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PubMed2005

A cohort study of cancer risk in relation to family histories of cancer in the Utah population database.

BACKGROUND: It is well known that genetic variability affects the risk of many cancers, but details of the patterning of inherited cancer risk across different sites and age groups still are not well quantified. METHODS: The authors conducted a nested case-control study of the familial risk of 40 cancers based on a cohort of 662,515 individuals from the Utah Population Database. From 1 to 10 controls selected from the cohort were matched individually on gender, birth year, and birthplace to each cancer case; and familial standardized incidence ratios (FSIR) were calculated for both cases and controls. Conditional logistic regression was used to estimate relative risks and population-attributable risks (PARs) of cancer in relation to FSIR. Relative risks of cancer in first-degree through fifth-degree relatives of cases, compared with controls, were calculated using the proportional hazards methods. All analyses were adjusted for spouse affection status and Latter Day Saints church affiliation. RESULTS: Thirty-five of 40 cancers exhibited positive associations between risk and FSIR, and 21 of those associations were statistically significant. PAR estimates were strikingly high for prostate carcinoma (57%), breast carcinoma (39%), colon carcinoma (32%), lip carcinoma (31%), chronic lymphocytic leukemia (35%), and melanoma (32%). Both the proportion and the number of all cancers attributable to family history peaked at 32% in the group ages 65-84 years and remained high in the group age >/= 85 years. CONCLUSIONS: A substantial portion of cancer risk was attributable to familial factors. The patterns of familial cancer recurrence among distant relatives suggested that simple genetic mechanisms may explain much of the familiality of cancer.

Adolescent↗
PubMed1995

Biochemical and anthropometric characterization of morbid obesity in a large Utah pedigree.

A Utah family with morbid obesity was extended to include 122 persons in four generations for the purpose of characterizing anthropometric and biochemical variables in family members with and without morbid obesity. Seventy-seven subjects had blood drawn for biochemical analyses. Of the 77 subjects, 12 were morbidly obese (> or = 44.5 kg or 100 pounds overweight), 20 were between 22.5-45.4 kg (50 and 99 pounds) overweight and 45 were less than 22.5 kg (50 pounds) overweight. Sixty-two randomly-ascertained controls were used for comparisons of age- and gender-adjusted study variables. Morbidly obese subjects had mean body mass indices (BMI) of 41.0 kg/m2 (62 kg over ideal weight) compared to 25.3 kg/m2 (10 kg overweight) in the < 22.5 kg family members (p < 0.001). The < 22.5 kg family members had lower BMI than the random controls (27.6 kg/m2, p < 0.05), indicating clear bimodality of obesity within the pedigree. Percent body fat from bioelectrical impedance was 35% versus 24% in the morbidly obese and the < 22.5 kg subjects, respectively. Idealbody weight was similar among the three pedigree weight groups. Hip and waist circumferences were much larger in the morbidly obese and the waist-to-hip ratio remained significantly greater in the morbidly obese subjects compared to the < 22.5 kg group. Morbidly obese subjects had elevated triglycerides and VLDL-C levels, low HDL-levels, and normal LDL-C levels. Fasting insulin was the best predictor of morbid obesity of all biochemical and lipid measurements (odds ratio of 4.5). Fasting insulin levels and the insulin-to-glucose ratio were more than twice as high as control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2002

Semi-parametric models of long- and short-term survival: an application to the analysis of breast cancer survival in Utah by age and stage.

A flexible class of semi-parametric survival models is proposed that takes account of long- and short-term covariate effects in cancer survival. The diversity of responses described by the models include non-proportional and crossing survival curves as well as a fraction of long-term survivors. Restricted non-parametric maximum likelihood estimation procedures (RNPMLE) are developed to provide point estimates, confidence intervals and tests for the models. Numerical algorithms to fit semi-parametric survival models are emphasized. The methods are applied to analyse post-treatment survival of breast cancer patients diagnosed in Utah by age and stage.

