The Clinical Next‐Generation Sequencing Database: A Tool for the Unified Management of Clinical Information and Genetic Variants to Accelerate Variant Pathogenicity Classification

Recent advances in next‐generation sequencing (NGS) have given rise to new challenges due to the difficulties in variant pathogenicity interpretation and large dataset management, including many kinds of public population databases as well as public or commercial disease‐specific databases. Here, we report a new database development tool, named the “Clinical NGS Database,” for improving clinical NGS workflow through the unified management of variant information and clinical information. This database software offers a two‐feature approach to variant pathogenicity classification. The first of these approaches is a phenotype similarity‐based approach. This database allows the easy comparison of the detailed phenotype of each patient with the average phenotype of the same gene mutation at the variant or gene level. It is also possible to browse patients with the same gene mutation quickly. The other approach is a statistical approach to variant pathogenicity classification based on the use of the odds ratio for comparisons between the case and the control for each inheritance mode (families with apparently autosomal dominant inheritance vs. control, and families with apparently autosomal recessive inheritance vs. control). A number of case studies are also presented to illustrate the utility of this database.     

Mode of inheritance of finger dermatoglyphic traits among Vaidyas of West Bengal, India

BACKGROUND: It is well established that dermatoglyphics are genetically determined. But, to date, few studies have given attention to the inheritance pattern of dermatoglyphics. Furthermore, despite the existence of different advanced statistical packages, none of these previous studies implemented a model-fitting technique to reveal the mode of inheritance. Thus, the genetic nature of dermatoglyphics is still not clear. AIM: In the present communication, an attempt has been made to provide some information regarding the genetics of finger dermatoglyphics by estimating the magnitude and mode of inheritance of these traits. SUBJECTS AND METHODS: The fingerprints of 824 individuals from 200 families including two generations were collected from Barasat in North 24-Parganas, West Bengal. The study includes familial correlations between first-degree relatives and corresponding heritabilities. In the final stage, segregation analyses by the Pedigree Analysis Package (PAP) were conducted on these data to understand the mode of inheritance. RESULTS: The major findings indicated the following: (a) Familial correlations in all possible relationships (except spouse correlation) were statistically significant and of comparable magnitude. (b) The corresponding heritabilities were in the range between 59% for Pattern Intensity Index (PII) and 77% for Total Finger Ridge Count (TFRC). These estimates were in agreement with previously published data on this subject. (c) By segregation analysis, the 'Sporadic', 'Environmental', 'No major gene effect' as well as 'No polygenic component' models were strongly rejected (p < 0.05) and the hypothesis of a major gene's (MG) influence on all studied traits was accepted, though the proportion of MG variance was low. (d) The Most Parsimonious Mendelian model clearly indicated the contribution of a major gene with dominant (for PII) and additive (for two ridge counts) effects. CONCLUSION: The present report supports the evidence of the existence of a major gene on these dermatoglyphic traits and the transmission of this effect is consistent with Mendelian expectation.     

Analysis of Functional SNP in Ifng/Ifngr1 in Chinese Han Population with Tuberculosis

Ifng/Ifngr1 are the main genes that are associated with tuberculosis. We continued to search for other functional single nucleotide polymorphisms (SNP) and investigated their influence on patients with tuberculosis in the Chinese population. Seven SNP located in the ifng and ifngr1 genes were genotyped by ligase detection reaction in 222 cases and 188 ethnically matched controls. A significant genetic association between rs7749390 (located on the exon/intron splice site of the ifngr1 gene) and tuberculosis was observed, and the log‐additive model was accepted as the best inheritance model to fit these data (OR: 1.35, 95% CI: 1.02–1.80, P = 0.038). Haplotype‐specific association analysis revealed that the result was consistent with the individual SNP study. The combination of rs2234711/rs1327474/rs7749390/rs41401746, which was in strong linkage disequilibrium (D′ > 0.75), showed a significant association of ifngr1 with tuberculosis (P = 0.00079). Neither the single SNP nor the haplotype analysis showed a significant association between tuberculosis and the ifng gene markers. Our data implied the involvement of the ifngr1 gene in susceptibility to tuberculosis.     

