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PubMed2007

Vitamin D receptor gene haplotype is associated with body height and bone size.

CONTEXT: Adult stature is a complex genetic trait. The vitamin D endocrine system has pleiotropic effects on several physiological processes, especially on skeletal metabolism. We recently identified promoter and 3'-untranslated region (UTR) haplotype alleles that influence vitamin D receptor (VDR) mRNA expression. OBJECTIVE: We studied whether VDR gene variants contribute to the genetic variation in height. DESIGN AND SUBJECTS: We studied VDR haplotype alleles and body height in two independent populations (n=7187). In a meta-analysis (n=14,157 from 27 studies and our current data), we evaluated the effect of the Bsm I polymorphism. RESULTS: Haplotypes of the linkage disequilibrium block 3 and block 5 were associated with body height differences with evidence for additive effects in the Rotterdam Study (P=0.00002) and the Longitudinal Aging Study Amsterdam study (P=0.001). Height differences between the extreme genotypes were 1.4 and 2.7 cm, respectively. The relationship was independent of age, gender, presence of vertebral fractures, and age-related height loss. In the Rotterdam population, we found the combined genotype to be associated with decreased vertebral area (P=0.03) and femoral narrow neck width (P=0.002). In the meta-analysis, subjects with the "BB" genotype were 0.6 cm (95% confidence interval, 0.2-1.1 cm) taller than those with the "bb" genotype (P=0.006). CONCLUSION: VDR gene variants are associated with differences in body height as evidenced by our study and by a meta-analysis. It remains for further studies to confirm whether the underlying mechanism of the association involves lower VDR expression in cells important for determining bone size.

Analysis of Variance↗

PubMed2004

Metabolic polymorphisms, smoking, and oral cancer in Puerto Rico.

Genetic polymorphisms resulting in variation in metabolism of tobacco carcinogens may influence oral cancer risk. In a population-based case-control study in Puerto Rico, genotypes of CYP1A1, GSTM1, and GSTT1 were determined by a PCR-based method for 132 oral cancer patients and 143 control subjects. Genotype-associated risks were estimated by logistic regression. The null variant of GSTM1 was associated with a marginally significant decrease in oral cancer risk [odds ratio (OR) = 0.6, 95% confidence interval (CI) = 0.3-1.0, and P for trend = 0.09]. Risks increased with increasing cigarette use among subjects with the GSTM1-present genotype (P for trend <0.0001), rising to OR = 9.5, 95% CI = 3.0-30, among the heaviest cigarette users. In contrast, among subjects with the GSTM1-null genotype, risks did not clearly increase with increasing cigarette use (P for trend <0.61; OR = 1.8, 95% CI = 0.6-5.2 among the heaviest tobacco users). The GSTT1-null variant (OR = 1.0, 95% CI = 0.5-1.9) and CYP1A1(462Val) variant (OR = 0.9, 95% CI = 0.5-1.7) were not associated with the risk. Risks rose with increasing cigarette use in a similar manner for subjects with or without the CYP1A1(462Val) variant (P for interaction = 0.3) and for subjects with or without the GSTT1-null genotype (P for interaction = 0.4). In conclusion, cigarette use significantly increased the risk of oral cancer in this population. The GSTM1-present genotype was associated with higher tobacco-associated risk for oral cancer among heavy smokers than the null genotype.

Aged↗

PubMed2004

Thyroid peroxidase antibodies in early pregnancy: utility for prediction of postpartum thyroid dysfunction and implications for screening.