Adult↗
PubMed2000

Hazard assessment of selenium and other trace elements in wild larval razorback sucker from the Green River, Utah.

Contaminant investigations of the Green River in northeastern Utah have documented selenium contamination at sites receiving irrigation drainage. The Green River provides critical habitat for four endangered fishes including the largest extant riverine population of endangered razorback sucker. Although 2175 larval razorback suckers were collected from the river between 1992 and 1996, very few juveniles have been captured within recent decades. Selenium concentrations were measured in larval razorback suckers collected from five sites in the Green River (Cliff Creek, Stewart Lake Drain, Sportsman's Drain, Greasewood Corral, and Old Charlie Wash) to assess the potential for adverse effects on recruitment of larvae to the juvenile stage and the adult population. Larvae from all sites contained mean selenium concentrations ranging from 4.3 to 5.8 microg/g. These values were at or above the proposed toxic threshold of 4 microg/g for adverse biological effects in fish, which was derived from several laboratory and field studies with a wide range of fish species. At two sites, Cliff Creek and Stewart Lake Drain, selenium concentrations in larvae increased over time as fish grew, whereas selenium concentrations decreased as fish grew at Sportsman's Drain. Evaluation of a 279-larvae composite analyzed for 61 elements demonstrated that selenium and, to a lesser extent, vanadium were elevated to concentrations reported to be toxic to a wide range of fish species. Elevated selenium concentrations in larval razorback suckers from the five sites suggest that selenium contamination may be widespread in the Green River, and that survival and recruitment of larvae to the juvenile stage may be limited due to adverse biological effects. Selenium contamination may be adversely affecting the reproductive success and recruitment of endangered razorback sucker.

Animals↗
PubMed2001

Demographics and health-related factors of men receiving prostate-specific antigen screening in Utah.

BACKGROUND: Identifying who is pursuing prostate-specific antigen (PSA) screening for prostate cancer is prerequisite to effectively influencing participation in PSA screening and educating people about potential screening implications and personal risk. This paper describes the relationship between select demographic and health-related factors with PSA screening. METHODS: Analysis was based on 1,293 men age 40 years or older who responded to a cross-sectional random telephone survey involving 12 health districts in the state of Utah from June 1 to August 31, 1996. Independent variables were current age, race, marital status, education, household income, medical insurance, level of physical activity, intake of fruits and vegetables, receipt of psychiatric help, religious preference, church attendance, general health status, and employment. RESULTS: Forty-eight percent of respondents reported having had a PSA in the past year. PSA screening in the previous year significantly increased and leveled off with age: 23.9% for ages 40-49, 51.4% for ages 50-59, 67.4% for ages 60-69, and 67.0% for ages 70+. After adjusting for age, only marital status and medical insurance were significantly related to PSA screening, with medical insurance having the largest effect. Approximately 50.6% married men and 33.5% unmarried men had a PSA in the past year. Percentages for insured and uninsured men were 49.4 and 16.6%, respectively. CONCLUSION: A substantial portion of elderly men, particularly those who are married and medically insured, have had a PSA test in the past year. This information makes it possible to more effectively influence participation in PSA screening and educate people about potential screening implications and personal risk.

Adult↗
PubMed1995

Reproductive factors and colon cancer: the influences of age, tumor site, and family history on risk (Utah, United States).

The Utah (United States) Population Database was used to evaluate the associations between reproductive factors and colon cancer risk and the impact that family history, age at diagnosis, and tumor site have on these associations. From the cohort of (White) women in the database, all first-primary cases of colon cancer (n = 819) and controls who had complete fertility information (n = 3,202) were examined. The majority of tumors (68.6 percent) among women diagnosed at age 64 years or less were in the distal segment of the colon, while among women 65 or older, the majority of tumors (55.7 percent) were proximal. Women diagnosed before age 65 had a lower risk of colon cancer with increasing numbers of liveborn children (odds ratio [OR] = 0.6, 95 percent confidence interval [CI] = 0.3-0.9 for women with five or more children compared with women with one or two children). A long interval between first and second births (first birth-interval) was associated with increased risk of tumors in the distal segment of the colon (OR = 1.4, CI = 1.0-2.0) and among women diagnosed before age 65 (OR = 1.6, CI = 1.0-2.5); a longer, average birth-interval was associated with increased risk of proximal tumors (OR = 1.5, CI = 1.1-2.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Is diabetes mellitus a risk factor for ovarian cancer? A case-control study in Utah and Washington (United States).

