Obesity is a known risk factor for cardiovascular disease. Early prediction of obesity is essential for prevention. The aim of this study is to assess the use of childhood clinical factors and the ...genetic risk factors in predicting adulthood obesity using machine learning methods.
A total of 2262 participants from the Cardiovascular Risk in YFS (Young Finns Study) were followed up from childhood (age 3-18 years) to adulthood for 31 years. The data were divided into training (n=1625) and validation (n=637) set. The effect of known genetic risk factors (97 single-nucleotide polymorphisms) was investigated as a weighted genetic risk score of all 97 single-nucleotide polymorphisms (WGRS97) or a subset of 19 most significant single-nucleotide polymorphisms (WGRS19) using boosting machine learning technique. WGRS97 and WGRS19 were validated using external data (n=369) from BHS (Bogalusa Heart Study). WGRS19 improved the accuracy of predicting adulthood obesity in training (area under the curve AUC=0.787 versus AUC=0.744,
<0.0001) and validation data (AUC=0.769 versus AUC=0.747,
=0.026). WGRS97 improved the accuracy in training (AUC=0.782 versus AUC=0.744,
<0.0001) but not in validation data (AUC=0.749 versus AUC=0.747,
=0.785). Higher WGRS19 associated with higher body mass index at 9 years and WGRS97 at 6 years. Replication in BHS confirmed our findings that WGRS19 and WGRS97 are associated with body mass index.
WGRS19 improves prediction of adulthood obesity. Predictive accuracy is highest among young children (3-6 years), whereas among older children (9-18 years) the risk can be identified using childhood clinical factors. The model is helpful in screening children with high risk of developing obesity.
Interindividual variation in the expression of tumor necrosis factor (TNF)-alpha suggests the existence of functionally distinct TNF alleles, which might play a role in sarcoidosis. We investigated ...five potentially functional biallelic TNF promoter polymorphisms at nucleotide positions -1,031(T/C), -863(C/A), -857(C/T), -307(G/A), and -237(G/A) in two clinically well-defined groups of white patients (British UK and Dutch NL) with sarcoidosis, each with their own control subjects. Polymorphisms were determined using SSP-PCR. A total of 772 individuals were studied (96 UK patients, 354 UK control subjects, 100 NL patients, 222 NL controls). A significant increase in the rarer TNF -857T allele was found in both sarcoidosis populations. In total 25.5% of the sarcoid patients carried the TNF -857T allele versus 14.1% of the control subjects (p = 0.003, p(c) = 0.02). In the sarcoidosis group the allele frequency of this polymorphism was 13.5% versus 7.3% in the control subjects (p = 0.0003, p(c) = 0.002). Subgroup analysis showed a significant increase in the rarer TNF -307A (TNF-2) allele in patients with Löfgren's syndrome (p = 0.006, p(c) = 0.03). Our finding does not necessarily imply that the two polymorphisms relate to different functions; it may be that one or both are in linkage disequilibrium with the causal site. This requires further studies of functionality and linkage disequilibrium.
The cytochrome P-450c17α (CYP17 ) gene, located on chromosome 10q24.3, encodes the enzyme cytochrome P-450c17α, which functions at key branch points in steroid hormone biosynthesis. Three ...polymorphisms have been described, but only the single base-pair change in the 5′-untranslated region (5′-UTR) has been investigated to any great extent. In single studies, the variant was associated with reduced messenger RNA level in ovarian cells but not with messenger RNA level in breast tissue. Homozygosity for the 5′-UTR variant is most common in East Asian (32%) and Japanese (22%) populations and is less common among White (mainly European and North American (14%)) and Black (mainly African-American (13%)) populations, but selection biases are likely to have affected these frequency estimates. Genotype appears to influence circulating estrogen levels in premenopausal women, while studies of relations with hormone levels in men have produced inconclusive results. However, relatively few studies have been conducted. Seven of 11 retrospective studies suggested a modest association between genotype and age at menarche. Random error in recall of age at menarche is likely to have attenuated this relation. Associations between genotype and postmenopausal estrogen use and bone mass have been observed in single studies. Further investigation of relations between genotype and hormone levels, exogenous hormone use, and markers of hormonal status may advance understanding of hormonally mediated diseases.
Gastric acid blockade in children with asymptomatic acid reflux has not improved asthma control in published studies. There is substantial population variability regarding metabolism of and response ...to proton pump inhibitors based on metabolizer phenotype. How metabolizer phenotype affects asthma responses to acid blockage is not known.
To determine how metabolizer phenotype based on genetic analysis of CYP2C19 affects asthma control among children treated with a proton pump inhibitor.
Asthma control as measured by the Asthma Control Questionnaire (ACQ) and other questionnaires from a 6-month clinical trial of lansoprazole in children with asthma was analyzed for associations with surrogates of lansoprazole exposure (based on treatment assignment and metabolizer phenotype). Groups included placebo-treated children; lansoprazole-treated extensive metabolizers (EMs); and lansoprazole-treated poor metabolizers (PMs). Metabolizer phenotypes were based on CYP2C19 haplotypes. Carriers of the CYP2C19*2, *3, *8, *9, or *10 allele were PMs; carriers of two wild-type alleles were extensive metabolizers (EMs).