Thyroid peroxidase antibodies (TPOAb) in pregnancy are a marker for postpartum (PPTD) and long-term thyroid dysfunction, with variable sensitivity and specificity in PPTD prediction. To test its utility in prediction, we recruited 308 TPOAb-positive (147 developed PPTD (PPTD group) and 161 remained euthyroid [PPTE group]) and 102 TPOAb-negative women (none developed PPTD), in early pregnancy (median, 18; range, 9-19 weeks' gestation). TPOAb levels were higher in the PPTD group (median) (125.2 kIU/L; p < 0.001), and in its hypothyroid (162.4 kIU.; p < 0.0001), hyperthyroid (114.2 kIU/L; p < 0.007), and biphasic (105.1 kIU/L; p < 0.02) variants, compared to the PPTE group (66.7 kIU/L) The incidence of PPTD was significantly higher with TPOAb levels above 58.2 kIU/L (early pregnancy versus postpartum; relative risk, 1.37 [95% confidence interval [CI] 1.17-1.61] versus 0.78 [95% CI 0.5-1.2]) compared to levels below. The integrated postpartum TPOAb response was higher in the PPTD group (median) (159 kIU/L per week) and its variants (hypothyroid; 199 kIU/L per week; biphasic, 180 kIU/L per week; hyperthyroid, 120 kIU/L per week), compared to the PPTE group (86 kIU/L per week p < 0.004). Median early pregnancy TPOAb levels in the PPTD and PPTE groups correlated well with the postpartum antibody response (r = 0.58, p < 0.001). The sensitivity of TPOAb in PPTD prediction was 100% (early pregnancy and postpartum), specificity 62% (early pregnancy) versus 41% (postpartum) and positive predictive value 48% (early pregnancy and postpartum). The timing of TPOAb testing, the sensitive assay used and the absence of PPTD in TPOAb-negative subjects contributed to this high sensitivity. We recommend TPOAb in early pregnancy as a useful predictor of PPTD, particularly in populations where PPTD does not occur in TPOAb-negative women.

Adolescent↗

PubMed2006

Association of the RIP2 gene with childhood atopic asthma.

BACKGROUND: Receptor-interacting protein (RIP)-2 is a serine/threonine kinase containing a caspase recruitment domain (CARD) that is involved in the Toll-like receptor-signaling pathway. Although associations between endotoxin exposure or respiratory infection and asthma have been recognized, the genetic influences in these conditions are unclear. The aim of our study was to examine whether polymorphisms or haplotypes in RIP2 were associated with childhood atopic asthma in a Japanese population. METHODS: We screened the RIP2 gene for polymorphisms by direct sequencing and characterized the linkage disequilibrium (LD) mapping of the gene. Seven variants were genotyped in childhood atopic asthma (n = 300) and normal controls (n = 637) . We conducted case-control and case-only association studies between the variants and asthma-related phenotypes. Haplotype association analyses were also performed. RESULTS: A total of 31 variants were identified and none of the alleles or haplotypes of RIP2 were associated with asthma susceptibility. In the case-only study, an association between an RIP2 promoter polymorphism and childhood severe asthma (P=0.0032; odds ratio (OR) 3.37, 95% confidence interval (CI) 1.45-7.87) was observed. CONCLUSIONS: Although polymorphisms in RIP2 are not likely to be associated with the development of asthma, the genetic variants might contribute to asthma severity in the Japanese population.

Adolescent↗

PubMed2003

[Genetic susceptibility to intermediate myasthenia syndrome following organophosphate insecticides poisoning].

OBJECTIVE: To explore the association of gene polymorphism of organophosphate insecticides (OPs) metabolic enzymes with intermediate myasthenia syndrome (IMS) following acute OPs poisoning. METHODS: Thirty six of 147 acute OPs poisoning patients developed IMS one to four days after poisoning. Peripheral blood samples were collected from all the patients and whole blood cholinesterase (ChE) activity was determined by DTNB spectrometry. The genetic polymorphism of CYP2E1 (1091C-->T) and GSTP1 (313A-->G) were analyzed by polymerase chain reaction (PCR)-restrict fragment length polymorphism, CYP1A1 (4889A-->G), GSTM1 and GSTT1 by allele-specific PCR, and PON1 at 55 codon (55L-->M) by PCR-single strand conformation polymorphism. RESULTS: The whole blood ChE activity in IMS patients was not significantly different from non-IMS patients at admission (38.22 +/- 17.56)% and (42.49 +/- 16.23)%, respectively, P > 0.05, but recovered much slower in IMS patients than that in non-IMS patients. The frequencies of heterozygote and variant homozygote of PON1 at 55 codon, GSTM1 null, and both GSTM1 and GSTT1 null were higher in IMS patients than those in non-IMS patients (P < 0.05), with odds ratios and their 95% confident intervals of 2.48 (1.06 - 5.78), 11.23 (2.95- 42.76), 2.53 (1.14 - 5.61) and 2.68 (1.20 - 5.97), respectively. CONCLUSIONS: Patients of OPs and its mixture poisoning with genotype of variant allele at 55 codon of PON1, GSTM1 null and both GSTM1 and GSTT1 null probably had higher risk for IMS.