Insulin resistance characterizes non-insulin dependent diabetes (NIDDM). Insulin resistance may coexist in clinical syndromes with hyperestrogenism and hyperandrogenism, suggesting that the ovary may be sensitive to effects of insulin. In addition, insulin-like growth factor-I receptors, which are capable of binding insulin, have been identified in ovarian cancer tissue and are proposed to regulate cell growth. We evaluated the association between a history of diabetes mellitus and ovarian cancer in a case-control study in seven counties in Washington and in Utah (United States) during the years 1975-87. Cases included women newly diagnosed with ovarian cancer over a five-year period who were identified through population-based cancer reporting. Controls similar to cases with regard to age and county of residence were identified via household surveys or random digit dialing. The study included 595 cases and 1,587 controls. Twenty-seven cases (4.5 percent) and 72 controls (4.5 percent) reported a history of diabetes. Logistic regression analysis of the association between diabetes and ovarian cancer controlling for age, body mass index, and race resulted in an odds ratio (OR) of 0.9 (95 percent confidence interval [CI] = 0.6-1.5). The OR was not changed with further controlling for prior oral contraceptive use or prior pregnancy. None of the 20 women with nonepithelial tumors (15 of which were stromal tumors) had a history of diabetes (upper CI = 4.0). These results, together with findings of two earlier cohort studies, do not support the hypothesis that diabetes is a risk factor for epithelial ovarian cancer.

Adult↗
PubMed1991

Adult dietary intake and prostate cancer risk in Utah: a case-control study with special emphasis on aggressive tumors.

A population-based case-control study in Utah of 358 cases diagnosed with prostate cancer between 1984 and 1985, and 679 controls categorically matched by age and county of residence, were interviewed to investigate the association between dietary intake of energy (kcal), fat, protein, vitamin A, beta-carotene, vitamin C, zinc, cadmium, selenium, and prostate cancer. Dietary data were ascertained using a quantitative food-frequency questionnaire. Data were analyzed separately by age (45-67, 68-74) and by tumor aggressiveness. The most significant associations were seen for older males and aggressive tumors. Dietary fat was the strongest risk factor for these males, with an odds ratio (OR) of 2.9 (95 percent confidence interval [CI] 1.0-8.4) for total fat; OR = 2.2 (CI = 0.7-6.6) for saturated fat; OR = 3.6 (CI = 1.3-9.7) for monounsaturated fat; and OR = 2.7 (CI = 1.1-6.8) for polyunsaturated fat. Protein and carbohydrates had positive but nonsignificant associations. Energy intake had an OR of 2.5 (CI = 1.0-6.5). In these older men, no effects were seen for dietary cholesterol, body mass, or physical activity. There was little association between prostate cancer and dietary intake of zinc, cadmium, selenium, vitamin C, and beta-carotene. Total vitamin A had a slight positive association with all prostate cancer (OR = 1.6, CI = 0.9-2.4), but not with aggressive tumors. No associations were found in younger males, with the exception of physical activity which showed active males to be at an increased but nonsignificant risk for aggressive tumors (OR = 2.0, CI = 0.8-5.2) and beta-carotene which showed a nonsignificant protective effect (OR = 0.6, CI = 0.3-1.6). The findings suggest that dietary intake, especially fats, may increase risk of aggressive prostate tumors in older males.

