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PubMed2005

STin2 variant and family history of suicide as significant predictors of suicide completion in major depression.

BACKGROUND: Suicide is the most serious outcome of major depression, yet not all depressed patients will commit suicide. Genes, along with other factors, might account for this difference. Serotonergic alterations have been observed in suicide and depression and impulsive-aggressive behaviors. Therefore, we aimed to identify predictors of suicide, considering genetic variation at the serotonin transporter (5-HTT) gene. METHODS: We investigated the 5-HTT gene-linked polymorphic region (5-HTTLPR) and intron 2 (STin2) variants of this gene and their relationship to behavioral and clinical risk factors for suicide in a sample of depressed suicides (n =106) and depressed control subjects (n =152), diagnosed by means of proxy-based interviews. RESULTS: We found a significant association of suicide completion with having at least one copy of the STin2 10 allele [chi(2)(1) = 10.833, p = .002]. No differences were found for the 5-HTTLPR variable number of tandem repeats. After controlling for behavioral and clinical risk factors for suicide, the STin2 variant remained a significant predictor of suicide in major depression when jointly considered with a family history of suicide (odds ratio 5.560, 95% confidence interval 1.057-29.247). CONCLUSIONS: The STin2 locus might account, at least in part, for the observed familial aggregation of suicidal behavior. These results should be further explored in families where clustering of suicidal behavior is observed.

Adolescent↗
PubMed2005

Diets, polymorphisms of methylenetetrahydrofolate reductase, and the susceptibility of colon cancer and rectal cancer.

The aim of this study was to investigate the association of environmental factors (dietary folate, methionine and drinking status) and polymorphisms in the methylenetetrahydrofolate reductase (MTHFR C677T and A1298C) gene, as well as the combination of these factors, with the risk of colon cancer and rectal cancer. A case-control study of 53 colon cancer patients, 73 rectal cancer patients and 343 healthy controls was conducted. Genotypes of C677T and A1298C polymorphisms were analyzed by PCR-RFLP. The dietary folate and methionine intakes were assessed using food-frequency questionnaires and food consumption tables. Unconditional logistic regression was applied to estimate the odds ratios (ORs) and their 95% confidence intervals (CIs). The frequency of MTHFR 677T and 1298C alleles in healthy population were 39.4 and 17.2%, respectively. After adjustment for specific variants, the MTHFR 677TT genotype showed a significantly reduced risk of colon cancer compared with the wild type (OR=0.22, 95% CI: 0.50-0.98), and 1298C allele-carrier showed an inverse association with the risk of rectal cancer compared to the wild type (OR=0.52, 95% CI: 0.28-0.98). Adequate intake of folate was a protective factor from colon cancer (OR=0.32, 95% CI: 0.12-0.88) and MTHFR C677T polymorphism showed a statistically significant effect (OR=0.25, 95% CI: 0.06-0.93), reducing the risk of colon cancer in groups that have an intake of folate exceeding 115.64ng per 1000kcal per day. This study suggests that MTHFR C677T and A1298C polymorphisms are associated with the reduced risk of colon and rectal cancers, respectively. Adequate folate intake shows an inverse association with the risk of colon cancer. There is a significant interaction between MTHFR C677T polymorphism and folate intake in reducing the risk of colon cancer.

Aged↗
PubMed2006

Modulation of the central nervous effects of levomethadone by genetic polymorphisms potentially affecting its metabolism, distribution, and drug action.

