumours, takes place chiefly in the second line, but is expected to shift to the first line. Figures from the Nijmegen Continuous Morbidity Registration show that an average (Dutch) general practitioner, caring for about 2500 patients, has in his practice 90 patients who have or have had cancer. This number will increase due to the increasing prevalence of cancer. In addition, extra consultations for each cancer patient will increase the demand for GP care.

Considering early detection of relapsed ovarian cancer: a review of the literature.

INTRODUCTION: Patients treated for ovarian cancer with curative intent receive an intensive follow-up program in the years after treatment. However, the aimed improved survival through early detection of recurrence is subject to debate. Theoretically, the survival benefit depends on the lead time and the preclinical detection rate and on the effectiveness of recurrence treatment. This systematic review aimed at determining the effectiveness of early detection of recurrent ovarian cancer. METHODS: A systematic literature search in PubMed, EMBASE, MEDLINE, and the Cochrane Library was performed for articles published in 1985 to 2009 in English, German, or Dutch, excluding editorials, letters, and case reports. RESULTS: In total, 67 articles were included. Of 4 observational studies and 1 randomized controlled trial, only 1 observational study reported a better survival for patients who attended routine follow-up compared with those who did not. The sensitivity of cancer antigen 125 for a preclinical recurrence, based on 38 articles using 35 U/mL as a cutoff level, was 65%, with a median lead time of 3 months (range, 1-7 months). Seven studies showed that, on average, 67% (ranging from 20% to 80%) of the 798 relapsed patients had no clinical symptoms when recurrent ovarian cancer was diagnosed. CONCLUSIONS: Routine follow-up may detect 2 of 3 recurrences asymptomatically with a lead time of 3 months. Recurrence treatment may extend survival by several months, but published studies did not show a survival advantage of early detection by routine follow-up examinations. Therefore, the content and aims of routine follow-up should be reconsidered, whereas routine cancer antigen 125 testing with the aim to improve life expectancy should be omitted.

No supportive evidence for clinical benefit of routine follow-up in ovarian cancer: a Dutch multicenter study.

INTRODUCTION: Routine follow-up is standard medical practice in ovarian cancer patients treated with curative intent. However, no strong evidence exists indicating that prognosis is improved. The objective of this study was to evaluate the routine follow-up schedule for ovarian cancer patients regarding the adherence to the Dutch protocol, the detection of recurrences, and the follow-up's impact on overall survival. METHODS: All 579 consecutive patients diagnosed with epithelial ovarian, primary peritoneal, or fallopian tube cancer in 4 Dutch hospitals between 1996 and 2006 were selected. Only patients in complete clinical remission after primary treatment were studied. Compliance to the Dutch follow-up guideline was assessed in a random sample of 68 patients. Of the 127 patients with recurrence, the mode of recurrence detection was addressed. Survival time since primary treatment was calculated using the Kaplan-Meier method. RESULTS: The patients received more follow-up visits than was recommended according to the guideline. The cumulative 5-year risk of recurrence was 55% (95% confidence interval [CI], 43%-67%). The survival of patients with recurrent ovarian cancer detected asymptomatically at a routine visit (n = 51) tended to be better compared with patients with symptomatic detection at a routine (n = 31) or diagnosed after an interval visit (n = 31). The median survival times were 44 (95% CI, 38-64), 29 (95% CI, 21-38), and 33 months (95% CI, 19-61), respectively (P = 0.08). The median time from primary treatment to recurrence was similar for the 3 groups: 14, 10, and 11 months, respectively (P = 0.26). CONCLUSIONS: Follow-up in line with (inter)national guidelines yields a seemingly longer life expectancy if the recurrence was detected asymptomatically. However, this result is expected to be explained by differences in tumor biology and length-time bias.

Healthy donor effect: its magnitude in health research among blood donors.