Aged↗
PubMed1994

Selenium in eggs and milt of razorback Sucker (Xyrauchen texanus) in the middle Green River, Utah.

Eggs from three female and milt from five male endangered razorback suckers (Xyrauchen texanus) were collected from the Razorback Bar (about 20 km upstream of Ashley Creek) in the Green River of northeastern Utah. Eggs, but not milt, had concentrations of selenium that were above the range of selenium concentrations in control fish from laboratory studies or reference fish from field studies. The concentrations, however, were below those reported in selenium-exposed fish that had reproductive problems in laboratory studies or field investigations. Tests with three streamside spawned pairs of razorback suckers, which were sampled for eggs and milt in this study, resulted in no hatching of fertilized eggs. Concentrations of selenium in eggs and milt were significantly correlated with selenium concentrations in muscle plugs taken from the same fish, but egg and milt concentrations were not significantly different from muscle plugs. Selenium concentrations in eggs of razorback suckers in the Green River may be sufficiently elevated to cause reproductive problems that are contributing to the decline of this species in the upper Colorado River Basin.

Animals↗
PubMed1994

Gender of the first offspring, age at diagnosis, and survival with breast cancer (Utah, United States).

We examined the relationship between the survival of women with breast cancer and the gender of their first children using a genealogy-based survival analysis. The study group consisted of 2,155 parous women diagnosed in Utah (United States) with first primary breast cancers (excluding in situ tumors). We calculated hazard rate ratios (HRR) which were adjusted for stage, median survival times, and proportions surviving for three-, five-, and 10-year intervals stratified by age at diagnosis. Median survival among women diagnosed under the age of 45 was 171 months if the first child was female, but only 66 months if the first child was male (HRR = 1.66, 95 percent confidence interval = 1.07-2.57, for male children). For women diagnosed at age 45 or older, all survival times were similar, although women whose first child was male had slightly longer median survival time. These findings suggest that the gender of the first child has a strong influence on survival among women diagnosed under 45 years of age, but not among those diagnosed later in life. Gender of the first offspring may be a useful clinical indicator of prognosis and survival and may provide insights into etiologic and promotional factors for breast cancer.

Adult↗
PubMed2004

A mutation in PCSK9 causing autosomal-dominant hypercholesterolemia in a Utah pedigree.

Familial hypercholesterolemia results from mutations in the low-density lipoprotein (LDL) receptor or apolipoprotein B genes. We have previously reported the identification of a Utah autosomal-dominant hypercholesterolemia pedigree (kindred 1173) that did not show linkage to either of these loci (Hunt et al. 2000). Expansion of the pedigree and increased marker density within the region of interest have resulted in a multipoint LOD score of 9.6 and enabled us to decrease the size of the linked region to approximately 7.5 Mbp. In addition, we were able to identify additional families sharing the same microsatellite haplotype. While all haplotype carriers in kindred 1173 (K1173) are affected, the haplotype carriers within the newly identified families are unaffected, suggesting that the causal mutation in K1173 had occurred after divergence of these pedigrees from a common ancestor. Mutation screening of genes in the region identified a single nucleotide variant (G-->T) present on the K1173 haplotype that was not present on the same haplotype in the other kindreds. This variant results in a D374Y missense change in the gene PCSK9.

Female↗
PubMed2001

Linkage of body mass index to chromosome 20 in Utah pedigrees.

Several linkage studies have hinted at the existence of an obesity predisposition locus on chromosome 20, but none of these studies has produced conclusive results. Therefore, we analyzed 48 genetic markers on chromosome 20 for linkage to severe obesity (BMI> or =35) in 103 extended Utah pedigrees (1,711 individuals), all of which had strong aggregation of severe obesity. A simple dominant model produced a maximum multipoint heterogeneity LOD score of 3.5 at D20S438 (55.1 cM). Two additional analyses were performed. First, a one-gene, two-mutation model (with one dominant mutation and one recessive mutation) increased the LOD score to 4.2. Second, a two-locus model (with one locus dominant and one recessive) generated a multipoint LOD score of 4.9. We conclude that one or more severe obesity predisposing genes lie within an interval of approx. 10 cM on chromosome 20. This study generated significant LOD scores which confirm suggestive linkage reports from previous studies. In addition, our analyses suggest that the predisposing gene(s) is localized very near the chromosome 20 centromere.

