Association of MYO9B haplotype with type 1 diabetes

MYO9B (myosin IXB) polymorphisms were associated with celiac disease and ulcerative colitis susceptibility, presumably through alteration of the intestinal permeability. Recently this gene was also associated with several diseases with an autoimmune component, such as rheumatoid arthritis and systemic lupus erythematosus. We aimed to test, for the first time, the potential role of MYO9B polymorphisms in type 1 diabetes (T1D), an autoimmune condition preceded by changes in intestinal barrier integrity. Three previously associated MYO9B polymorphisms (rs962917, rs2279003, and rs2305764) were studied in 316 T1D patients and 706 ethnically matched controls. Minor alleles of those polymorphisms were more frequent in diabetic patients than in controls and the haplotype carrying major alleles in those positions, rs962917*G/rs2279003*C/rs2305764*G, significantly reduced the risk of T1D in the Spanish population (p = 0.004; OR [95% confidence interval] = 0.68 [0.52-0.90]). Our data suggest an involvement of this MYO9B chromosomal region in T1D predisposition, indicating extensive influence on autoimmune diseases.     

Interchromosomal duplications of the adrenoleukodystrophy locus: a phenomenon of pericentromeric plasticity

A 9.7 kb segment encompassing exons 7-10 of the adrenoleukodystrophy (ALD) locus of the X chromosome has duplicated to specific locations near the pericentromeric regions of human chromosomes 2p11,10p11, 16p11 and 22q11. Comparative sequence analysis reveals 92-96% nucleotide identity, indicating that the autosomal ALD paralogs arose relatively recently during the course of higher primate evolution (5-10 million years ago). Analysis of sequences flanking the duplication region identifies the presence of an unusual GCTTTTTGC repeat which may be a sequence-specific integration site for the process of pericentromeric- directed transposition. The breakpoint sequence and phylogenetic analysis predict a two-step transposition model, in which a duplication from Xq28 to pericentromeric 2p11 occurred once, followed by a rapid distribution of a larger duplicon cassette among the pericentromeric regions. In addition to facilitating more effective mutation detection among ALD patients, these findings provide further insight into the molecular basis underlying a pericentromeric-directed mechanism for non- homologous interchromosomal exchange.      

Matrix composition and mechanics of decellularized lung scaffolds

The utility of decellularized native tissues for tissue engineering has been widely demonstrated. Here, we examine the production of decellularized lung scaffolds from native rodent lung using two different techniques, principally defined by use of either the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) or sodium dodecyl sulfate (SDS). All viable cellular material is removed, including at least 99% of DNA. Histochemical staining and mechanical testing indicate that collagen and elastin are retained in the decellularized matrices with CHAPS-based decellularization, while SDS-based decellularization leads to loss of collagen and decline in mechanical strength. Quantitative assays confirm that most collagen is retained with CHAPS treatment but that about 80% of collagen is lost with SDS treatment. In contrast, for both detergent methods, at least 60% of elastin content is lost along with about 95% of native proteoglycan content. Mechanical testing of the decellularized scaffolds indicates that they are mechanically similar to native lung using CHAPS decellularization, including retained tensile strength and elastic behavior, demonstrating the importance of collagen and elastin in lung mechanics. With SDS decellularization, the mechanical integrity of scaffolds is significantly diminished with some loss of elastic function as well. Finally, a simple theoretical model of peripheral lung matrix mechanics is consonant with our experimental findings. This work demonstrates the feasibility of producing a decellularized lung scaffold that can be used to study lung matrix biology and mechanics, independent of the effects of cellular components.     

Repetitive conundrums of centromere structure and function

In the last few years, a paradox has emerged regarding the relationship of centromere structure and its function. Most centromeric DNAs analyzed to date are composed of a remarkably complex array of repeat structures. In contrast, recent analyses of neocentromeric DNA reveal that repetitive DNA is not a prerequisite for centromere activity. The ubiquity of repetitive sequences among diverse species at sites of primary constriction argues that there is a strong evolutionary link between centromere structure and function. Dynamic mutational processes resulting in amplification, deletion and transposition of repetitive sequences appear to occur frequently in such regions, resulting in considerable interspecific diversity in structure and sequence. One possible solution to this conundrum may be that the rapid accumulation of repetitive sequences within centromeric and pericentromeric DNA is a consequence of functionally active centromeres. Emerging repetitive structures at centromeric sites may be an important byproduct of a functional centromere which ensures that site as an evolutionarily favored position in subsequent meiotic and mitotic lineages. The recent identification of large gene duplications in the vicinity of centromeres may be another example of the enhanced mutational lability of such regions of the genome.      

