Homozygous Women Research Articles

Blood pressure, arterial stiffness and endogenous lithium clearance in relation to AGTR1 A1166C and AGTR2 G1675A gene polymorphisms

Introduction:Although recently a matter of epidemiologic controversy, sodium overload and its interaction with genetic factors predispose to hypertension and related target organ complications.Methods:In 131 (66 male) treated hypertensives, we measured peripheral and central arterial pressures and pulse wave augmentation indexes (AIxP, AIxC1, AIxC2), pulse wave velocity (PWV), daily urinary sodium excretion and did genetic studies of AGTR1 A1166C and AGTR2 G1675A polymorphisms. Proximal (FELi) and distal (FDRNa) sodium reabsorption measurements were performed using endogenous lithium clearance.Results:In men, we found interaction between FDRNa and AGTR2 G1675A polymorphism with respect to AIxC1 (pINT=0.01), AIxC2 (pINT=0.05) and AIxP (pINT=0.006). Arterial stiffness increased with higher sodium reabsorption in the distal tubule, in the presence of AGTR2 G allele with the opposite tendency in A allele carriers. In the subgroup with FDRNa below median, as compared to those with FDRNa above median, the AIxC1 (139.6±3.8 vs 159.1±5.7%; p=0.009), AIxC2 (26.3±1.8 vs 33.3±1.7%; p=0.016) and AIxP (83.4±2.5 vs 96.5±2.6%; p<0.0001) were lower, in the G allele carrying men and GG homozygous women.Conclusions:The relation between sodium reabsorption in the distal tubule and the development of arterial stiffness depends on the AGTR2 G1675A polymorphism in blood pressure independent fashion.

Polymorphisms of the NOS3 gene in Tunisian patients with Behçet's disease

Behçet's disease (BD) is a multisystem inflammatory disease characterized by recurrent orogenital ulceration, ocular inflammation and skin lesions. Reduced plasma nitric oxide (NO) levels in patients with BD have been implicated in the development of the endothelial abnormalities and thrombotic complications occurring in these patients. Polymorphisms in the endothelial nitric oxide synthase gene (NOS3) have been inconsistently associated with BD. This inconsistency may derive from population stratification secondary to ethnic diversity, and consideration limited to only one rather than combinations of polymorphisms. We studied three genetic variations in the NOS3 gene: a single nucleotide polymorphism in the promoter region -786T>C, in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4 (4a4b) of the NOS3 gene in 100 unrelated Tunisian patients with BD and 148 healthy controls. In addition, we also examined the association of NOS3 gene haplotypes with BD. Analyses of the Glu298Asp, -786T>C and 4a4b polymorphisms were made by the polymerase chain reaction (PCR) restriction fragment length polymorphism technique and PCR genotyping, respectively. The distribution of the Glu298Asp genotype differed significantly between patients with BD and controls (P = 0.01). Allele Asp298 was significantly more frequent in patients with BD than in controls (P = 0.005, OR = 1.70, 95% CI 1.14-2.54). In contrast, distribution of alleles and genotypes of -786T>C and 4a4b polymorphisms was not different between the control and BD group. However, the frequency of Asp-T-4b haplotype was significantly higher in patients with BD than in healthy controls. By gender, the signification remained only for heterozygous men (P = 0.03) and homozygous women (P = 0.02). These results suggest that Glu298Asp polymorphism of the NOS3 gene is associated with BD susceptibility in Tunisian patients.

Factor XIII-A subunit Val34Leu polymorphism in fatal atherothrombotic ischemic stroke

Factor XIII (FXIII) is a regulator of fibrinolysis and clot firmness. Val34Leu polymorphism of its potentially active A subunit (FXIII-A) leads to faster activation of FXIII, influences clot structure and provides a moderate protection against coronary artery disease. The effect of FXIII-A Val34Leu polymorphism on the risk of atherothrombotic ischemic stroke (AIS) has been investigated in a few studies with contradictory results. In all previous studies, only patients surviving AIS were enrolled and sex-specific effects were not explored. In this retrospective multicenter cohort, we investigated the effect of FXIII-A Val34Leu polymorphism on the risk of fatal AIS in women and men. DNA isolation and genetic determinations in the case of 316 patients who died of AIS were carried out on paraffin-embedded tissue specimens. Genetic analyses for population controls, patients with history of AIS and sex-matched controls were performed on extracted genomic DNA from peripheral blood leukocytes. The prevalence of homozygous wild-type, and heterozygous genotypes, Leu34 carriers and Leu34 allele was not different significantly between the patients with fatal AIS and their respective controls. Logistic regression analysis with age as co-variant demonstrated that in women, homozygous presentation of Leu34 allele represented a more than three-fold increased risk of AIS with fatal outcome. The results demonstrate that FXIII-A Val34Leu polymorphism does not influence the occurrence of AIS, but has an effect on the severity of its outcome. This effect is sex-specific and in homozygous women, the prothrombotic/antifibrinolytic effects of FXIII-A Val34Leu polymorphism seem to prevail.