Adult↗

PubMed2005

DNA repair polymorphisms and risk of colorectal adenomatous or hyperplastic polyps.

Genetic variability in DNA repair genes may contribute to differences in DNA repair capacity and susceptibility to cancer, especially in the presence of exposures such as smoking. In a Minnesota-based case-control study of cases with only adenomatous polyps (n = 384), only hyperplastic polyps (n = 191), or both types of polyps (n = 119) versus polyp-free controls (n = 601), we investigated the role of polymorphisms in the DNA repair genes O(6)-methylguanine methyltransferase (MGMT; p.L84F and p.I143V), XPD (p.D312N and p.K751Q), and XPG (p.D1104H). MGMT polymorphisms were not associated with polyp risk. Overall, a homozygous variant XPD-combined genotype was associated with an increased risk of adenomatous polyps [odds ratio (OR), 1.57; 95% confidence interval (95% CI), 1.04-2.38] and an XPGHH1104 genotype with a decreased risk of hyperplastic polyps (OR, 0.36; 95% CI, 0.13-0.98). However, age stratification showed that the XPD association was present only in subjects >/=60 years old (OR, 3.77; 95% CI, 1.94-7.35), whereas the XPG association was observed largely in subjects <60 years old (OR, 0.20; 95% CI, 0.05-0.91). Smokers did not have a significantly increased risk of adenomatous polyps in the absence of synchronous hyperplastic polyps, except for subjects with a homozygous variant XPD genotype or a homozygous wild-type XPG genotype (OR, 3.93; 95% CI, 1.68-9.21 and OR, 1.59; 95% CI, 1.01-2.50, respectively). Smoking was associated with a statistically significant 2.5- to 6-fold increased risk of hyperplastic polyps for individuals with most of the DNA repair genotypes. However, no substantial increase was observed among individuals who were homozygous variant for XPG (1104HH; OR, 1.38; 95% CI, 0.25-7.65). Our data suggest that polymorphisms in DNA repair genes may be risk factors for colorectal neoplasia and that they may exacerbate the effects of exposures to carcinogens.

Adenoma↗

PubMed1998

Cigarette smoking, cytochrome P450 1A1 polymorphisms, and breast cancer risk in the Nurses' Health Study.