Body Mass Index↗
PubMed2000

The Utah paradigm of skeletal physiology: an overview of its insights for bone, cartilage and collagenous tissue organs.

In a 1960 paradigm of skeletal physiology, effector cells (chondroblasts, fibroblasts, osteoblasts, osteoclasts, etc.) regulated by nonmechanical agents wholly determined the architecture, strength, and health of bones, joints, fascia, ligaments, and tendons. Biomechanical and tissue-level phenomena had no roles in that paradigm. Subsequent studies and evidence slowly revealed skeletal tissue-level mechanisms and their functions, including biomechanical ones, as well as "game rules" that seem to govern them. That slow discovery process found that effector cells are only parts of tissue-level mechanisms, as kidney cells are only parts of nephrons and wheels are only parts of cars. Normally all those things help to determine skeletal architecture, strength, and health, and adding them to the 1960 paradigm led to the still-evolving Utah paradigm of skeletal physiology that concerns, in part, how load-bearing skeletal organs adapt to the voluntary mechanical loads on them. That caused controversies this article does not try to resolve; instead, it describes some issues they concern. In that regard, controversy can depend on how one assesses the relevance of facts to a problem more than on their accuracy. If a paradigm added new facts to a former one and the new one's advocates viewed all those facts as relevant, but the former's advocates questioned the relevance of some of the new facts, their views about a problem could differ even though each view depended on accurate facts. Readers would make their own judgments about the bearing of those ideas on this article's content.

Bone and Bones↗
PubMed2005

The power to detect genetic linkage for quantitative traits in the Utah CEPH pedigrees.

Quantitative trait phenotypes and linked marker genotypes were simulated for a range of models with different sets of assumptions based on displacement, prevalence, and heritability of the trait in 30 Utah Centre d'Etude du Polymorphisme Humain (CEPH) families. The gain in power by the addition of 15 families was also estimated by extrapolation. Power was evaluated using both parametric single locus (PSL) models and variance components (VC) methods for two situations: (1) a single marker with 75% heterozygosity and a recombination fraction of 0.05, and (2) a fully informative marker as an approximation to multipoint analysis. When the simulation and analysis models were both dominant with the same prevalence, power > or =80% for lod >3 was estimated when quantitative trait locus variance was > or =40% with a displacement of 2.5 or 3. Power was 5-15% lower for recessive models compared to dominant models. With the addition of 15 families, an average increase in power of 17% and 22% was estimated for the dominant and recessive models, respectively. In PSL analyses, power was estimated at < or =20% when the dominance was misspecified. This investigation delineates parameter conditions under which this unique sample affords adequate power to detect linkage using both PSL and VC methods.

Genetic Linkage↗
PubMed1999

A novel LDLR mutation, H190Y, in a Utah kindred with familial hypercholesterolemia.

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein (LDL) cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications together with diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary atherosclerosis. Previously published blood cholesterol criteria greatly under-diagnosed new cases of FH among members of known families with FH and over-diagnosed FH among participants of general population screening. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To carry out molecular genetic diagnosis of the disease, we screened DNA samples for mutations in all 18 exons and the exon-intron boundaries of the LDL receptor gene (LDLR). Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 631, causing substitution of tyrosine for histidine at codon 190 in exon 4 of the LDLR gene. The mutant allele-specific amplification method was used to examine 12 members of the family recruited for the diagnosis. This method helped to unequivocally diagnose 7 individuals as heterozygous for this particular LDLR mutation, while excluding the remaining 5 individuals from carrier status with FH.