Insulin resistance as a predictor of incident asthma‐like symptoms in adults

Background There is accumulating evidence that obesity is associated with an increased risk of asthma. It has been hypothesized that insulin resistance may be involved in obesity‐induced asthma, but till date there is no prospective data on this issue. Objective To investigate the association of obesity and insulin resistance with the incidence of asthma‐like symptoms in adults. Methods Out of a random sample of 12 934 persons from a general population, 6784 (52.5%) were included and participated in a health examination in 1999–2001. After 5 years they were re‐invited and 4516 (66.6%) participated at follow‐up. At baseline three obesity measures were considered: body mass index, waist circumference, and waist‐to‐hip ratio. In addition, fasting glucose and insulin were measured for determination of insulin resistance. Information on asthma‐like symptoms at baseline and follow‐up were obtained by questionnaires. A total of 3441 participants defined as non‐asthmatic at baseline and with complete information on all the considered variables were included in the analyses. Data were controlled for confounding by sex, age, social status, and smoking. Results All obesity measures were associated with incident wheezing and asthma‐like symptoms. In addition, insulin resistance was associated with incident wheezing [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.38–2.54] and asthma‐like symptoms (OR 1.61, 95% CI 1.23–2.10). The effect of insulin resistance was stronger than that of obesity and was independent of sex. Conclusion We found that insulin resistance was associated with an increased risk of developing asthma‐like symptoms. This finding supports the hypothesis that obesity and asthma may be linked through inflammatory pathways also involved in insulin resistance.     

Inheritance of open‐angle glaucoma in the Barbados family study

The majority of genetic studies on open‐angle glaucoma (OAG) have been conducted in primarily white populations, with investigations of inheritance patterns largely based on self‐reported information. The Barbados Family Study of Open‐Angle Glaucoma (BFSG) is the first study to investigate the transmission pattern(s) for OAG in a predominantly black population, based on standardized examinations. Each BFSG participant received a comprehensive examination including anthropometric and other measurements, best‐corrected visual acuity, perimetry, tonometry, lens gradings, fundus photography, venipuncture, an extensive interview including ocular, medical and family history information and a comprehensive ophthalmologic evaluation. Conservative criteria were used to define glaucoma status, including the presence of both visual field defects and optic disc damage. The study included 207 OAG‐affected probands (median age: 68 years) and 1,056 of their relatives (median age: 47 years). Among the relatives examined 10% (n = 106) had OAG and 13% (n = 141) had probable OAG. Segregation analyses were performed to determine the mode of inheritance for glaucoma in these families. The results indicate that transmission of OAG or probable OAG is most likely due to a major codominant gene. Both age and gender are shown to be significant factors as well; with an increase in risk being associated with each year of age over 54 years and an increase in risk for all ages and genotypes observed in males. These analyses do not, however, preclude the possible existence of an environmental component or other genetic determinants in OAG. Further evidence for the existence of a major gene may be obtained by additional follow‐up of the relatively young cohort of relatives, as well as ongoing linkage analyses. © 2001 Wiley‐Liss, Inc.     

Evidence for the multigenic inheritance of schizophrenia

Schizophrenia is assumed to have complex inheritance because of its high prevalence and sporadic familial transmission. Findings of linkage on different chromosomes in various studies corroborate this assumption. It is not known whether these findings represent heterogeneous inheritance, in which various ethnic groups inherit illness through different major gene effects, or multigenic inheritance, in which affected individuals inherit several common genetic abnormalities. This study therefore examined inheritance of schizophrenia at different genetic loci in a nationally collected European American and African American sample. Seventy‐seven families were previously genotyped at 458 markers for the NIMH Schizophrenia Genetics Initiative. Initial genetic analysis tested a dominant model, with schizophrenia and schizoaffective disorder, depressed type, as the affected phenotype. The families showed one genome‐wide significant linkage (Z = 3.97) at chromosome 15q14, which maps within 1 cM of a previous linkage at the α7‐nicotinic receptor gene. Chromosome 10p13 showed suggestive linkage (Z = 2.40). Six others (6q21, 9q32, 13q32, 15q24, 17p12, 20q13) were positive, with few differences between the two ethnic groups. The probability of each family transmitting schizophrenia through two genes is greater than expected from the combination of the independent segregation of each gene. Two trait‐locus linkage analysis supports a model in which genetic alleles associated with schizophrenia are relatively common in the general population and affected individuals inherit risk for illness through at least two different loci. © 2001 Wiley‐Liss, Inc.     

