Genes and environment

Many quantitative characters depend on the action of a large number of genes and environmental factors. The mode of inheritance of these characters is polygenic. The phenotypic variance of the character is the sum of the components, thus the genetic and the environmental variances (VP = VG + VE). The degree of genetic determination VG/VP and VE/VP are difficult to estimate in man. The heritability a related coefficient to VG/VP can be estimated from the degree of ressemblance between relatives. The heritability is the additive genetique variance as a proportion of the phenotypic variance. Polygenic threshold inheritance can account for the familial non mendelian distribution of multifactorial diseases.     

Rotating night shift work and risk of type 2 diabetes: two prospective cohort studies in women

Background

Rotating night shift work disrupts circadian rhythms and has been associated with obesity, metabolic syndrome, and glucose dysregulation. However, its association with type 2 diabetes remains unclear. Therefore, we aimed to evaluate this association in two cohorts of US women.

Methods and Findings

We followed 69,269 women aged 42–67 in Nurses'' Health Study I (NHS I, 1988–2008), and 107,915 women aged 25–42 in NHS II (1989–2007) without diabetes, cardiovascular disease, and cancer at baseline. Participants were asked how long they had worked rotating night shifts (defined as at least three nights/month in addition to days and evenings in that month) at baseline. This information was updated every 2–4 years in NHS II. Self-reported type 2 diabetes was confirmed by a validated supplementary questionnaire. We documented 6,165 (NHS I) and 3,961 (NHS II) incident type 2 diabetes cases during the 18–20 years of follow-up. In the Cox proportional models adjusted for diabetes risk factors, duration of shift work was monotonically associated with an increased risk of type 2 diabetes in both cohorts. Compared with women who reported no shift work, the pooled hazard ratios (95% confidence intervals) for participants with 1–2, 3–9, 10–19, and ≥20 years of shift work were 1.05 (1.00–1.11), 1.20 (1.14–1.26), 1.40 (1.30–1.51), and 1.58 (1.43–1.74, p-value for trend <0.001), respectively. Further adjustment for updated body mass index attenuated the association, and the pooled hazard ratios were 1.03 (0.98–1.08), 1.06 (1.01–1.11), 1.10 (1.02–1.18), and 1.24 (1.13–1.37, p-value for trend <0.001).

Conclusions

Our results suggest that an extended period of rotating night shift work is associated with a modestly increased risk of type 2 diabetes in women, which appears to be partly mediated through body weight. Proper screening and intervention strategies in rotating night shift workers are needed for prevention of diabetes. Please see later in the article for the Editors'' Summary     

Lung cancer,smoking, and environment: a cohort study of the Danish population.

OBJECTIVE--The almost twofold difference in lung cancer incidence between people living in Copenhagen and in rural area of Denmark in the 1980s led to public concern; this study was undertaken to assess the effects of air pollution and occupation on lung cancer in Denmark, with control for smoking habits. DESIGN--Cohort study of national population. SUBJECTS--People aged 30-64 and economically active in 1970 (927,470 men and 486,130 women). MAIN OUTCOME MEASURES--Relative risks for lung cancer estimated with multiplicative Poisson modelling of incidence rates. RESULTS--Differences in smoking habit explained about 60% of the excess lung cancer risk in Copenhagen for men and 90% for women. After control for smoking, workers had double the lung cancer risk of teachers and academics. There was only a small independent effect of region. CONCLUSION--Smoking is the main factor behind the regional differences in lung cancer incidence in Denmark, and occupational risk factors also seem to have an important role. The outdoor air in Copenhagen around 1970 contained on average 50-80 micrograms/m3 of sulphur dioxide, 80-100 micrograms/m3 total suspended particulate matter, and up to 10 ng/m3 benzo(a)pyrene and had peak values of daily smoke of 120 micrograms/m3. Region had only a small effect on incidence of lung cancer int eh present study, which suggests that an influence of outdoor air pollution on lung cancer is identifiable only above this pollution level.     