Decreased iron burden in overweight C282Y homozygous women: Putative role of increased hepcidin production

An excess of visceral adipose tissue could be involved as a modulator of the penetrance of HFE hemochromatosis since fat mass is associated with overexpression of hepcidin and low transferrin saturation was found to be associated with being overweight in women. This study was aimed at assessing the relationship between body mass index (BMI), a surrogate marker of insulin resistance, and iron burden in HFE hemochromatosis. In all, 877 patients from a cohort of C282Y homozygotes were included in the study when BMI at diagnosis and amount of iron removed (AIR) by phlebotomy were available. No relationship between AIR and BMI was found in men, whereas 15.1% (52/345) of women with AIR <6 g had BMI ≥28 versus 3.9% (2/51) of women with AIR ≥6 g (P = 0.03). At multivariate analysis, BMI was an independent factor negatively associated with AIR (odds ratio: 0.13; 95% confidence interval [CI]: 0.03-0.71) together with serum ferritin, serum transferrin, transferrin saturation, hemoglobin, and alanine aminotransferase. In a control group of 30 C282Y homozygous women, serum hepcidin was significantly higher in overweight (14.3 mmoL/L ± 7.1) than in lean (7.9 mmoL/L ± 4.3) women (P = 0.0005). In C282Y homozygous women, BMI ≥28 kg/m(2) is independently associated with a lower amount of iron removed by phlebotomy. BMI is likely a modulator factor of the phenotypic expression of C282Y homozygosity, likely through an increase of circulating levels of hepcidin.

Analysis of inconsistencies in terminology of spinal and bulbar muscular atrophy and its effect on retrieval of research

Diseases are sometimes known by many names 1–9, which complicates the retrieval of publications. Rare and emerging diseases may be especially vulnerable to this. Health sciences librarians do not often encounter rare diseases and may be unaware of the search challenges that these diseases present. To effectively retrieve publications for research, a strategy to identify all the different names of a disease is needed so that these can be incorporated into a comprehensive search. The author was engaged in a research project to create a comprehensive bibliography of the rare disease spinal and bulbar muscular atrophy (SBMA). The project utilized a strategy to identify all of the various names for the disease. This strategy should be helpful not only for SBMA researchers, but for anyone interested in a methodology for obtaining a comprehensive list of names for a disease. Spinal and bulbar muscular atrophy (SBMA) SBMA (ORPHA481, OMIM #313200, SNOMED CT Concept ID 230253001†) is a rare progressive neuromuscular disorder of males marked by proximal muscle weakness, cramping, fasciculations (twitching of individual muscle fibers), and muscle atrophy. Symptoms have been reported to first begin to develop between the third to sixth decades of life. Prevalence of SBMA has been reported alternately as 1 in 40,000 10, 1–2 in 100,000 11, and less than 1 in 50,000 live male births 12, but it is thought to be underdiagnosed 13–15. Degeneration of anterior horn cells (lower motor neurons) in the spinal cord of affected individuals is observed. Additional symptoms may include gynecomastia (abnormal growth of breasts in males), testicular atrophy, dysarthria (difficulty speaking), and dysphagia (difficulty swallowing). At this time, there is no known cure for most such neuromuscular diseases 16. Inheritance of SBMA is by traditional X-linked genetics. The disorder is related to a genetic defect in which a trinucleotide repeat occurs in the first exon of the androgen receptor gene on the X chromosome, first identified by La Spada in 1991 17. The string of three nucleotides of a trinucleotide repeat is present in a normal gene but is an unusually long string in a defective gene. The trinucleotide repeat of SBMA is cytosine-adenine-guanine (CAG), which codes for the amino acid glutamine. The presence of the repeat in DNA translation results in a string of glutamine molecules in the resulting peptide. Normal CAG repeat length in the androgen receptor gene is 11–34. SBMA is diagnosed if the number of CAG repeats exceeds 38 18, 19. Women do not develop SBMA, but heterozygous and homozygous women may exhibit mild symptoms, particularly muscle twitching and cramping 13, 20, 21. SBMA was identified as a unique disorder in 1968 by William R. Kennedy, but the disorder existed before its discovery 22. As far back as 1897, Japanese neurologist Hiroshi Kawahara first described what appeared to be SBMA in two brothers suffering from muscle atrophy and fasciculation of the tongue and limbs, with adult onset and sex-linked recessive inheritance 23, 24. Several disorders of varying severity and outcomes resemble SBMA, and the disorder is thought to be frequently misdiagnosed 25–29. The most well known is amyotrophic lateral sclerosis. The most challenging are the spinal muscular atrophies (SMA). However, SMA is an autosomal recessive genetic disease. Symptoms of most forms of SMA arise in childhood, but SMA3 is suggested to possibly first appear in adolescence or young adulthood. SMA4 symptoms may appear after age 30 30.