Risk of HIV infection as a function of the duration of intravenous drug use: a non-parametric Bayesian approach

We analyse the elapsed time between intravenous (IV) drug initiation and HIV infection in a cohort of 972 injecting drug users attending a hospital detoxification unit. We use the time of seroconversion instead of the time of HIV infection because the date of HIV infection is rarely known and the gap between these two times is negligible (around one to three months). Although seroconversion time cannot be determined exactly, it can be inferred at least to within an interval. This seroconversion interval is determined from the dates of HIV antibody tests, if available. The data is consequently interval-censored. We estimate the distribution function of the elapsed time from IV drug initiation to seroconversion as well as the risk of seroconversion by means of a non-parametric Bayesian approach. The analysis is conducted according to the following four calendar periods: before or at 1980; between 1981 and 1985; between 1986 and 1991; after or at 1992 where the IV drug use was initiated. The methodology used is based on an alternating conditional sampling algorithm. The Bayesian approach allows not only the incorporation of prior beliefs about the distribution function, but also the analysis of the risk of seroconversion without assuming restrictive parametric models. Furthermore, the estimator for the distribution function is smooth and thus differences between groups can be easily interpreted.     

Jewish ethnicity and prostate cancer mortality in two large US cohorts

Objective: To investigate prospectively the relationship between Jewish ethnicity and prostate cancer mortality. Methods: Men were selected from white male participants in two large American Cancer Society cohorts: Cancer Prevention Studies I (CPS-I) (enrolled in 1959 and followed through 1972) and II (CPS-II) (enrolled in 1982 and followed through 1996). During the follow-up periods there were 1751 prostate cancer deaths among 417,018 men in CPS-I and 3594 deaths among 447,780 men in CPS-II. Cox proportional hazards modeling was used to compute rate ratios (RR) and to adjust for known and suspected risk factors for prostate cancer. Results: Prostate cancer death rates were substantially lower among Jewish men than other white men in both cohorts (multivariate adjusted rate ratios (RR) = 0.54, 95% CI = 0.38–0.77 in CPS-I; RR = 0.72, 95% CI = 0.61–0.86 in CPS-II). Factors such as tobacco avoidance and measured dietary patterns did not account for this difference. Lower prostate cancer death rates were observed among Jewish men regardless of place of birth of the participants or their parents. Conclusions: Prostate cancer death rates are lower among Jewish men in the US and in Israel than among non-Jewish US white men. This may reflect persistent differences in unknown environmental risk factors or possible genetic susceptibility.     

Tobacco use and cancer: an epidemiologic perspective for geneticists

Much of what is known about the deleterious effects of tobacco use on health was learned from epidemiologic studies over the last half century. These studies establish unequivocally that tobacco use, particularly manufactured cigarette smoking, causes most cancers of the lung, oropharynx, larynx, and esophagus in the USA, and approximately one-third of all cancers of the pancreas, kidney, urinary bladder and uterine cervix. More recent evidence also implicates smoking with cancers of the stomach, liver and colorectum. While over half of the estimated 440 000 smoking-attributable deaths that occur annually in the USA involve non-malignant cardiovascular and respiratory conditions, smoking-attributable cancers are more recognized and feared. Geneticists increasingly study tobacco use as a model for environmental carcinogenicity. Tobacco-exposed populations provide opportunities to characterize the somatic mutations that give rise to specific cancers and to identify the inherited genetic traits that confer susceptibility or resistance. Studies to identify the genetic determinants of addiction may be particularly important. Future research to identify other susceptibility factors, such as genes that modify carcinogen metabolism or DNA repair, will need to be substantially larger and to quantify lifetime tobacco exposure with more precision than have past studies in order to distinguish gradations in risk due to exposure from those caused by genetic susceptibility. This review considers: (a) the epidemiology of tobacco use; (b) cancers presently classified as smoking-attributable by the US Surgeon General; (c) the magnitude of the epidemic of cancers and other diseases caused by tobacco use; (d) selected issues in the epidemiology of lung cancer; and (e) the interface of genetics and epidemiology in understanding, preventing, and treating tobacco-attributable disease.     