Environmental exposure to carcinogens may contribute to increasing breast cancer rates and geographic variation in breast cancer incidence in the United States. One class of chemicals that has received much attention are the polyaromatic hydrocarbons that are ubiquitous in the environment and occur in cigarette smoke. The cytochrome P450 1A1 (CYP1A1) gene codes for an enzyme that contributes to aryl hydrocarbon hydroxylase activity, which is involved in the metabolism of polyaromatic hydrocarbons. Genotypic variants of CYP1A1 have been associated with increased aryl hydrocarbon hydroxylase activity, and some epidemiological studies suggest that women with the variant genotype(s) are at increased risk for breast cancer. We prospectively evaluated the associations between the CYP1A1 polymorphisms and breast cancer risk, as well as the potential modification of these associations by cigarette smoking, in a case-control study nested within the Nurses' Health Study. We analyzed the T-->C transition at nucleotide 6235 (MspI) and the A-->G transition at nucleotide 4889 (exon 7) in CYP1A1 by PCR-RFLP assays among 466 incident breast cancer cases and 466 matched controls. Relative risks (RRs) and 95% confidence intervals (CIs) were used to quantify the risk of breast cancer among subjects who had at least one variant allele relative to subjects who were homozygous for the wild-type allele, using conditional logistic regression. No overall increase in breast cancer risk with the variant CYP1A1 genotypes was apparent (RR(MspI), 1.05; 95% CI, 0.74-1.50 and RR(exon7), 0.88; 95% CI, 0.58-1.33). However, a suggestive increase in breast cancer risk was observed among women who had commenced smoking before the age of 18 and had the CYP1A1-MspI variant genotype compared to nonsmokers who were homozygous wild type for the polymorphism (RR, 5.65; 95% CI, 1.50-21.3; percentage of all breast cancer cases attributable to this risk factor, 2.5%). A similar gene-environment association was observed for the exon 7 polymorphism (RR, 3.61; 95% CI, 1.11-11.7; percentage of all breast cancer cases attributable to this risk factor, 2.2%). These data are compatible with the hypothesis that cigarette smoking early in life is a modifiable cause of breast cancer in a subpopulation of genetically susceptible women. However, the proportion of breast cancer attributable to cigarette smoking at a young age among Caucasian women with the variant form of the CYP1A1 polymorphisms is low.

Adult↗

PubMed2006

Promoter polymorphism (-786t>C) in the endothelial nitric oxide synthase gene is associated with risk of sporadic breast cancer in non-Hispanic white women age younger than 55 years.

BACKGROUND: Nitric oxide (NO) is constitutively synthesized in the endothelium by endothelial nitric oxide synthase (eNOS) and acts as a pleiotropic regulator involved in carcinogenesis. Most breast cancers develop from mammary epithelial cells; therefore, NO may play a role in their development. It was hypothesized that eNOS polymorphisms are associated with risk of breast cancer. METHODS: In the current hospital-based case-control study of 421 non-Hispanic white women with sporadic breast cancer and 423 frequency-matched control subjects, we genotyped 3 polymorphisms of eNOS (i.e., -786T>C, the 27-base pair [bp] variable number of tandem repeats [VNTR] in intron 4, and 894G>T [Glu298Asp]) and assessed their associations with risk of breast cancer. RESULTS: It was found that, compared with -786TT, the -786C variant genotypes were associated with a significantly increased risk of breast cancer in an allele dose-dependent manner (adjusted odds ratio [OR], 1.33 [95% confidence interval (95% CI)], 0.99-1.77 for -786TC; and OR, 1.79 [95% CI, 1.11-2.87] for -786CC; P(trend) = .007), but 27-bp VNTR and 894G>T genotypes were not. Stratification analysis demonstrated that the risk associated with -786C variant genotypes (-786TC/CC) was more pronounced in smokers and in those 50 years or older (OR, 1.82 [95% CI, 1.19-2.80] and OR, 2.08 [95% CI, 1.25-3.45], respectively), and in the estrogen and progesterone receptor-negative cases (OR, 1.70 [95% CI, 1.10-2.62] and OR, 1.57 [95% CI, 1.07-2.32], respectively). Furthermore, the C4G haplotype derived from the observed genotypes was also associated with a significantly increased risk of breast cancer (OR, 2.16; 95% CI, 1.07-4.36). CONCLUSIONS: The results suggest that eNOS polymorphisms (especially -786T>C) may play a role in the development of sporadic breast cancer.

Adult↗

PubMed2004

Polymorphisms of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, and IL-18 and the risk of ovarian cancer.