Adult↗
PubMed1993

Documented need for more effective diagnosis and treatment of familial hypercholesterolemia according to data from 502 heterozygotes in Utah.

A project to help Utah residents with heterozygous familial hypercholesterolemia (FH) identified affected individuals by collecting detailed questionnaires from: (1) very high-risk persons in computer files of screening data (very high cholesterol levels, very early coronary artery disease, and strong positive family history); (2) confirmed FH index cases from a university lipid clinic; and (3) relatives of any confirmed FH cases. Questionnaires were received from 2,143 persons identifying 101 living index cases and 502 relatives meeting the criteria for the diagnosis of FH. Finding new FH heterozygotes was about one fourth as expensive by tracing relatives of confirmed FH cases by evaluating very high-risk persons. Of those meeting criteria for the diagnosis of heterozygous FH, only 31% reported being told by their physicians that they had FH, only 42% indicated that they were taking a cholesterol-lowering prescription medication, and only 23% had reasonably controlled cholesterol levels (below the 90th percentile). However, the data also suggest that good control is achievable in motivated patients. Among 106 FH heterozygotes who were early responders to a second follow-up questionnaire, 79% were taking prescription medications, of whom 49% had achieved cholesterol levels below the 90th percentile, and 17% even achieved cholesterol levels below the 50th percentile. We conclude that most patients with heterozygous FH are not diagnosed and not adequately treated. We demonstrated how many of these persons needing help could be identified efficiently by tracing relatives of known index cases.

Adolescent↗
PubMed1989

Cross-spouse correlates of blood pressure in hypertension-prone families in Utah.

This study used a subsample of 543 married couples from a large group of families in Utah, who were originally studied to assess the genetic and environmental determinants of hypertension. Excluding individuals on medication and controlling for the major risk factors for hypertension, evidence was obtained for cross-spouse blood pressure associations equal in magnitude to self-psychosocial and demographic measures. Observed spouse-spouse similarity for blood pressures remained significant after adjustment for shared psychological factors. It is speculated that different aspects of each spouse's nonmarital environments (e.g. work, social support) have differential impacts on the marital environment and on physiologic indicators of health.

Adult↗
PubMed1996

A population-based study of congenital diaphragmatic hernia in Utah: 1988-1994.

OBJECTIVE: To define the natural history of congenital diaphragmatic hernia and to determine the potential impact of fetal therapy. METHODS: This retrospective case series consisted of all fetuses and neonates with congenital diaphragmatic hernia born between 1988 and 1994 in the state of Utah that could be identified through genetic counseling referrals, delivery logs, and neonatal intensive care unit discharge diagnosis records. Maternal and neonatal hospital records were reviewed for antepartum, intrapartum, and postpartum variables. Based on existing recommendations, fetuses who might have benefited from fetal therapy were identified. RESULTS: Ninety-six cases were identified, for a frequency of one case in 2710 live births per year. Five pregnancies were terminated before 21 weeks' gestation. The overall survival rate excluding these five cases was 58.2%. Among the remaining 91 cases, survival was significantly better for infants diagnosed in the neonatal period than for those diagnosed prenatally (78% versus 35%; P < .001). The frequency of associated anomalies was similar for antepartum and postpartum cases. Sixty-two percent of nonsurvivors had some type of other anomaly, but no pattern was apparent. There were no accurate prenatal predictors for lethal pulmonary hypoplasia, but preterm birth and the presence of severe cardiac anomalies were predictors of neonatal death. Only two of 96 fetuses would have potentially benefited from fetal therapy. CONCLUSION: The outcome of infants with congenital diaphragmatic hernia is worse with preterm birth and if diagnosed prenatally. The survival rate we found was better than that reported in earlier studies, suggesting improved perinatal and neonatal management. Fetal therapy based on current eligibility criteria would have a minimal impact on survival of fetuses with congenital diaphragmatic hernia.

Congenital Abnormalities↗