Soft drinks,fructose consumption,and the risk of gout in men: prospective cohort study

Objective To examine the relation between intake of sugar sweetened soft drinks and fructose and the risk of incident gout in men.Design Prospective cohort over 12 years.Setting Health professionals follow-up study.Participants 46 393 men with no history of gout at baseline who provided information on intake of soft drinks and fructose through validated food frequency questionnaires.Main outcome measure Incident cases of gout meeting the American College of Rheumatology survey criteria for gout.Results During the 12 years of follow-up 755 confirmed incident cases of gout were reported. Increasing intake of sugar sweetened soft drinks was associated with an increasing risk of gout. Compared with consumption of less than one serving of sugar sweetened soft drinks a month the multivariate relative risk of gout for 5-6 servings a week was 1.29 (95% confidence interval 1.00 to 1.68), for one serving a day was 1.45 (1.02 to 2.08), and for two or more servings a day was 1.85 (1.08 to 3.16; P for trend=0.002). Diet soft drinks were not associated with risk of gout (P for trend=0.99). The multivariate relative risk of gout according to increasing fifths of fructose intake were 1.00, 1.29, 1.41, 1.84, and 2.02 (1.49 to 2.75; P for trend <0.001). Other major contributors to fructose intake such as total fruit juice or fructose rich fruits (apples and oranges) were also associated with a higher risk of gout (P values for trend <0.05).Conclusions Prospective data suggest that consumption of sugar sweetened soft drinks and fructose is strongly associated with an increased risk of gout in men. Furthermore, fructose rich fruits and fruit juices may also increase the risk. Diet soft drinks were not associated with the risk of gout.     

Rapid, easy, and cheap randomization: prospective evaluation in a study cohort

Background

Incisional hernia is a frequent complication in abdominal surgery. This article describes the development of a prospective randomized clinical trial designed to determine whether watchful waiting is an acceptable alternative to surgical repair for patients with oligosymptomatic incisional hernia.

Methods/Design

This clinical multicenter trial has been designed to compare watchful waiting and surgical repair for patients with oligosymptomatic incisional hernia. Participants are randomized to watchful waiting or surgery and followed up for two years. The primary efficacy endpoint is pain/discomfort during normal activities as a result of the hernia or hernia repair two years after enrolment, as measured by the hernia-specific Surgical Pain Scales (SPS). The target sample size of six hundred thirty-six patients was calculated to detect non-inferiority of the experimental intervention (watchful waiting) in the primary endpoint. Sixteen surgical centers will take part in the study and have submitted their declaration of commitment giving the estimated number of participating patients per year. A three-person data safety monitoring board will meet annually to monitor and supervise the trial.

Discussion

To date, we could find no published data on the natural course of incisional hernias. To our knowledge, watchful waiting has never been compared to standard surgical repair as a treatment option for incisional hernias. A trial to compare the outcome of the two approaches in patients with oligosymptomatic incisional hernias is urgently needed to provide data that can facilitate the choice between treatment options. If watchful waiting was equal to surgical repair, the high costs of surgical repair could be saved. The design for such a trial is described here. This multicenter trial will be funded by the German Research Foundation (DFG). The ethics committee of the Charité has approved the study protocol. Approval has been obtained from ten study sites at time of this submission. The electronic Case Report Forms have been created. The first patient was to be randomized November 14^th, 2011. An initiation meeting took place in Berlin January 9^th, 2012.

Trial Registration

ClinicalTrials.gov: NCT01349400     

Predictive value of minor anomalies: II. Use in cohort studies to identify teratogens

Cohort studies of putative human teratogens can identify the full spectrum of phenotypic effects, including both major malformations and minor anomalies. Cohort studies which include the much more common minor anomalies make it possible to use a relatively small number of exposed and unexposed infants to identify an increase in the frequency of malformations. We evaluated this use of minor anomalies in a cohort study of newborn infants who had been exposed in utero to three putative teratogens: insulin-dependent diabetes mellitus in the mother and the use of the anticonvulsant phenytoin and exogenous sex hormones by the mother. In addition, the reproducibility of identifying minor anomalies was tested by comparing the results of examinations by two independent observers of 444 unexposed infants. The frequency of minor anomalies was increased among infants of diabetic mothers. However, the reproducibility of identifying minor anomalies was poor. We conclude that the examination of teratogen-exposed infants for minor anomalies cannot be used in epidemiologic studies of putative teratogens unless special efforts are made to maximize consistency in the identification of these features.     

Hormone treatment, estrogen receptor polymorphisms and mortality: a prospective cohort study

Background

The association between hormone treatment (HT) and mortality remains controversial. This study aimed to determine whether the risk of mortality associated with HT use varies depending on the specific characteristics of treatment and genetic variability in terms of the estrogen receptor.