OBJECTIVE: Recent studies of ovarian cancer have suggested a role for inflammation in carcinogenesis. Data from a population-based case-control study in Hawaii were examined to assess the relation between polymorphisms in cytokines involved with the inflammatory response, specifically members of the interleukin (IL) family and the incidence of ovarian cancer. PATIENTS AND METHODS: The analysis of 182 epithelial ovarian cancer cases and 219 controls focused on the polymorphisms in the following genes: IL-1alpha, IL-1beta, IL-6, IL-10, and IL-18. Genotype data were obtained from blood samples collected in participants' homes, and reproductive, demographic, and lifestyle histories were collected during interview. RESULTS: There were no significant odds ratios (ORs) for ovarian cancer by allelic variants in any of the IL genes after adjusting for age, ethnicity, education, oral contraceptive pill use, pregnancy, and history of tubal ligation. Although there was a significantly reduced risk of ovarian cancer risk among women with an IL-1alpha (-4845) T allele compared to women with two G alleles (OR: 0.59; 95% confidence interval: 0.37-0.97) after adjustment for age and ethnicity, the trend was not significant (p = 0.10). Further examination of the data suggested that women with at least one IL-18 variant allele (a G to C transition at position -137) were at significantly decreased risk of advanced ovarian cancer (OR: 0.51; 95% confidence interval: 0.28-0.90) compared to women with the IL-18 GG genotype. There was a significant difference in the risk of ovarian cancer associated with the IL-18 C allele by stage at diagnosis (p = 0.04 for homogeneity in the ORs): cases with IL-18 GC or CC genotypes were less likely to be diagnosed at regional/distant stages. Analysis of the data within ethnic subgroups revealed a significant positive association of the heterozygous IL-18 GC genotype with ovarian cancer risk among Native Hawaiian women (OR: 9.96; 95% CI: 1.88-52.90). The OR for ovarian cancer was not significant for Native Hawaiian women homozygous for the IL-18 C allele, but only one case and control had the IL-18 CC genotype. CONCLUSIONS: Overall, this study does not support an association of selected IL-1alpha, IL-1beta, IL-6, IL-10, or IL-18 polymorphisms with the risk for ovarian cancer. However, the IL-18 G137C variant may be a marker for ovarian cancer progression or metastasis.

Adult↗

PubMed2026

Risk of venous thromboembolism after SARS-CoV-2 vaccination-Evidence from genome-wide association study and population-based observational study.

AIM: We aimed to investigate whether genetic variation is associated with venous thromboembolism after immunization with SARS-CoV-2 vaccines. METHODS: We conducted a genome-wide association study (GWAS) on cases of venous thromboembolism within 42 days after SARS-CoV-2 vaccination, recruited from reports of adverse drug reactions sent to the Swedish Medical Products Agency. Two hundred one cases (43% women, 91% Swedish) were compared with 4891 Swedish population controls. Analyses were performed on two candidate variants in coagulation factor II (rs1799963) and coagulation factor V (rs6025), on 14 prespecified candidate genes and across the whole genome. To support the findings, we conducted an observational register study of the Swedish general population with/without a diagnosis of thrombophilia and the risks of venous thromboembolism after SARS-CoV-2 vaccination. RESULTS: In the GWAS, the main findings were that the candidate variants of coagulation factors II rs1799963 and V rs6025 were significantly associated with venous thromboembolism (odds ratio [OR] 2.4 [95% confidence interval (CI) 1.2-4.8], p = .015 and OR 1.8 [95% CI 1.3-2.6], p = .0022). No genetic marker passed the significance threshold in the candidate gene analysis or the full genome-wide analysis. In the register study, people with a thrombophilia diagnosis had a five-fold elevated risk of venous thromboembolism within 42 days after vaccination, adjusted for potential confounders, OR 5.06 [95% CI 3.98-6.44]. CONCLUSION: Well-characterized genetic variants in the genes of coagulation factors II and V were associated with thromboembolism after SARS-CoV-2 immunization. Further research is recommended to elucidate their potential role in vaccine-related thromboembolic events.

Adult↗

PubMed2005

Allelic variants of cytochrome P450 2C9 modify the interaction between nonsteroidal anti-inflammatory drugs and coumarin anticoagulants.