Mutations in the caveolin‐3 gene: When are they pathogenic?

Limb‐girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic disorders usually with autosomal recessive (AR) inheritance and, less often, displaying autosomal dominant (AD) inheritance. Mutations in the caveolin‐3 gene (CAV‐3) associated with a reduction of protein expression cause AD‐LGMD1C muscular dystrophy. Based on a previous study in the American and Brazilian population, it has been suggested that CAV‐3 mutations might also cause AR‐LGMD. Here we report the analysis of the CAV‐3 gene in 61 additional Brazilian LGMD patients and 100 additional Brazilian normal controls. Two rare G55S and C71W missense changes previously detected only in LGMD patients (and not detected in 100 normal controls from the American population) were now found in normal Brazilian controls. In addition, we have identified a novel R125H missense change in one LGMD female patient that was also found in two of her unaffected siblings. These observations, together with the normal immunofluorescence caveolin pattern in the muscle biopsy from two patients with the G55W and R125H changes in the CAV‐3 gene suggest that the G55S, C71W, and R125H polymorphisms, on their own, are not sufficient to produce the pathology. © 2001 Wiley‐Liss, Inc.     

Evidence for a major gene underlying bone size variation in the Chinese

Osteoporosis is a major public health problem defined as a loss of bone strength, of which bone size is an important determinant. In the present study, familial correlation and segregation analyses for the spine and hip bone sizes were performed for the first time in a Chinese sample composed of 393 nuclear families with a total of 1,193 individuals. The results indicate a major gene of codominant inheritance for spine bone size; however, there is no evidence of a major gene influencing hip bone size. Significant familial residual effects are found for both traits, suggesting their polygenic inheritance. Heritability estimates (±SE) for spine and hip bone size were 0.62 (0.13) and 0.59 (0.12), respectively. Sex and age differences in genotype‐specific average bone size were observed. Compared with our previous study on bone mineral density (BMD) in the same population, this study suggests that genetic determination of bone size may be different from that of BMD, and thus studying bone size as one surrogate phenotype for osteoporotic fractures may be necessary. Am. J. Hum. Biol. 16:68–77, 2004. © 2003 Wiley‐Liss, Inc.     

Variants of CARD15, TNFA and PTPN22 and susceptibility to Crohn's disease in the Czech population: high frequency of the CARD15 1007fs

Crohn's disease (CD) has been shown to be associated with the variants in the CARD15 gene as well as in other genes involved in the immune response. The frequencies of the variants profoundly differ among populations and so does the associated risk. We examined the associations of variants in the CARD15, TNFA and PTPN22 genes with pediatric-onset and adult-onset CD in the Czech population. Genotype, phenotype and allelic frequencies were compared between 345 patients with CD (136 pediatric-onset and 209 adult-onset patients) and 501 unrelated healthy controls. At least one minor allele of the CARD15 gene was carried by 46% patients and only 21% control subjects (OR = 3.2, 95% CI 2.4-4.4). In a multiple logistic regression model, the strongest association with CD was found for the 1007fs variant (OR = 4.6, 95% CI 3.0-7.0), followed by p.G908R (OR = 2.9, 95% CI 1.5-5.7) and p.R702W (OR = 1.7, 95% CI 1.0-2.9), while no independent association was found for the remaining variants in the CARD15 gene (p.268S, p.955I and p.289S), for the p.R620W variant in the PTPN22 gene or for the g.-308G>A variant in the TNFA gene. The age at CD onset was strongly modified by positivity for the 1007fs allele: it was present in 42% pediatric-onset and only 25% adult-onset patients. In conclusion, we report a high frequency of the minor allele of the CARD15 1007fs polymorphism in the Czech population and a strong effect of this allele on the age at disease onset.     