Methodology/Principal Findings

A prospective, population-based study of 5135 women aged 65 years and older who were recruited from three cities in France and followed over six years. Detailed information related to HT use was obtained and five estrogen receptor polymorphisms were genotyped. The total follow-up was 25,436 person-years and during this time 352 women died. Cancer (36.4%) and cardiovascular disease (19.3%) were the major causes of death. Cox proportional hazards models adjusted for age, education, centre, living situation, comorbidity, depression, physical and mental incapacities, indicated no significant association between HT and mortality, regardless of the type or duration of treatment, or the age at initiation. However, the association between HT and all-cause or cancer-related mortality varied across women, with significant interactions identified with three estrogen receptor polymorphisms (p-values = 0.004 to 0.03) in adjusted analyses. Women carrying the C allele of ESR1 rs2234693 had a decreased risk of all-cause mortality with HT (HR: 0.42, 95% CI: 0.18–0.97), while in stark contrast, those homozygous for the T allele had a significantly increased risk of cancer-related mortality (HR: 3.18, 95% CI: 1.23–8.20). The findings were similar for ESR1 rs9340799 and ESR2 rs1271572.

Conclusions/Significance

The risk of mortality was not associated with HT duration, type or age at initiation. It was however not equal across all women, with some women appearing genetically more vulnerable to the effects of HT in terms of their estrogen receptor genotype. These findings, if confirmed in another independent study, may help explain the differential susceptibility of women to the beneficial or adverse effects of HT.     

The value of joint ultrasonography in predicting arthritis in seropositive patients with arthralgia: a prospective cohort study

Background

The value of joint ultrasonography (US) in the prediction of clinical arthritis in individuals at risk of developing rheumatoid arthritis (RA) is still a point of debate, due to varying scanning protocols and different populations. We investigated whether US abnormalities assessed with a standard joint protocol can predict development of arthritis in seropositive patients with arthralgia.

Methods

Anti-citrullinated protein antibodies and/or rheumatoid factor positive patients with arthralgia, but without clinical arthritis were included. US was performed at baseline in 16 joints: bilateral metacarpophalangeal 2–3, proximal interphalangeal 2–3, wrist and metatarsophalangeal (MTP) joints 2–3 and 5. Images were scored semi-quantitatively for synovial thickening and for positive signs on power Doppler (PD). Association between US abnormalities and arthritis development at the joint and at the patient level was evaluated. Also, we investigated the added value of US over clinical parameters.

Results

Out of 163 patients who underwent US examination, 51 (31%) developed clinical arthritis after a median follow-up time of 12 (interquartile range 5–24) months, of which 44 (86%) satisfied the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. US revealed synovial thickening and PD in at least one joint in 49 patients (30%) and 7 patients (4%), respectively. Synovial thickening was associated with both development and timing of clinical arthritis in any joint (patient level) when MTP joints were excluded from the US assessment (odds ratio 6.6, confidence interval (CI) 1.9–22), and hazard ratio 3.4, CI 1.6–6.8, respectively, with a mean time to arthritis of 23 versus 45?months when synovial thickening was present versus not present). There was no association between US and arthritis development at the joint level. Predictive capacity was highest in the groups with an intermediate and high risk of developing arthritis based on a prediction rule with clinical parameters.

Conclusions

Synovial thickening on US predicted clinical arthritis development at the patient level in seropositive patients with arthralgia when MTPs were excluded from the US assessment. Positive PD signs were infrequently seen in these at-risk individuals and was not predictive. In patients at intermediate risk of RA, US may help to identify those at higher risk of developing arthritis.

     

The role of pre-existing diabetes mellitus on hepatocellular carcinoma occurrence and prognosis: a meta-analysis of prospective cohort studies

Background

The impact of pre-existing diabetes mellitus (DM) on hepatocellular carcinoma (HCC) occurrence and prognosis is complex and unclear. The aim of this meta-analysis is to evaluate the association between pre-existing diabetes mellitus and hepatocellular carcinoma occurrence and prognosis.

Methods

We searched PubMed, Embase and the Cochrane Library from their inception to January, 2011 for prospective epidemiological studies assessing the effect of pre-existing diabetes mellitus on hepatocellular carcinoma occurrence, mortality outcomes, cancer recurrence, and treatment-related complications. Study-specific risk estimates were combined by using fixed effect or random effect models.