Asthma control through most of the treatment period was unaffected by lansoprazole exposure or metabolizer phenotype. At 6 months, PMs displayed significantly worsened asthma control compared with EMs (+0.16 vs. -0.13; P = 0.02) and placebo-treated children (+0.16 vs. -0.23; P < 0.01). Differences in asthma control were not associated with changes in gastroesophageal reflux symptoms. Recent upper respiratory infection worsened asthma control, and this upper respiratory infection effect may be more pronounced among lansoprazole-treated PMs.
Children with the PM phenotype developed worse asthma control after 6 months of lansoprazole treatment for poorly controlled asthma. Increased exposure to proton pump inhibitor may worsen asthma control by altering responses to respiratory infections. Clinical trial registered with www.clinicaltrials.gov (NCT00604851).
Endotoxin exposure may have a protective effect against asthma and atopy. An Asp299Gly polymorphism in the Toll-like receptor 4 (TLR4) gene reduces responsiveness to endotoxin. This study determined ...the effect of TLR4 polymorphism on the risk and severity of asthma and atopy. In all, 336 UK Caucasian families with > or = 2 affected sibs (physician's diagnosis of asthma and current medication use) and 179 Caucasians without asthma or a family history of asthma were genotyped using ARMS-PCR. No association of the TLR4 polymorphism was found with the risk of developing asthma, either in parent-affected sibling trios, or in case-control analyses (P>0.05). In the first affected asthmatic siblings, the atopy severity score (based on size and number of positive skin-prick tests and specific IgE) was higher in those with the Asp/Gly or Gly/Gly genotypes (mean 1.8, s.d. 1.1, n=39) compared to those with the Asp/Asp genotype (mean 1.2, s.d. 1.0, n=279) (P=0.003, t-test). No associations were found with total IgE, FEV(1) % predicted, slope of FEV(1) response to methacholine or asthma severity score (P>0.05). This study confirms the previously observed lack of association of TLR4 polymorphisms with asthma. In contrast, the findings suggest that genetically determined hyporesponsiveness to endotoxin may increase atopy severity.
Many studies have been done to identify the factors that influence the development and progression of osteoporosis. One genetic factor is polymorphisms of
gene. Regarding the lack of comprehensive ...study on polymorphisms of
gene in the north of Iran, mainly Mazandaran Province, we decided to investigate the polymorphism of this gene in postmenopausal women with osteoporosis.
This case-control study has been conducted at GhaemShahr Valiasr Hospital on 100 female patients with osteoporosis (average age of 58.1) and 90 healthy females without osteoporosis (average age of 55.2). After sampling and extraction of genomic DNA via of the salt deposition method, the genotype and SNP (rs9667108) polymorphism of
gene were evaluated with the PCR-RFLP method. Restriction enzymes cut the PCR products. In order to identify patients, their bone mineral density was tested by the DEXA method. The results of digestion (digestion enzyme) were analyzed by MedCalc, SPSS software, Hardy-Weinberg equilibrium, and Chi2.
The statistical analysis has shown the significant relationship between SNP (rs9667108) polymorphism and the risk of osteoporosis disease in patients and control groups (
<0.05). In SNP (rs9667108), the GC genotype, compared to GG, increased the risk of disease significantly (1.556 time). Similarly, CC genotype, compared to GG genotype, increased the risk of this disease by 2.091 time.
The existence of mutation in the
gene could increase susceptibility to osteoporosis disease. Moreover, determining this patient's genotype in SNP (rs9667108) can be used to identify individuals who are in endanger osteoporosis.
Inflammation and innate immunity may play a role in the pathogenesis of atherosclerosis. The Asp299Gly polymorphism in the toll-like receptor 4 (
TLR4) gene reduces responsiveness to ...lipopolysaccharide and has been associated with reduced incidence and slower progression of carotid atherosclerosis. We analyzed this polymorphism in relation to susceptibility to and severity of coronary artery disease.
Methods: 1400 participants (mean age: 63 years, 31% female) in the Southampton Atherosclerosis Study were genotyped for the
TLR4 Asp299Gly polymorphism using the tetra-primer PCR method.
Results: There was no significant difference between the frequencies of the Asp/Gly or Gly/Gly genotypes combined, compared to the Asp/Asp genotype, in patients with 0, 1, 2 or 3 coronary arteries with >50% stenosis (
χ
3
d.
f.
2
=0.4,
P=0.94). No associations were observed between genotype groups and cardiac risk factors (
P>0.05).
Conclusion: The findings of this study do not support the hypothesis that the
TLR4 Asp299Gly polymorphism influences predisposition to and progression of coronary artery disease.