AIM: Our aim was to judge the importance of candidate pharmacogenetic modulators of the central nervous effects of levomethadone by both magnitude of the modulatory effect and frequency of the mutation to assess the utility of genotyping for clinical levomethadone therapy in a random sample of subjects that, by distribution of genotypes, resembled the clinical setting. METHODS: Candidate pharmacogenetic modulators were polymorphisms reported to be of functional consequence and therefore potentially important for metabolism, distribution, or pharmacodynamic action of levomethadone, consisting of genes coding for cytochrome P450 (CYP) 2B6 and 3A, as well as 1A2, 2C8, 2C9, 2C19, and 2D6, for P-glycoprotein (ABCB1), and for mu-opioid receptors (OPRM1). The central nervous effects of levomethadone were investigated by means of measuring pupil size in a random sample of 51 healthy volunteers for 9 hours after oral administration of 0.075 mg/kg levomethadone. Plasma concentrations of levomethadone and its metabolites were assessed concomitantly, and to judge the role of metabolites, the affinities of levomethadone and its metabolites at mu-opioid receptors were estimated by use of displacement of the selective mu-opioid receptor agonist [(3)H]-DAMGO ((3)H-[D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin). RESULTS: Pupil size decreased to -41.8% +/- 9.6% from baseline at 3.5 +/- 1.1 hours after levomethadone administration. Miosis was still manifest to a lower degree (-25.1% +/- 12.3%) at the end of the observation period. In carriers of the variant 118G allele (118A>G single-nucleotide polymorphism) of the mu-opioid receptor gene (OPRM1), levomethadone had a 1.74 times (95% confidence interval, 1.4-2.2 times) lower miotic potency (P < .001) as compared with noncarriers (concentration at half-maximum effects, 52.3 nmol/L; 95% confidence interval, 36.7-66.2 nmol/L). The maximum percent decrease in pupil diameter from baseline was 44.9% +/- 7.6%, 33% +/- 6.5%, and 24% +/- 6.9% for carriers of the OPRM1 118AA, AG, and GG genotypes, respectively (P < .001 for AG and GG versus wild type, without significant differences between AG and GG). Other candidate polymorphisms in the ABCB1 or in CYP genes had no significant influence on the effects of levomethadone, either because of lack of functional consequences or because of their low allelic frequency. The metabolites of levomethadone did not contribute to the effects as indicated by low metabolite plasma concentrations and their 120- to 1300-fold lower affinities at mu-opioid receptors as compared with levomethadone. CONCLUSIONS: Among polymorphisms in OPRM1, ABCB1, and CYP genes previously associated with functional consequences in a different context, the most important pharmacogenetic factor modulating the short-term effects of levomethadone is a polymorphism (OPRM1 118A>G) affecting mu-opioid receptors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Hepatitis C virus genotypes and risk of cirrhosis in southern Italy.

Because hepatitis C virus (HCV) genotypes have raised considerable interest as variables that influence chronic hepatitis C progression, a case-control study was conducted to estimate their effects on patients with cirrhosis. Case patients (n = 46) had tested positive for anti-HCV antibody and HCV RNA and were residents of the study area who had cirrhosis recently diagnosed. Controls (n = 138) were drawn randomly from a residents' cohort from the same area. Demographic and other information were recorded. Presence of HCV infection, presence of HCV RNA, and HCV genotypes were assessed. Crude, stratified, and logistic regression analyses were performed. HCV genotype 2a/c occurred in 84 controls (60.9%) and 9 case patients (19.6%); HCV genotype 1b was found in 45 controls (32.6%) and 34 case patients (73.9%). HCV 1b genotype showed an independent effect on the risk of cirrhosis (odds ratio, 7.49; 95% confidence interval, 3.15--17.81). No significant effects related to other variables were observed. These results indicate that the genetic diversity of HCV phylogenetic variants may explain differences in biological behaviors.

Adult↗
PubMed2005

Association of NCOA3 polymorphisms with breast cancer risk.

The nuclear receptor coactivator 3 (NCOA3, also known as AIB1) is a coactivator of nuclear receptors like the estrogen receptor. NCOA3 is overexpressed in approximately 60% of primary human breast tumors, and high levels of NCOA3 expression are associated with tamoxifen resistance and worse survival rate. In contrast, NCOA3 deficiency suppresses v-Ha-ras-induced breast cancer initiation and progression in mice. Here, we analyzed the influence of NCOA3 coding single nucleotide polymorphisms on breast cancer risk by performing a case-control study using a German and a Polish study population and identified an association between NCOA3 polymorphisms and breast cancer. A joint analysis of the German and the Polish study population revealed a significant protective effect for the 1758G>C (Q586H) and 2880A>G (T960T) variants. In addition, haplotype analysis showed a protective effect of the 1758C-2880A and 1758G-2880G haplotypes (odds ratio 0.79; 95% confidence interval, 0.67-0.93; P = 0.004). Because of the impact of NCOA3 in antiestrogen therapy resistance, these polymorphisms might also influence therapy outcome in breast cancer.

Acetyltransferases↗
PubMed2005

Polymorphisms in ERCC1 and grade 3 or 4 toxicity in non-small cell lung cancer patients.