Segregation Analysis of Prostate Cancer in France: Evidence for Autosomal Dominant Inheritance and Residual Brother-brother Dependence

Four segregation analyses concerning prostate cancer (CaP), three conducted in the United States and one in Northern Europe, have shown evidence for a dominant major gene but with different parameter estimates. A recent segregation analysis of Australian pedigrees has found a better fit of a two‐locus model than single‐locus models. This model included a dominantly inherited increased risk that was greater at younger ages and a recessively inherited or X‐linked increased risk that was greater at older ages. Recent linkage analyses have led to the detection of at least 8 CaP predisposing genes, suggesting a complex inheritance and genetic heterogeneity. To assess the nature of familial aggregation of prostate cancer in France, segregation analysis was conducted in 691 families ascertained through 691 CaP patients, recruited from three French hospitals and unselected with respect to age at diagnosis, clinical stage or family history. This mode of family inclusion, without any particular selection of the probands, is unique, as probands from all previous analyses were selected according to various criteria. Segregation analysis was carried out using the logistic hazard regressive model, as incorporated in the REGRESS program, which can accommodate a major gene effect, residual familial dependences of any origin (genetic and/or environmental), and covariates, while including survival analysis concepts. Segregation analysis showed evidence for the segregation of an autosomal dominant gene (allele frequency of 0.03%) with an additional brother‐brother dependence. The estimated cumulative risks of prostate cancer by age 85 years, among subjects with the at‐risk genotype, were 86% in the fathers' generation and 99% in the probands' generation. This study supports the model of Mendelian transmission of a rare autosomal dominant gene with high penetrance, and demonstrates that additional genetic and/or common sibling environmental factors are involved to account for the familial clustering of CaP.     

Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis

OBJECTIVES: Three recent studies revealed a haplotypic association of alcohol dependence with the gene encoding the alpha2 subunit of the gamma-aminobutyric acid type A (GABAA) receptor (GABRA2). The present study examined whether variation of the GABRA2 gene confers susceptibility to different subtypes of alcohol dependence in the German population. METHODS: A total of 257 German alcohol-dependent patients and 88 healthy population controls were genotyped for six single-nucleotide polymorphisms covering the middle part and the 3' end of GABRA2. Allelic, genotypic and haplotypic comparisons were done for subgroups of alcohol-dependent patients with a presumed high genetic load. RESULTS: The overall alcohol-dependent patients vs. control group comparison confirmed positive allelic association for five of six single-nucleotide polymorphisms mapping from intron 3 to the 3' end of GABRA2 (P=0.01-0.02). Haplotype analysis revealed two common haplotypes accounting for approximately 90% of the chromosomes within the patients and controls. The less frequent haplotype was significantly more prevalent among the alcohol-dependent patients (45%) than among the controls [29%; odds ratio (OR)=1.97, 95% confidence interval (CI): 1.30-2.96]. The strength of association increased, if the subsets of alcohol-dependent patients with a positive family history (OR=2.60, 95% CI: 1.63-4.13), withdrawal seizures (OR=2.22, 95% CI: 1.30-3.79) or an early onset (OR=2.19, 95% CI: 1.24-3.88) were analyzed. CONCLUSIONS: Although our study was limited by the number of cases being larger than the number of controls, the results confirm GABRA2 as a susceptibility gene for alcohol dependence in the German population. We found a consistent increase of the susceptibility effect in alcohol-dependent patients with a presumed strong genetic predisposition.     

Association of APOE ε2/ε3/ε4 and promoter gene variants with dementia but not cardiovascular mortality in old age

The common apolipoprotein E (APOE) alleles ε2, ε3, and ε4 are associated with the risk of dementia and cardiovascular disease. Recently, two functional variants (? 219G/T and ?491A/T) were identified in the promoter of the APOE gene that enable a further characterization of the role of the APOE locus in disease. We investigated the contribution of these APOE gene variants to dementia and cardiovascular mortality in old age using a population‐based cohort of 648 subjects aged 85 years and over (Leiden 85‐Plus Study). Genotypes containing an APOE ε4 allele were associated with a 4.1‐fold (95% CI, 2.2–7.7) increased risk of dementia as compared to the ε3/ε3 genotype in old subjects. Moreover, homozygosity for the ?219T allele was found to be associated with a 2.4‐fold (95% CI, 1.0–5.8) increased risk independently of ε2 and ε4; the ?491A/T variant was not associated with dementia. Over a 10‐year follow‐up period, the risk of cardiovascular mortality was not increased among ε4 carriers (RR, 0.6; 95% CI, 0.4–1.0) or ?219T homozygous subjects (RR, 1.1; 95% CI, 0.7–1.7), nor did it decrease among ?491T homozygous subjects (RR, 1.4; 95% CI, 0.6–3.1). In conclusion, both the APOE ε2/ε3/ε4 and the ?219G/T variant were identified as risk factors for dementia but not cardiovascular mortality in old age. Our results support the hypothesis that both the isoform and the amount of APOE may influence the risk of dementia. Furthermore, they emphasize that variation at the APOE locus has a higher impact on the risk of dementia than on the risk of cardiovascular disease in old age. © 2001 Wiley‐Liss, Inc.     