INTRODUCTION: Cytochrome P450 (CYP) plays a key role in the metabolism of coumarin anticoagulants and nonsteroidal anti-inflammatory drugs (NSAIDs). Because CYP2C9 is a genetically polymorphic enzyme, genetic variability could play an important role in the potential interaction between NSAIDs and coumarins. We investigated whether NSAIDs were associated with overanticoagulation during therapy with coumarins and evaluated the effect of the CYP2C9 polymorphisms on this potential interaction. METHODS: We conducted a population-based cohort study among patients of an anticoagulation clinic who were treated with acenocoumarol or phenprocoumon between April 1, 1991, and May 31, 2003, and whose CYP2C9 status was known. Patients were followed up until an international normalized ratio (INR) of 6.0 or greater was reached or until the end of treatment, death, or the end of the study. Proportional hazards regression analysis was used to estimate the risk of an INR of 6.0 or greater in relation to concomitant use of a coumarin anticoagulant and NSAIDs after adjustment for several potentially confounding factors. To study effect modification by CYP2C9 genotype, stratified analyses were performed for wild-type patients and patients with a variant genotype. RESULTS: Of the 973 patients in the cohort, 415 had an INR of 6.0 or greater. Several NSAIDs increased the risk of overanticoagulation. The risk of overanticoagulation was 2.98 (95% confidence interval, 1.09-7.02) in coumarin-treated patients taking NSAIDs with a CYP2C9*2 allele and 10.8 (95% confidence interval, 2.57-34.6) in those with a CYP2C9*3 allele. CONCLUSIONS: Several NSAIDs were associated with overanticoagulation. For NSAIDs that are known CYP2C9 substrates, this risk was modified by allelic variants of CYP2C9. More frequent INR monitoring of patients taking NSAIDs is warranted.

Acenocoumarol↗

PubMed2006

Angiotensin-converting enzyme I/D polymorphism and preeclampsia risk: evidence of small-study bias.

BACKGROUND: Inappropriate activation of the renin-angiotensin system may play a part in the development of preeclampsia. An insertion/deletion polymorphism within the angiotensin-I converting enzyme gene (ACE-I/D) has shown to be reliably associated with differences in angiotensin-converting enzyme (ACE) activity. However, previous studies of the ACE-I/D variant and preeclampsia have been individually underpowered to detect plausible genotypic risks. METHODS AND FINDINGS: A prospective case-control study was conducted in 1,711 unrelated young pregnant women (665 preeclamptic and 1,046 healthy pregnant controls) recruited from five Colombian cities. Maternal blood was obtained to genotype for the ACE-I/D polymorphism. Crude and adjusted odds ratio (OR) and 95% confidence interval (CI) using logistic regression models were obtained to evaluate the strength of the association between ACE-I/D variant and preeclampsia risk. A meta-analysis was then undertaken of all published studies to February 2006 evaluating the ACE-I/D variant in preeclampsia. An additive model (per-D-allele) revealed a null association between the ACE-I/D variant and preeclampsia risk (crude OR = 0.95 [95% CI, 0.81-1.10]) in the new case-control study. Similar results were obtained after adjusting for confounders (adjusted per-allele OR = 0.90 [95% CI, 0.77-1.06]) and using other genetic models of inheritance. A meta-analysis (2,596 cases and 3,828 controls from 22 studies) showed a per-allele OR of 1.26 (95% CI, 1.07-1.49). An analysis stratified by study size showed an attenuated OR toward the null as study size increased. CONCLUSIONS: It is highly likely that the observed small nominal increase in risk of preeclampsia associated with the ACE D-allele is due to small-study bias, similar to that observed in cardiovascular disease. Reliable assessment of the origins of preeclampsia using a genetic approach may require the establishment of a collaborating consortium to generate a dataset of adequate size.

Bias↗

PubMed2006

Melanocortin receptor-1 gene polymorphisms and the risk of cutaneous melanoma in a low-risk southern European population.