PURPOSE: ERCC1 is a lead enzyme in the nucleotide excision repair pathway of DNA repair. Polymorphisms have been identified in the ERCC1 gene, the C8092A and codon 118 polymorphisms, which may lead to an altered capacity to regenerate damaged normal tissue and greater treatment-related toxicity. EXPERIMENTAL DESIGN: Using logistic regression models, we evaluated the ERCC1 C8092A and codon 118 polymorphisms and their association with the occurrence of grade 3 or 4 toxicity in 214 stage III and IV non-small cell lung cancer patients treated first line with platinum-based chemotherapy. Adjusting covariates were performance status and type of treatment regimen. RESULTS: There was no statistically significant association between either the C8092A or codon 118 polymorphism and overall or hematologic grade 3 or 4 toxicity. However, carrying at least one variant ERCC1 C8092A allele was associated with a significantly increased risk of grade 3 or 4 gastrointestinal toxicity (adjusted odds ratio, 2.33; 95% confidence interval, 1.07-5.05; P = 0.03). CONCLUSIONS: Adjusting for performance status and type of treatment regimen, carrying at least one ERCC1 8092A allele is associated with a >2-fold increase in grade 3 or 4 gastrointestinal toxicity among platinum-treated non-small cell lung cancer patients.

Adult↗
PubMedDate not supplied

Primary thyroid malignancies in Tehran, Iran.

OBJECTIVE: The aim of this study was to present a descriptive epidemiology of primary thyroid cancer in Tehran, Iran, using cancer registry data. SUBJECTS AND METHODS: All cases of thyroid cancer registered from 1998 to 2001 in Tehran Metropolitan Area Population-Based Cancer Registry were used for this study. The incidence of thyroid cancer was estimated for the area covered by the cancer registry. Survival of patients was ascertained by telephone call to the patients or the patient's family and/or linkage of registry data to mortality data from the Bureau of Vital Statistics. Patient's survival was based on sex, age and morphological type of tumour. RESULTS: Four hundred and twenty-nine cases of primary thyroid cancer were registered in the Tehran Metropolitan Area Cancer Registry. The incidence of thyroid cancer was 3.5 and 1.0 per 100,000 population per year for females and males, respectively. Seventy percent of tumours were papillary, 11% follicular, 6.2% medullary, and the rest were other subtypes. The papillary and follicular variants occurred in younger age: 43 +/- 16 and 46 +/- 13 years, respectively; the medullary and anaplastic variants occurred in older age: over 50 years. A 5-year survival rate was 82.2%, with median survival of 66 months and 95% confidence interval of 63 and 69 months. Men and women had a similar survival experience. CONCLUSIONS: While the incidence of thyroid cancer was slightly high, the descriptive epidemiology of thyroid cancer in Tehran did not manifest a unique feature. Tehran patients experienced a high rate of survival, and the survival time for males and females was similar.

Adolescent↗
PubMed1980

Pseudomasses in the suprapatellar pouch at arthrography.

An arthrographic appearance, confidently diagnosed as synovial chrondromatosis, showed no abnormality at surgery. This experience prompted further investigation which led to the conclusion that a normal variant of the suprapatellar pouch may be confused with synovial masses. Single or multiple pseudomasses in this region may relate to the presence of an embryonic remnant of the synovial folds, the plicae synovialis. If the finding is looked for, with careful arthrographic technique and palpation under fluoroscopic control, along with correlation with the clinical findings, unnecessary arthrotomy may be avoided.

Adolescent↗
PubMed2006

The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with familial breast cancer.

Overexpression of cAMP-dependent protein kinase A (PKA) is a hallmark of the great majority of human cancers including breast cancer. A-kinase anchoring proteins (AKAPs) coordinate the specificity of PKA signalling by localizing the kinase to its subcellular sites. We tested the hypothesis whether the functional amino acid exchange Ile646Val, located in the kinase-binding domain of AKAP10, is a low-penetrance familial breast cancer risk factor. Ile646Val alters the binding of AKAP10 to PKA and is associated with morbidity. The analysis of 787 BRCA1/2 mutation-negative familial breast cancer patients and 993 controls revealed an association of the AKAP10 Ile646Val polymorphism with increased familial breast cancer risk [odds ratio (OR)=1.25, 95% confidence interval (CI) 1.03-1.51, P=0.024]. Our previous study has shown that AKAP13 Lys526Gln is associated with familial breast cancer (OR=1.58). Here, we discovered that carriers of both variants, AKAP10 Ile646Val and AKAP13 Lys526Gln, are at a further enhanced breast cancer risk (OR=2.41, 95% CI 1.30-4.46, P=0.005). PKA is a major target of therapeutic anticancer strategies. Phosphorylation of the estrogen receptor (ER) alpha by PKA induces resistance against the anti-estrogen tamoxifen. Our results indicate for the first time the importance of AKAP10 Ile646Val for familial breast cancer susceptibility. Due to the impact of Ile646Val on the subcellular localization of PKA, it will be interesting to investigate whether this polymorphism influences the effectiveness of PKA and tamoxifen based therapeutic anticancer concepts.