Association of Monocyte Chemoattractant Protein‐1 (MCP‐1)‐2518A>G Polymorphism with Susceptibility to Coronary Artery Disease: A Meta‐Analysis

We attempted to systematically elucidate the association between monocyte chemoattractant protein‐1 (MCP‐1) ‐2518A>G polymorphism and risk of coronary artery disease (CAD). Eligible studies were identified through PubMed, EBSCO, and Web of Science Databases. The magnitude of MCP‐1 polymorphism effect and its possible mode of action on CAD were estimated. The odds ratio (OR) with 95% confidence intervals (CI) were pooled in a specific genetic model to assess the association. A total of 21 studies were involved. There was significant gene effect on CAD risk in the overall population (likelihood ratio test: p < 0.0001). Patients with GG and AG genotypes had 1.435 (95% CI: 1.183–1.740) and 1.087 (95% CI: 1.008–1.172) times higher risk of CAD than those with AA genotype. These gene effects suggested a recessive model to be appropriate. The pooled OR was 1.362 (95% CI: 1.137–1.631; p_uncorrected = 0.001, p_FDR = 0.005) in the recessive model. In the ethnicity‐stratified analysis, significant association was observed in the Caucasian population (OR = 1.492; 95% CI: 1.106–2.014; p_uncorrected = 0.009, p_FDR = 0.015), whereas no statistical significant association was detected in the Asian population (adjusted p = 0.124). The results suggested that MCP‐1 ‐2518A>G polymorphism may be associated with susceptibility to CAD, especially in Caucasians.     

Serotonin transporter gene polymorphisms are associated with anxiety‐related personality traits in women

Several studies have reported an association between anxiety‐related personality traits and a promoter polymorphism in the human serotonin transporter (5‐HTT) gene (5‐HTT gene‐linked polymorphic region, 5‐HTTLPR). In the present study, a population of 251 subjects was assessed with the Karolinska Scales of Personality (KSP) and genotyped both for the 5‐HTTLPR and for a variable number of tandem repeats polymorphism in the second intron of the same gene. The interpretation of previous studies has to some extent been confounded by the studied subjects differing with respect to ethnicity, sex, and age. To circumvent this problem, all included subjects were Caucasians, women, and born in the same year (1956). Associations were found between the 5‐HTTLPR and four of the five anxiety‐related KSP scales (psychic anxiety, muscular tension, psychasthenia, and lack of assertiveness), subjects being homozygous for the short allele displaying higher anxiety scores than those of the long/long or long/short genotype. In addition, an association was found between the intron 2 polymorphism and one anxiety‐related personality trait (somatic anxiety). © 2001 Wiley‐Liss, Inc.     

Spontaneous fetal loss rates in a non‐selected population

The objective of this work was to determine the rate of spontaneous fetal loss up to 28 weeks of gestation in uncomplicated pregnancies of a low‐risk population after sonographically identified intact intrauterine pregnancy during the first trimester. Transvaginal ultrasounds were given to 2,534 women at between six and 12 weeks of gestation. Inclusion criteria were a positive fetal cardiac activity and no antecedent signs of vaginal bleeding. Gestational age was confirmed by measurement of the crown‐rump length and/or biparietal diameter (BIP). Patients were followed until delivery or up to a fetal loss. The mean fetal loss rate between 12 and 28 weeks was 3.86% (n = 99). Fetal loss increased with maternal age: fetal loss rate under 20 yr: 2.94% (OR 0.75; CI 0.23–2. 46), 20–24 yr: 3.20% (OR 0.77; CI 0.48–1.23), 25–29 yr: 3.39% (OR 0.77; CI 0.50–1.19), 30–34 yr: 3.89% (OR 1.01; CI 0.59–1.71), 35–39 yr: 7.82% (OR 2.13; CI 1.04–4.32), 40–45 y: 50% (OR 13.84; CI 6.67–28.72) and > 45 yr: 50% (OR 13.05; CI 1.96–86.71) respectively. The frequency of spontaneous fetal loss before 28 weeks gestation was assessed systematically in a low‐risk population. There was a very clear correlation with advancing maternal age. These data now can be used as background loss rate information for evaluating the safety of invasive prenatal diagnosis, and they will be more valid for this purpose than the available data taken from selected cohorts of women, such as those from hospital clinics or from infertility programs. © 2001 Wiley‐Liss, Inc.     