Individuals with melanocortin 1 receptor (MC1R) gene variants have been shown to carry an increased risk for the development of melanoma. In this study, we investigated the relationship of MC1R gene variants and the risk of melanoma in 123 melanoma patients and 155 control subjects from Greece. The entire MC1R gene was sequenced for polymorphisms and the results were correlated with host factors and pigmentary characteristics. MC1R polymorphisms were present in 59.4% of melanoma patients compared to 37.5% of controls, yielding an odds ratio (OR) of 2.43 (95% confidence interval (CI) = 1.50-3.96, P < 0.001) for melanoma among MC1R carriers. The risk of melanoma was enhanced in individuals carrying multiple variant alleles (OR = 6.97; 95% CI = 1.86-26.12, P = 0.004). Only the Val60Leu, Arg142His, and Arg151Cys variants were significantly associated with melanoma risk. In stratified analysis, the risk of melanoma among MC1R carriers was not influenced by skin phototype, skin color, or hair color. No association was found between MC1R genotype and the age of onset of melanoma, the tumor location, or the tumor thickness. In conclusion, MC1R polymorphisms are a predisposing factor of melanoma in a southern European population with a relatively low incidence of the disease.

Adult↗

PubMed2026

Risk of desmoid tumor based on APC pathogenic variant location and surgical history in familial adenomatous polyposis: a U.S. community cohort study.

Desmoid tumors (DT) are a leading cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP), yet available data on DT risk remain limited and have been largely derived from large registries or tertiary referral centers. Risk in community-based U.S. populations is poorly defined, which hinders presurgical counseling. We conducted a retrospective cohort study of patients with pathogenic or likely pathogenic variants (PV/LPV) in APC identified through the Kaiser Permanente Northern California Electronic Database, a community-based system serving 4.6 million members. We evaluated the association of APC PV/LPV location and prior abdominal surgery with DT risk using multivariable logistic regression, adjusting for sex, race and ethnicity, and family history. Among 328 patients with FAP, 36 (11.0%) developed DT. DT risk was highest when the APC variant was centrally located (codon 600-1600). Family history was independently associated with increased risk (adjusted odds ratio [aOR] 4.34; 95% confidence interval [CI] 1.12-16.86). All colorectal surgeries were associated with a significantly elevated DT risk: ileostomy (aOR 12.07; 2.10-69.47), subtotal colectomy with ileorectal anastomosis (aOR 9.03; 1.63-49.96), and total proctocolectomy with ileal pouch-anal anastomosis (aOR 10.98; 2.12-56.81). In contrast, non-colorectal surgery was not associated with increased risk (aOR 0.73). In this large community-based U.S. cohort, central APC variant location, family history, and colorectal surgery were associated with increased DT risk. Our findings extend the current literature on DT risk in FAP and help refine presurgical risk-stratification and counseling for these patients.

Humans↗

PubMed2003

Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred.

We previously have identified a large kindred from Colombia in which Alzheimer's disease (AD) is caused by the E280A presenilin 1 (PS1) mutation. The objective of this study was to examine whether environmental and genetic factors are responsible for variation in the phenotypic expression of the E280A PS1 mutation. We genotyped coding and promoter polymorphisms of the APOE gene in carriers of the E280A PS1 mutation. Kaplan-Meier product-limit and Cox proportional hazard models were used in the statistical analyses. DNA was available from 114 carriers of the E280A PS1 mutation, including 52 subjects with AD. APOE epsilon 4 allele carriers were more likely to develop AD at an earlier age than subjects without the epsilon 4 allele (hazard ratio, 2.07; 95% confidence interval, 1.07-3.99; p = 0.030). Subjects with low education were more likely to develop AD later than those with higher education (hazard ratio, 0.476; 95% confidence interval, 0.26-0.87). Low educational level was associated with rural residence (p < 0.001). Promoter APOE variants did not influence either the onset or the duration of the disease. This study is the first to our knowledge to demonstrate that genetic and environmental factors influence age of onset in a kindred with a familial AD mutation.