A Kinase Anchor Proteins↗
PubMed2003

Epidemiological evidence of an association between SLC6A2 gene polymorphism and hypertension.

Selective blockade of the norepinephrine transporter with reboxetine has been reported to induce a slight but significant increase in blood pressure. This study was designed to examine the relation of genetic variants of the norepinephrine transporter gene (solute carrier family 6, member 2; SLC6A2) with hypertension in a Japanese population. We genotyped five genetic variants of SLC6A2, three in the promoter region and two in the intronic sequence, in 1,950 subjects recruited from the Suita study. One of the variants, an A > G polymorphism in the promoter region (Promoter 3 polymorphism), was found to be associated with hypertension. Multiple logistic analysis indicated that sex (p = 0.0223), age (p < 0.0001), body mass index (p < 0.0001), alcohol consumption (p = 0.0002), and the Promoter 3 genotype (AA = 1, AG + GG = 2) (p = 0.0090) were predictive of hypertensive status. The odds ratio of the AG + GG genotypes for hypertension was 1.35 (95% confidence interval: 1.08-1.69) over the AA genotype. SLC6A2 may be one of the genes that contribute to hypertension in Japanese. To our knowledge, this is the first report to detect associations between SLC6A2 genetic variants and blood pressure.

Blood Pressure↗
PubMed2006

Genetic variants of the ADPRT, XRCC1 and APE1 genes and risk of cutaneous melanoma.

Sunlight causes various kinds of DNA damage, including oxidative lesions that are removed effectively by the base excision repair (BER) pathway, in which ADPRT, XRCC1 and APE1 play a key role. However, genetic variation in these genes may alter their functions. We hypothesized that ADPRT, XRCC1 and APE1 polymorphisms are associated with risk of cutaneous melanoma (CM). In a hospital-based case-control study of 602 CM patients and 603 cancer-free control subjects frequency matched on age, sex and ethnicity, we genotyped for three non-synonymous single nucleotide polymorphisms (SNPs) (i.e. the ADPRT Val762Ala, XRCC1 Arg399Gln and APE1Asp148Glu) and assessed their associations with risk of CM. We found no significant difference in the allele frequencies between cases and controls for any of these three SNPs. However, we found that, compared with the APE1 Asp/Asp genotype, a significantly decreased risk of CM was associated with the APE1 Asp/Glu [adjusted odds ratio (OR), 0.60; 95% confidence interval (CI), 0.41-0.86], Glu/Glu (OR, 0.58; 95% CI, 0.38-0.88) and combined APE1 Asp/Glu+Glu/Glu (OR, 0.59; 95% CI, 0.42-0.83) genotypes, but not for other XRCC1 variant genotypes. Moreover, there was evidence for a possible gene-gene interaction between XRCC1 and APE1 variants in the association with risk of CM (P=0.030). We conclude that the APE1 Glu variant may have an effect or interact with XRCC1 in the etiology of CM or in linkage disequilibrium with other untyped protective alleles. Larger studies with more SNPs in the BER genes are needed to verify these findings.

Adult↗
PubMed2006

Screening for the alpha-adducin Gly460Trp variant in hypertensive patients: a cost-effectiveness analysis.