Interrelationship between bone aging traits and basic anthropometric characteristics

Using plain hand radiographs, the age dependence of various bone‐aging traits (bone mineral density [BMD], cortical index [CI], osteoarthritis [OA], and osseographic [OSS] scores) was evaluated to test whether the correlation among these traits is an individual‐ or population‐based phenomenon. In addition, the effect of anthropometric features on variation of bone‐aging traits was estimated. The study included 1,295 individuals from Chuvasha, Russia, 18 to 89 years. BMD was measured from the compact compartment of the middle and distal phalanges of both 3^rd fingers. The CI of the II–IV metacarpal bones and II–IV proximal phalanges was obtained. The development of OA was based on the standard Kellgren and Lawrence grading scheme for 28 hand joints. OSS score, a surrogate measure that takes into account different kinds of bone changes, was also obtained for each individual. Body weight and height, eight skinfold thicknesses on the trunk and extremities, and breadths of the long bones were measured. Sex‐based univariate analyses and multivariate statistical analysis showed the following: 1) Age dependence was defined more strongly in “OA‐linked” compared to “osteoporosis (OP)‐linked” traits; 2) While “OP‐linked” bone‐aging traits correlated with age differently between sexes, “OA‐linked” traits did not; 3) The strong interrelationship between OA‐linked and OP‐linked traits in both sexes became very weak and statistically insignificant (P > 0.10) after adjustment for age. Thus, OA and OP conditions in the same individual develop independently and probably reflect different underlying physiological mechanisms. 4) Anthropometric characteristics were significantly correlated with bone‐aging traits, but correlations were low (r < 0.20). Thus, the contribution of anthropometric characteristics to the rate and pattern of bone aging of the hand was to relatively small. Am. J. Hum. Biol. 14:380–390, 2002. © 2002 Wiley‐Liss, Inc.     

Effects of continuous positive airway pressure treatment on aortic stiffness in patients with resistant hypertension and obstructive sleep apnea: A randomized controlled trial

Resistant hypertension (RHT) is associated with obstructive sleep apnea (OSA) and increased aortic stiffness, measured by carotid‐femoral pulse wave velocity (cf‐PWV). We aimed to evaluate in a randomized controlled trial, the effect of Continuous positive airway pressure (CPAP) treatment on cf‐PWV in comparison with a control group in patients with RHT and moderate‐severe OSA. One‐hundred and sixteen patients were randomized to 6‐month CPAP treatment (56 patients) or no therapy (60 patients), while keeping their antihypertensive treatment unchanged. Carotid‐femoral pulse wave velocity was performed at the beginning and end of the 6‐month period. Intention‐to‐treat intergroup differences in cf‐PWV changes were assessed by a generalized mixed‐effects model with the allocation group as a fixed factor and adjusted for age, sex, changes in mean arterial pressure and the baseline cf‐PWV values. Subgroup sensitivity analyses were performed, excluding patients with low CPAP adherence and low cf‐PWV at baseline. CPAP and control groups had similar clinic‐laboratorial characteristics. Patients had a mean cf‐PWV of 9.4 ± 1.6 m/s and 33% presented cf‐PWV > 10 m/s. During treatment, the control group had a mean increase in cf‐PWV of +0.43 m/s (95% confidence interval [CI], +0.14 to +0.73 m/s; p = .005), whereas the CPAP group had a mean increase of +0.03 m/s (95% CI, ?0.33 to +0.39 m/s; p = .87), resulting in a mean difference in changes between CPAP and control of ?0.40 m/s (95% CI, ?0.82 to +0.02 m/s; p = .059). Subgroup analyses did not change the results. In conclusion, a 6‐month CPAP treatment did not reduce aortic stiffness, measured by cf‐PWV, in patients with RHT and moderate/severe OSA, but treatment may prevent its progression, in contrast to no‐CPAP therapy.     