The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics

BACKGROUND: Large-scale, prospective cohort studies have played a critical role in discovering factors that contribute to variability in cancer risk in human populations. Epidemiologists and volunteers at the American Cancer Society (ACS) were among the first to establish such cohorts, beginning in the early 1950s and continuing through the present, and these ACS cohorts have made landmark contributions in many areas of epidemiologic research. METHODS AND RESULTS: The Cancer Prevention Study II Nutrition Cohort was established in 1992 and was designed to investigate the relation between diet and other lifestyle factors and exposures and the risk of cancer, mortality, and survival. The cohort includes over 84,000 men and 97,000 women who completed a mailed questionnaire in 1992. New questionnaires are sent to surviving cohort members every other year to update exposure information and to ascertain new occurrences of cancer; a 90% response rate was achieved for follow-up questionnaires in 1997 and 1999. Reported cancers are verified through medical records, registry linkage, or death certificates. The cohort is followed actively for all cases of incident cancer and for all causes of death. Through a collaborative effort among ACS national and division staff, volunteers, and the American College of Surgeons, blood samples were collected from a subgroup of 40,000 cohort members and are in storage at a central repository for future investigation of dietary, hormonal, genetic, and other factors and cancer risk. Collection of DNA samples from buccal cells in an additional 50,000 cohort members is underway currently and will be completed in 2002. CONCLUSIONS: This new cohort of both men and women promises to be particularly valuable for the study of cancer occurrence, mortality, and survival as they relate to obesity and weight change, physical activity at various points in life, vitamin supplement use, exogenous hormone use, other medications (such as aspirin and nonsteroidal anti-inflammatory drugs) and cancer screening modalities.     

Association of polymorphisms in the paraoxonase 1 gene with breast cancer incidence in the CPS-II Nutrition Cohort.

Paraoxonase 1 (PON1) plays an important role in the high-density lipoprotein-mediated prevention of low-density lipoprotein oxidation and the metabolism of lipid-soluble radicals. In this study, we investigated the association of two common, nonsynonymous polymorphisms in the PON1 gene (Q192R and L55M) with breast cancer risk in postmenopausal women through a nested case-control study within the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Using conditional logistic regression of genotyping results from 502 cases and 502 cancer-free controls matched on age, race/ethnicity, and date of blood draw, we found that the L55M single nucleotide polymorphism (SNP) was associated with an increased risk of breast cancer [odds ratio (OR), 1.58; 95% confidence interval (95% CI), 1.05-2.37 for MM]. No association was found for the Q192R SNP. The L55M association with breast cancer was modified by nonsteroidal anti-inflammatory drug (NSAID) use. The association was limited to women who took NSAIDs and was somewhat stronger among women who reported regular (> or = 15 times per month) NSAID use (OR, 3.24; 95% CI, 1.17-9.00) than in those who reported any NSAID use (OR, 2.46; 95% CI, 1.39-4.36). These results suggest that genetic variation in PON1, particularly at the L55M SNP, may be associated with increased risk of breast cancer in postmenopausal women. Furthermore, NSAID use seems to modify this risk.     

Cigarette smoking and colorectal cancer mortality in the cancer prevention study II

BACKGROUND: Recent studies suggest that long-term cigarette smoking is associated with an increased risk of colorectal cancer. Whether the association is causal or due to confounding remains unclear. METHODS: We examined cigarette smoking in relation to colorectal cancer mortality, evaluating smoking duration and recency and controlling for potential confounders in the Cancer Prevention Study II. This prospective nationwide mortality study of 1 184 657 adults (age > or =30 years) was begun by the American Cancer Society in 1982. After exclusions, our analytic cohort included 312 332 men and 469 019 women, among whom 4432 colon or rectal cancer deaths occurred between 1982 and 1996 among individuals who were cancer free in 1982. Rate ratios (RRs) and 95% confidence intervals (CIs) were estimated by fitting Cox proportional hazards models. All statistical tests were two-sided. RESULTS: Multivariate-adjusted colorectal cancer mortality rates were highest among current smokers, were intermediate among former smokers, and were lowest in lifelong nonsmokers. The multivariate-adjusted RR (95% CI) for current compared with never smokers was 1.32 (1.16-1.49) among men and 1.41 (1.26-1.58) among women. Increased risk was evident after 20 or more years of smoking for men and women combined as compared with never smokers. Risk among current and former smokers increased with duration of smoking and average number of cigarettes smoked per day; risk in former smokers decreased significantly with years since quitting. If the multivariate-adjusted RR estimates in this study do, in fact, reflect causality, then approximately 12% of colorectal cancer deaths among both men and women in the general U.S. population in 1997 were attributable to smoking. CONCLUSIONS: Long-term cigarette smoking is associated with increased risk of colorectal cancer mortality in both men and women. Clear reduction in risk is observed with early smoking cessation.