BACKGROUND: Studies have shown that approximately 80% of hypertensive patients do not take diuretics despite their recommendation as a first-line therapy. A recent study reported that hypertensive patients with the Gly460Trp variant in the alpha-adducin gene are more likely to benefit from diuretic therapy. The objective of this study was to evaluate the potential cost effectiveness of screening for the alpha-adducin Gly460Trp variant among hypertensive patients. METHODS: A decision analytic Markov model was developed to estimate the clinical and economic outcomes comparing screening for the Gly460Trp variant to identify patients for addition of a diuretic compared to no screening and no addition of diuretic (usual care) in a hypothetical cohort of treated hypertensive patients not receiving diuretic therapy. We used a lifetime horizon and payer perspective. Cost, utility and epidemiological data were obtained from the literature. One-way, probabilistic, and scenario sensitivity analyses were conducted to evaluate the uncertainty in the results. RESULTS: The screening strategy increased quality adjusted life years (QALYs) by 0.14 (95% confidence range [CR]: 0.05, 0.36) and saved dollar 1834 (dollar 505, dollar 5174) compared to usual care. The most influential input was the strength of the interaction between the alpha-adducin gene variant and diuretic effect. CONCLUSIONS: Our results suggest that screening for the alpha-adducin gene variant may be a useful mechanism to identify patients most likely to benefit from diuretic therapy and improve compliance with current treatment guidelines.

Aged↗
PubMed2003

The relationship between twenty missense ATM variants and breast cancer risk: the Multiethnic Cohort.

Deficiencies in tasks of detecting and repairing DNA damage lead to mutations and chromosomal abnormalities, a hallmark of cancer. The gene mutated in ataxia-telangiectasia (A-T), ATM, is a proximal component in performing such tasks. Studies of A-T families have suggested an increased risk of breast cancer among obligate female heterozygous carriers of ATM mutations. Paradoxically, studies of sporadic and familial breast cancer have failed to demonstrate an elevated prevalence of mutations among breast cancer cases. We characterized the prevalence and distribution of 20 ATM missense mutations/polymorphisms in a population-based case-control study of 854 African-American, Latina, Japanese, and Caucasian women aged >/==" BORDER="0">45 years participating in the Multiethnic Cohort Study. The study population included 428 incident breast cancer cases and 426 controls. The prevalence of variants ranged from 0% to 13.6% among controls and varied by ethnicity (0-32.5%). Overall, these data provide little support for an association of ATM missense mutations with breast cancer among older women. We observed only one sequence variation (L546V), common among African-American women, to be overrepresented among all high-stage breast cancer cases (odds ratio, 3.35; 95% confidence interval, 1.27-8.84). After correction for multiple comparisons, this observed risk modification did not attain statistical significance. The distribution of ATM missense mutations and polymorphisms varied widely across the four ethnic groups studied. Although a single missense variant (L546V) appeared to act as a modest predictor of risk, the remaining variants were no more common in breast cancer cases as compared with controls.

Black or African American↗
PubMed2001

Platelet glycoprotein IIb polymorphism, traditional risk factors and non-fatal myocardial infarction in young women.

Several platelet glycoprotein polymorphisms have been associated with an increased risk of myocardial infarction (MI) in studies that included predominantly men. In a population-based sample of 68 Caucasian women < 45 years old with non-fatal MI and 346 demographically similar control subjects, we found an increased risk of MI among women who possessed at least one copy of the glycoprotein IIb Ser843 allele compared with those lacking the Ser843 allele (odds ratio 1.85; 95% confidence interval = 1.03-3.33). The increased risk was present only in subgroups of women who smoked cigarettes, had hypercholesterolaemia or who had a family history of early onset MI. The Ser843 variant of glycoprotein IIb may be associated with an increased risk of MI in young women with other cardiovascular risk factors. Additional studies involving larger numbers of subjects are needed to confirm this preliminary finding.

Adult↗
PubMed2006

The BARD1 Cys557Ser variant and breast cancer risk in Iceland.

BACKGROUND: Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer. METHODS AND FINDINGS: The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. CONCLUSIONS: Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.

Adult↗
PubMed1995

Increased PiZ gene frequency for alpha 1 antitrypsin in patients with genetic haemochromatosis.