In the western Pyrenees (Southwest France and Northwest Spain), a narrow hybrid zone exists between the common chiffchaff Phylloscopus (collybita) collybita and the Iberian chiffchaff Phylloscopus ...(c.) brehmii. In this zone, which is approximately 20 km wide, mixed matings and individuals singing the songs of both taxa occur at substantial frequencies (24 and 8.6%, respectively), suggesting frequent hybridization. Previous studies have shown very weak mitochondrial gene flow (Nm = 0.065), whereas four microsatellites suggested much higher nuclear gene flow (Nm = 4.9). In this study we used the amplified fragment length polymorphism (AFLP) method in order to identify hybrids and early backcrosses. We typed 91 birds from both allopatric and sympatric areas for 12 informative AFLP markers (of > 141 polymorphic fragments), obtained by screening 13 AFLP primer combinations. These individuals were previously typed for song (brehmii, collybita or mixed singers), mitochondrial DNA (mtDNA) haplotype and allelic genotypes at four microsatellite loci. Assignment tests demonstrated that in the zone of sympatry, a substantial number of intermediate genotypes existed among the birds previously believed to be pure collybita and brehmii, based on song and mtDNA haplotype. The majority of the mixed singers had intermediate genotypes. Our data suggest that the fraction of the adult population having a hybrid origin (hybrids or backcrosses) is in the order of 10%. With such a frequency of genetic hybrids, there would have been much more mtDNA introgression than observed, had female hybrids been perfectly fertile/viable. This result is consistent with male‐biased gene flow and Haldane’s rule.
An amino acid changing polymorphism in the UDP-glucuronosyltransferase (UGT) 2B15 gene has been described at codon 85 (aspartate>tyrosine). The UGT2B15
85Asp allele exhibits 2-fold decreased activity ...for dihydrotestosterone, which was suggested to be associated with the risk of prostate cancer based on in vitro functional analysis. We determined whether this polymorphism can be used to predict individual susceptibility to prostate cancer.
UGT2B15 expression was determined by reverse transcription-polymerase chain reaction of normal prostate tissues. Prevalence of the UGT2B15 Asp85Tyr polymorphism was compared between cases and controls by allele specific polymerase chain reaction analysis using genomic DNA isolated from 155 incident white patients with primary prostate cancer and 155 individually age matched (±5 years) white controls.
UGT2B15 mRNA was detected in all prostate tissues tested. A significant association was found between UGT2B15 genotypes and prostate cancer risk. A significantly increased risk of prostate cancer was observed in subjects with the homozygous UGT2B15
85Asp/Asp genotype (OR 2.7, 95% CI 1.1 to 6.6).
These results suggest that the UGT2B15 enzyme may have a role in the metabolism of dihydrotestosterone in prostate tissue and UGT2B15 Asp85Tyr polymorphism is associated with prostate cancer risk.
Genetic variation in DNA repair genes can modulate DNA repair capacity and may be related to the risk of cancer. The human papillomavirus is considered to be a necessary but not sufficient cause for ...cervical cancer and, therefore, other factors contribute to the carcinogenesis. A hereditary component for this neoplasia has been reported. Evaluation of the association of six polymorphisms was carried out in the following DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), ERCC1 (Asp118Asp), ERCC2 (Lys751Gln), and ERCC4 (Arg415Gln). The cases (n = 110) included 65 squamous cell carcinomas (SCCs) and 45 squamous intraepithelial lesions (SIL). Controls (n = 68) were recruited from among women without cervical abnormalities. Genotypes were determined by PCR-restriction fragment length polymorphism and DNA sequencing. A positive association was observed between the polymorphisms of XRCC1 genes, that is, in codons 194 P = 0.001, odds ratio (OR) = 20.1, 95% confidence interval (CI) = 5.9–68.8, 280 (P = 0.001, OR = 5.4, 95% CI = 2.3–12.6), and 399 (P = 0.008, OR = 4.2, 95% CI = 1.5–12.1) and cervical cancer. SIL patients also showed a significant association with codon 194 (P = 0.012, OR = 3.8, 95% CI = 1.3–10.6), but not with 280 (P = 0.35) and 399 (P = 0.81). A positive correlation was also found in ERCC4 Gln415Gln in both SCCs and SILs (P = 0.001, OR = 21.3, 95% CI = 7.1–64.0 and P = 0.001, OR = 7.8, 95% CI = 2.9–20.9, respectively). For ERCC2 Gln751Gln, the association was significant for both SCCs (P = 0.001, OR = 10.1, 95% CI = 2.6–37.9) and SILs (P = 0.001, OR = 8.9, 95% CI = 2.8–28.3). However, the risk of SCC did not appear to differ significantly among individuals with the ERCC1 Asp118Asp genotype (P = 0.404). For SILs, it appeared to be a protective genotype (95% CI = 0.1–0.7). This study indicates that variant types of DNA repair genes play an important role in modifying individual susceptibility to SCC.
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