BACKGROUND: The healthy donor effect has been mentioned as a methodologic problem in blood donor health research. The aim of this study was to investigate different elements of the healthy donor effect. STUDY DESIGN AND METHODS: First, recent donors (<4 years registered as a donor) were compared with the general population. Second, active and lapsed donors were compared. Third, short-career donors (<14 donations) were compared with long-career donors (>37 donations). Various health and lifestyle indicators were used as outcome measures. RESULTS: Compared to the general population, recent donors had a better self-rated health (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.27-1.61), visited the general practitioner (GP) less often (OR, 0.66; 95% CI, 0.60-0.72), and were less often treated by a specialist (OR, 0.83; 95% CI, 0.75-0.93). Recent donors also exhibited a healthier lifestyle compared to the general population. When examining active versus lapsed donors, similar results were found in favor of active donors. With respect to donation career, long-career donors were healthier than short-career donors, but effects were less strong; the ORs were 1.33 (95% CI, 1.15-1.54) for self-rated health, 0.85 (95% CI, 0.76-0.94) for GP visit, and 0.83 (95% CI, 0.68-1.00) for specialist treatment. When comparing long- and short-career donors on lifestyle indicators, there were barely any significant differences. CONCLUSIONS: The findings strongly point to the presence of a healthy donor effect when comparing donors with the general population and active versus lapsed donors. The healthy donor effect was less pronounced within active donors, when comparing long- and short-career donors. Therefore, health research should primarily be carried out within active donors.

Cardiovascular and demographic characteristics in whole blood and plasma donors: results from the Donor InSight study.

BACKGROUND: Within blood establishments little comparative information is available about donors versus the general population. In this study, a description of the donor pool was made in terms of demographic factors and cardiovascular risk factors. The general Dutch population was used as a reference group. STUDY DESIGN AND METHODS: The Donor InSight study provided information on donors. Extensive information has been gathered by a self-administered questionnaire addressing various topics, like demographics, lifestyle, and health. Aggregated donor responses were compared with general population summary data. RESULTS: The study population consisted of 15,076 donors. The median age was 46.3 years and 47.3% were men. Donors were more likely to be highly educated (34.6%), married (71.7%), and of Dutch origin (97.4%), when compared to the general population. Donors were less often smokers (donors, 17.1%; general population, 31.8%), more often moderate drinkers (donors, 82.8%; general population, 74.7%), and physically more active (donors, 2.0 hr/week; general population, 1.0 hr/week). Male donors were more often moderately overweight (47.7%) than men from the general population (39.9%). In donors, 0.9% reported to have Type 2 diabetes versus 1.9% in the general population. In donors, 3.4% reported high cholesterol versus 4.6% in the general population. CONCLUSION: The study provided important knowledge about demographic distributions and cardiovascular risk factors within donors. A proper understanding of demographic characteristics of donors will help us to focus recruitment and retention strategies. The reported beneficial cardiovascular profile suggests a need for further research on the role of blood donation in cardiovascular risk reduction.

Association of variants at UMOD with chronic kidney disease and kidney stones-role of age and comorbid diseases.

Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1x10(-10)). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3 x 10(-23)) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0 x 10(-17)) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0 x 10(-6)), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7 x 10(-5)).

Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density.

Kidney stone disease is a common condition. To search for sequence variants conferring risk of kidney stones, we conducted a genome-wide association study in 3,773 cases and 42,510 controls from Iceland and The Netherlands. We discovered common, synonymous variants in the CLDN14 gene that associate with kidney stones (OR = 1.25 and P = 4.0 x 10(-12) for rs219780[C]). Approximately 62% of the general population is homozygous for rs219780[C] and is estimated to have 1.64 times greater risk of developing the disease compared to noncarriers. The CLDN14 gene is expressed in the kidney and regulates paracellular permeability at epithelial tight junctions. The same variants were also found to associate with reduced bone mineral density at the hip (P = 0.00039) and spine (P = 0.0077).

A variant associated with nicotine dependence, lung cancer and peripheral arterial disease.

Smoking is a leading cause of preventable death, causing about 5 million premature deaths worldwide each year. Evidence for genetic influence on smoking behaviour and nicotine dependence (ND) has prompted a search for susceptibility genes. Furthermore, assessing the impact of sequence variants on smoking-related diseases is important to public health. Smoking is the major risk factor for lung cancer (LC) and is one of the main risk factors for peripheral arterial disease (PAD). Here we identify a common variant in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24 with an effect on smoking quantity, ND and the risk of two smoking-related diseases in populations of European descent. The variant has an effect on the number of cigarettes smoked per day in our sample of smokers. The same variant was associated with ND in a previous genome-wide association study that used low-quantity smokers as controls, and with a similar approach we observe a highly significant association with ND. A comparison of cases of LC and PAD with population controls each showed that the variant confers risk of LC and PAD. The findings provide a case study of a gene-environment interaction, highlighting the role of nicotine addiction in the pathology of other serious diseases.