Adult↗

PubMed2026

A transcriptome-wide approach for rapid pathotype discrimination of Puccinia striiformis f. sp. tritici in north-western India.

Stripe rust of wheat caused by Puccinia striiformis f. sp. tritici (Pst) remains a major constraint to wheat production in India due to the rapid evolution and frequent emergence of virulent pathotypes. Rapid and reliable discrimination of Pst pathotypes is essential for effective resistance deployment and surveillance. In the present study, transcriptome-wide simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs) were exploited to develop and validate molecular markers for pathotype-specific detection of Pst pathotypes prevalent in North India (110S119, 238S119, 46S119, 110S84 and 78S84). Microsatellite mining from 6103 core orthologous clusters comprising 51,127 transcripts mined 14,634 SSR loci, from which 93 primer pairs were synthesized. However, only three SSR markers exhibited polymorphism indicating limited discrimination potential of expressed sequence-derived (EST) SSRs for pathotype differentiation. In contrast, SNP discovery through stringent variant calling and filtration yielded 186 pathotype-specific homokaryotic SNPs, of which 56 high-confidence loci were selected for Kompetitive Allele-Specific PCR (KASP) assay development. A total of 48 KASP markers were synthesized and 14 demonstrated clear pathotype- or cluster-specific polymorphism representing substantially higher resolution than SSR markers. The high SNP-to-KASP conversion efficiency (~ 95%) and reproducible fluorescence-based clustering emphasize the robustness of KASP assay. Comparative evaluation revealed that SNP-based KASP markers provide superior discriminatory capacity for closely related Pst pathotypes and represent a promising complementary molecular approach for rapid identification of predominant Indian Pst pathotypes. The validated marker panel developed in this study can complement conventional virulence phenotyping and field pathogenomics approaches for surveillance of currently known pathotypes, while continued refinement may accommodate future changes in pathogen populations.

India↗

PubMed2006

Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood.

Atopic dermatitis (AD) is a common disease with a complex etiology in childhood and adult life. A significant proportion of childhood AD is transient, but in many cases it persists into adulthood. We have recently shown that null mutations in the filaggrin gene (FLG) are an important predisposing factor for childhood eczema and eczema-associated asthma, but persistence to adulthood has not been analyzed. Here we studied a cohort of adult patients with persistent AD, which had been present since early childhood. In this cohort, the combined allele frequency of the two common FLG null variants was 0.270 (cf. population frequency 0.046). This represents an odds ratio of 7.7 with 95% confidence interval of 5.3-10.9 and a chi2 P-value of 1.7 x 10(-53). Our data conclusively demonstrate that identification of FLG null alleles is an indicator of a poor prognosis in AD, predisposing to a form of eczema that starts in early infancy and persists into adulthood. This study helps to further define the nature of the AD phenotype associated with FLG null alleles.

Adolescent↗

PubMed2006

The association between HTR2C polymorphisms and obesity in psychiatric patients using antipsychotics: a cross-sectional study.

The use of antipsychotics is associated with an increased risk of obesity. This consideration makes it important to search for determinants that can predict the risk for antipsychotic-induced obesity. In this cross-sectional study, we investigated whether polymorphisms in the HTR2C gene were associated with obesity (body mass index >30 kg/m2) in patients using antipsychotics. We examined polymorphisms in the promoter region of the HTR2C gene ((HTR2C:c.1-142948(GT)n, rs3813928 (-997 G/A), rs3813929 (-759 C/T), rs518147 (-697 G/C)) and an intragenic polymorphism (rs1414334:C>G). The results of the logistic regression were expressed as adjusted odds ratios (OR). In total, we included 127 patients mainly diagnosed with schizophrenia or schizoaffective disorder (89%). The results indicate that a combined genotype carrying the variant HTR2C:c.1-142948(GT)n 13 repeat allele, the common allele rs3813929 C, the variant allele rs518147 C and the variant allele rs1414334 C is significantly related to an increased risk of obesity (OR 3.71 (95% confidence interval: 1.24-11.12)).

Adult↗