The putative relationship between genetic haemochromatosis and PiZ alpha 1 antitrypsin deficiency was studied using a monoclonal antibody against the PiZ variant in 67 consecutive patients with genetic haemochromatosis seen at Karolinska Hospital and Huddinge University Hospital, Stockholm over a 10 year period. Three (4.5%) of the patients with haemochromatosis were found to be PiZ homozygotes (odds ratio = 82, confidence interval = 26, 256; p < 0.0001). The prevalence of the heterozygous (PiZ) phenotype was similar to that in the general population (p = 0.937). During the ascertainment period, liver biopsy was performed in 65 (97%) of the patients; 66% (2 of 3) of the PiZ homozygotes were found to have cirrhosis compared with 10% (6/59) of the non-carriers of the PiZ variant (p = 0.039). None of the homozygous or heterozygous alpha 1 antitrypsin deficient patients had developed hepatocellular carcinoma compared with 3.4% (2 of 59) of the non-PiZ gene carriers (p = 1.0). Two of those with the homozygous phenotype had developed severe emphysema. HLA typing was performed in 18 patients, 16 (89%) of whom manifested antigens known to be linked to haemochromatosis. There were no significant differences between the PiZ gene carriers and non-carriers in mean age at onset of disease, sex distribution, or HLA type. Two of the PiZ heterozygotes had plasma alpha 1 antitrypsin concentrations below the normal range, though the group mean was lower than that of the non-PiZ carriers (p = 0.0003). The data suggest that the presence of the PiZ allele for alpha1 antitrypsin deficiency, in a double dose, is associated with genetic haemochromatosis and may contribute to the earlier onset of cirrhosis in these patients, though it does not increase the risk of hepatocellular carcinoma.

Adult↗
PubMed2006

Functional variants of the lipoprotein lipase gene and the risk of preeclampsia among non-Hispanic Caucasian women.

Hypertriglyceridemia is an important pathophysiologic feature of preeclampsia, a common vascular disorder of pregnancy. Three well-documented functional variants (N291S, S447X, and D9N) of the lipoprotein lipase gene were related to hypertriglyceridemia. Results from the only two studies concerning the relationship between these variants and preeclampsia risk have been inconsistent. We investigated this relationship in a case-control study including 144 preeclamptic and 290 normotensive pregnant women (all non-Hispanic Caucasians). We estimated odds ratios (OR) and 95% confidence intervals (CI) adjusted for maternal age, pre-pregnancy body mass index, and parity. After adjusting for covariates, women with the 291 N/S or S/S genotype had significantly increased risk of preeclampsia (OR 6.9, 95% CI 1.9-25.4) compared with women with the common 291N/N genotype. The 447 S/X or X/X genotype was not significantly associated with preeclampsia risk. The frequency of the 9N variant allele was 1.8% in controls, while this allele was not observed among cases. Haplotype 9D/291S/447S was strongly associated with higher risk of preeclampsia as compared with the most common haplotype 9D/291N/447S (adjusted OR 6.6, 95% CI 1.7-25.0). Results from our study support the thesis that abnormal lipid metabolism is important in the pathogenesis of preeclampsia.

Adult↗
PubMed2004

Risk factors for severe hyperbilirubinemia in neonates.

The incidence of severe neonatal hyperbilirubinemia is higher in Asians than in whites. A case-control study was designed to investigate the effects of eight known risk factors [breast feeding, ABO incompatibility, premature birth, infection, cephalohematoma, asphyxia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and variant UDP-glucuronosyltransferase 1A1 (UGT1A1) gene] and a suspicious analog [organic anion transporter 2 (OATP 2) gene] on severe hyperbilirubinemia in Taiwanese neonates. The 72 study subjects and 100 hospital control subjects consisted of neonates with peak serum bilirubin levels > or =342 microM and <256.5 microM, respectively. The PCR-restriction fragment length polymorphism method was applied to detect the UGT1A1, OATP 2, and G6PD genes. The results of multivariate logistic regressions, adjusted for covariates, revealed odds ratios (ORs) of 4.64 [95% confidence interval (CI): 2.25-9.57; p < 0.001], 3.36 (95% CI: 1.54-7.35; p=0.002), and 3.02 (95% CI: 1.30-6.99; p=0.010) for neonates who were fed with breast milk, and carry the variant UGT1A1 gene at nucleotide 211 and the variant OATP 2 gene at nucleotide 388, respectively. The ORs, adjusted for covariates, for the other six risk factors were not statistically significant. The ORs in neonates who had one, two, and three significant risk factors were 8.46 (95% CI: 2.75-34.48; p < 0.001), 22.0 (95% CI: 5.50-88.0; p < 0.001), and 88.0 (95% CI: 12.50-642.50; p < 0.001), respectively. In conclusion, neonates who carry the 211 and 388 variants in the UGT1A1 and OATP 2 genes, respectively, as well as feed with breast milk are at high risk to develop severe hyperbilirubinemia.

Case-Control Studies↗