Results

The database search generated a total of 28 prospective studies that met the inclusion criteria. Among these studies, 14 reported the risk of HCC incidence and 6 studies reported risk of HCC specific mortality. Six studies provided a total of 8 results for all-cause mortality in HCC patients. Four studies documented HCC recurrence risks and 2 studies reported risks for hepatic decomposition occurrence in HCC patients. Meta-analysis indicated that pre-existing diabetes mellitus (DM) was significantly associated with increased risk of HCC incidence [meta-relative risk (RR) = 1.87, 95% confidence interval (CI): 1.15–2.27] and HCC-specific mortality (meta-RR = 1.88, 95%CI: 1.39–2.55) compared with their non-DM counterparts. HCC patients with pre-existing DM had a 38% increased (95% CI: 1.13–1.48) risk of death from all-causes and 91% increased (95%CI: 1.41–2.57) risk of hepatic decomposition occurrence compared to those without DM. In DM patients, the meta-RR for HCC recurrence-free survival was 1.93(95%CI: 1.12–3.33) compared with non-diabetic patients.

Conclusion

The findings from the current meta-analysis suggest that DM may be both associated with elevated risks of both HCC incidence and mortality. Furthermore, HCC patients with pre-existing diabetes have a poorer prognosis relative to their non-diabetic counterparts.     

Genes and environment in susceptibility to visceral leishmaniasis

Kala azar (KA) is a lethal disease caused by Leishmania parasites (Leishmania donovani s.l.) that multiply in large numbers in deep organs such as spleen and liver. The host immunological response to these organisms is complex and experimental studies in animals have detected a large number of genetic loci involved in the control of infection and disease. We report here on a study in a human population of Sudan carried out during an outbreak of KA. The following conclusions are presented: (1) environmental factors that could have affected the distribution of the insect vector, influenced progression of KA in the initial phase of the epidemics - but they became less important later at the peak of transmission, probably after infected phlebotomies had spread to all parts of the village -; (2) Leishmania population during the epidemics was heterogeneous, suggesting a possible parasite evolution during the outbreak; (3) the incidence of KA varied markedly among age groups, families and ethnic groups. Susceptibility to KA was shown to depend on a locus on chromosomes 22q12 and on NRAMP1 on chromosome 2q35; the data also suggested a third locus in the region 2q23-q24. Overall, this study indicates complex interactions between host genes and environment in the spreading of KA in that population. It is also suspected that the large parasite diversity observed in the outbreak has contributed to disease spreading across host genetic barriers.     

Human papillomavirus persistence in young unscreened women, a prospective cohort study

Objective

To evaluate hr-HPV persistence and associated risk factors in a prospective cohort of young unscreened women. Additionally, the relation between hr-HPV status and cytology/histology results is examined.

Methods and Principal Findings

Two year follow-up of 235 out of 2065 young women (18–29 years), participating in a large, one year epidemiological study, with questionnaires, self-collected cervico-vaginal samples (Vibabrush), and SPF₁₀LiPA for HPV detection. Only women hr-HPV positive at sample month 12 were invited for a second year of follow-up. After study follow-up, available cytology/histology data were requested from PALGA (the national network and registry of histo- and cytopathology in The Netherlands). These data were compared with available cytology/histology data of the month 12 hr-HPV negative women from the same cohort. 44.1% of the hr-HPV types detected at study month 12, persisted during follow-up. HPV types 45, 31, 16 and 18 were most likely to persist with percentages of 60.0%, 56.8%, 54.4%,and 50.0%, respectively. Compared to newly detected infections at month 12, infections present since 6 months or baseline had an increased risk to persist (OR 3.09 [95% CI: 1.74–5.51] and OR 4.99 [95% CI: 2.67–9.32], respectively). Other co-factors influencing persistence were, multiple HPV infections, smoking and multiple lifetime sexual partners. The percentage of women with a HSIL/CIN2+ (12.1%) in the persistent HPV group, was not significantly different (p = 0.107) from the 5.3% of the women who cleared the hr-HPV infection, but was significantly (p 0.000) higher than to the 1.6% of women in the hr-HPV negative control group.

Conclusion

We showed that HPV genotype, multiple infections, smoking, and multiple lifetime sexual partners are co-factors that increase the risk of hr-HPV persistency. Most importantly, we showed that hr-HPV infections are more likely to persist the longer they have been present and that women with a persistent hr-HPV infection have a high risk of HSIL/CIN2+ development.     