History of fractures as predictor of subsequent hip and nonhip fractures among older Mexican Americans

OBJECTIVE: To examine the association between previous fracture and risk of new hip and nonhip fractures over a seven-year period among older Mexican Americans. METHOD: Data used are from the Hispanic Established Population for the Epidemiological Study of the Elderly (H-EPESE) (1993-2001). Measures included history of previous fracture (hip fracture only, a nonhip fracture, hip and nonhip fractures, and no fractures), sociodemographic factors, smoking status, medical conditions (arthritis, diabetes, stroke and cancer), activities of daily living disability, and high depressive symptoms. Cox proportional regression model was used to estimate the seven-year incidence of fractures. RESULTS: Of the 2,589 subjects, 42 reported a hip fracture, 328 reported a nonhip fracture, and 2,219 did not report a fracture at baseline. After controlling for all covariates, the hazard ratio (HR) of new hip fracture at seven-year follow-up was 6.48 (95% CI: 3.26-12.97) for subjects with only hip fracture at baseline and 1.96 (95% CI: 1.22-3.16) for subjects with nonhip fracture at baseline. The HR of new nonhip fracture was 1.90 (95% CI: 0.96-3.77) for subjects with only hip fracture at baseline and 2.62 (95% CI: 1.95-3.52) for subjects with nonhip fracture at baseline. CONCLUSIONS: A previous history of fractures in older Mexican Americans is the strongest predictor of recurrent fractures at hip and nonhip sites, independent of other health measures. Our findings of recurrent fractures suggest the need for more aggressive detection and adequate treatment of osteoporosis- and fall-related factors in this population.     

Different familial transmission patterns in bipolar I disorder with onset before and after age 25

Gene identification in common disorders such as Alzheimer disease and breast cancer has greatly profited from the use of age of onset as criterion to delineate subgroups of disease characterized by different inheritance patterns. In bipolar affective disorder, where the majority of linkage studies have produced conflicting results, studies reporting clinical characteristics and familial occurrence of disease have suggested that age of onset might serve as an indicator for identifying more homogeneous subgroups of disease. Our study was the first to examine this hypothesis by the means of segregation analysis. We investigated a sample of 177 bipolar I probands recruited from consecutive admissions and their first‐ and second‐degree relatives (2,407 subjects). Probands were subdivided into an early‐onset (n = 107) and a late‐onset group (n = 70) using an age of onset of 25 as a cut‐off point. This age was chosen because the observed age of onset distribution was bimodal with a cut‐off of 25 years. Morbid risks for affective disorder were found significantly higher (P = 0.01) in relatives of probands with an early onset than in probands with late onset of disease. The segregation analysis showed that the disease is transmitted differently in early‐ and late‐onset groups. In the early‐onset group, a non‐Mendelian major gene with a polygenic component was favored while the data in the late‐onset group were compatible with a multifactorial model. This result may have important implications for future molecular studies aiming at the identification of disease‐associated genes. © 2001 Wiley‐Liss, Inc.     

Maternal Epstein‐Barr virus and cytomegalovirus infections and risk of testicular cancer in the offspring: a nested case‐control study

During recent decades the incidence of testicular cancer (TC) has increased rapidly around the world. Associated exogenous etiological factors might therefore be identifiable. We performed a case‐control study nested within Finnish, Swedish and Icelandic maternity cohorts exploiting early pregnancy serum samples to evaluate the role of congenital or neonatal infections with Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) as risk factors of TC in the offspring. For each case‐index mother pair, three or four matched control‐control mother pairs were identified using national population registries. First trimester sera were retrieved from the index mothers of 66 TC cases and 258 matched control mothers, and were tested for antibodies to EBV and CMV. High level of maternal EBV IgG antibodies was associated with significantly increased risk of TC in the offspring (odds ratio (OR), 2.50; 95% confidence interval (CI), 1.15, 5.40), especially with risk of non‐seminoma TC (OR, 2.73; 95% CI, 1.25, 5.99) and non‐seminoma TC diagnosed under 8 years of age (OR, 2.72; 95% CI, 1.05, 7.04). In contrast, offspring of CMV IgG‐seropositive mothers had a decreased risk of TC diagnosed under 8 years of age (OR, 0.35; 95% CI, 0.14, 0.89). Our results suggest that EBV and CMV infections may be associated with TC.