Protein,iron, and meat consumption and risk for rheumatoid arthritis: a prospective cohort study

A recent prospective study showed that higher consumption of red meat and total protein was associated with increased risk for inflammatory polyarthritis. We therefore prospectively examined the relationship between diet (in particular, protein, iron, and corresponding food sources) and incident rheumatoid arthritis (RA) among 82,063 women in the Nurses' Health Study. From 1980 to 2002, 546 incident cases of RA were confirmed by a connective tissue disease screening questionnaire and medical record review for American College of Rheumatology criteria for RA. Diet was assessed at baseline in 1980 and five additional times during follow up. We conducted Cox proportional hazards analyses to calculate the rate ratio of RA associated with intakes of protein (total, animal, and vegetable) and iron (total, dietary, from supplements, and heme iron) and their primary food sources, adjusting for age, smoking, body mass index, and reproductive factors. The multivariate models revealed no association between RA and any measure of protein or iron intake. In comparisons of highest with lowest quintiles of intake, the rate ratio for total protein was 1.17 (95% confidence interval 0.89–1.54; P for trend = 0.11) and for total iron it was 1.04 (95% confidence interval 0.77–1.41; P for trend = 0.82). Red meat, poultry, and fish were also not associated with RA risk. We were unable to confirm that there is an association between protein or meat and risk for RA in this large female cohort. Iron was also not associated with RA in this cohort.     

Structural, kinetic, and mutational studies of the zinc ion environment in tetrameric cytidine deaminase

The zinc-containing cytidine deaminase (CDA, EC 3.5.4.5) is a pyrimidine salvage enzyme catalyzing the hydrolytic deamination of cytidine and 2'-deoxycytidine forming uridine and 2'-deoxyuridine, respectively. Homodimeric CDA (D-CDA) and homotetrameric CDA (T-CDA) both contain one zinc ion per subunit coordinated to the catalytic water molecule. The zinc ligands in D-CDA are one histidine and two cysteine residues, whereas in T-CDA zinc is coordinated to three cysteines. Two of the zinc coordinating cysteines in T-CDA form hydrogen bonds to the conserved residue Arg56, and this residue together with the dipole moments from two alpha-helices partially neutralizes the additional negative charge in the active site, leading to a catalytic activity similar to D-CDA. Arg56 has been substituted by a glutamine (R56Q), the corresponding residue in D-CDA, an alanine (R56A), and an aspartate (R56D). Moreover, one of the zinc-liganding cysteines has been substituted by histidine to mimic D-CDA, alone (C53H) and in combination with R56Q (C53H/R56Q). R56A, R56Q, and C53H/R56Q contain the same amount of zinc as the wild-type enzyme. The zinc-binding capacity of R56D is reduced. Only R56A, R56Q, and C53H/R56Q yielded measurable CDA activity, R56A and R56Q with similar K(m) but decreased V(max) values compared to wild-type enzyme. Because of dissociation into its inactive subunits, it was impossible to determine the kinetic parameters for C53H/R56Q. R56A and C53H/R56Q display increased apparent pK(a) values compared to the wild-type enzyme and R56Q. On the basis of the structures of R56A, R56Q, and C53H/R56Q an explanation is provided of kinetic results and the apparent instability of C53H/R56Q.     

Clinical characteristics, cardiac events and coronary angiographic findings in the prospective PREVEND cohort: an observational study

Background: The use of invasive procedures has mostly been studied in retrospective (multi)- national registries. Limited evidence exists on the association between microalbuminuria and coronary artery disease (CAD). Methods: The incidence of major adverse cardiac events (MACE) and invasive cardiac procedures was registered between 1997 and 2003 in 8139 subjects, without prior documented CAD, in the PREVEND cohort study (the Netherlands), in which the focus is on microalbuminuria and cardiovascular risk. Qualitative coronary angiographic analysis was performed. Results: During 5.5 years of follow-up, a first MACE occurred in 271 (3.3%) and a first coronary angiography (CAG) was performed in 264 (3.2%) subjects. Of these, 216 CAGs were available for qualitative angiographic analysis. Indications for CAG were stable angina in 129, acute coronary syndrome (ACS) in 55 and ST-elevation myocardial infarction (STEMI) in 32 subjects. Obstructive coronary artery disease was present in 61, 53 and 30 subjects, respectively. A revascularisation was performed in 50 (39%), 50 (91%) and 25 (78%) subjects, respectively. Microalbuminuria was associated with a first MACE, after adjustment for established risk factors. Microalbuminuria was present at baseline in 9% of subjects with normal coronary arteries, in 21% of subjects with one- and two-vessel CAD and in 39% of subjects with threevessel or left main CAD at CAG during follow-up (Ptrend=0.005). Conclusion: This large cohort study shows that two-thirds of diagnostic CAGs for stable angina were not followed by a revascularisation, in contrast to CAGs for STEMI or ACS. Furthermore, this study shows that microalbuminuria is associated with CAD. (Neth Heart J 2007;15:133-41.)