Cancer risk in HFE C282Y homozygotes: results from the HUNT 2 study

Objective. In addition to hepatocellular cancer, HFE C282Y homozygotes are reported to have increased risk of colorectal cancer and breast cancer. This study was done to further explore the cancer risk in C282Y homozygotes. Material and methods. We studied cancer incidence in 292 homozygotes and 62,568 others that participated in the HUNT 2 population screening in 1995–1997. Using Cox proportional hazard models, we estimated cancer hazard ratio as a function of C282Y homozygosity and several screening variables including serum transferrin saturation, alcohol consumption and daily smoking. Results. Cancer was diagnosed in 36 homozygotes, five of which had two cancer diagnoses. The overall cancer incidence was not increased in C282Y homozygotes (hazard ratio 1.10 [95% CI 0.60–2.03] in women and 0.94 [95% CI 0.53–1.66] in men). However, homozygous men had increased risk of colorectal cancer (hazard ratio 3.03 [95% CI 1.17–7.82], p = 0.022) and primary liver cancer (hazard ratio 54.0 [95% CI 2.68–1089], p = 0.009). The risk of breast cancer in homozygous women was not increased (hazard ratio 1.13 [95% CI 0.35–3.72]). Adjusted for other variables including C282Y homozygosity, very low and very high serum transferrin saturation were associated with increased overall cancer incidence. Conclusions. C282Y homozygosity is associated with increased risk of colorectal cancer and hepatocellular cancer in men. In the general population, individuals with a very low or a very high serum transferrin saturation may have increased cancer risk.

Genetic Variations in the Vitamin D Binding Protein and Season-Specific Levels of Vitamin D Among Older Adults

Vitamin D insufficiency is common among older adults. Genome-wide association studies have found an association between variants in the vitamin D binding protein and serum levels of vitamin D. The quantification of this association among older women and men and its potential variation by season remain unexplored. Serum levels of 25-hydroxyvitamin D [25(OH)D] and genetic variants in the vitamin D binding protein were analyzed in 2160 women and 1581 men age 50 to 74 years participating in a large population-based cohort study (ESTHER study-epidemiologic study assessing chances of prevention and early detection of various chronic diseases, including cancer among older adults) in Germany. Serum levels of 25(OH)D were assessed in relation to four single nucleotide polymorphisms (SNPs; rs4588, rs2282679, rs1155563, and rs12512631) by descriptive and multivariate analysis. Both heterozygous and homozygous women and men carrying the rare allele with SNPs rs4588, rs2282679, or rs1155563 had lower levels of 25(OH)D in summer months than those homozygous for the wild-type alleles. Adjusted differences ranged from 5.1 to 5.4 nmol/l among heterozygous carriers of the rare alleles and from 8.8 to 9.6 nmol/l among homozygous carriers of the rare alleles. During winter months, 25(OH)D differences by genotype were smaller among women and not apparent among men. Older women and men living in a high-latitude region and carrying the rare alleles of SNPs rs4588, rs2282679, or rs1155563 seem to benefit less from higher levels of ultraviolet radiation during the summer season.

Effect of Maternal Cystic Fibrosis Genotype on Diabetes in Pregnancy

To evaluate the association between the cystic fibrosis (CF) genotype and the rate of diabetes complicating pregnancy. We conducted a retrospective cohort analysis of all pregnant patients with CF from 1972-2011 at a single institution. Patients who were homozygous for the ΔF508 mutation were compared with patients who were heterozygous for the ΔF508 mutation. Primary outcomes measured were incidence of CF-related diabetes and gestational diabetes mellitus (GDM) stratified by CF genotype. Secondary outcomes measured included pancreatic insufficiency, preterm premature rupture of membranes, preterm delivery, mode of delivery, gestational age at delivery, and maternal mortality. We identified 54 pregnancies among 36 women who met inclusion criteria. Of these pregnancies, 28 (51.9%) were carried by women who were homozygous for the ΔF508 mutation. Homozygous women had a significantly greater incidence of pancreatic insufficiency (89.3% compared with 61.5%, P=.03) and diabetes complicating pregnancy (60.7% compared with 23.1%, P<.01) compared with heterozygous women. In addition, there was some evidence of an increased incidence of GDM specifically among homozygous women (35.7% compared with 15.4%, P=.12). Regarding neonatal outcome, there was a lower mean birthweight (2,881 g compared with 3,203 g, P=.04) among the women who were homozygous for the ΔF508 mutation. There was no statistical difference in preterm deliveries, mode of delivery, gestational age at delivery, rate of preterm premature rupture of membranes, or incidence of maternal mortality between the two groups. Women with CF who are homozygous for the ΔF508 mutation have an increased risk of having a pregnancy complicated by diabetes.

Codon 72 polymorphism of p53 and HPV type 16 E6 variants as risk factors for patients with squamous epithelial lesion of the uterine cervix

The Arg/Arg genotype versus Arg/Pro or Pro/Pro at codon 72 of the p53 gene in association with human papillomavirus (HPV) 16 E6 variants has been implicated as a risk marker in cervical neoplasia. However, research on this topic has produced controversial results. The association of p53 codon 72 polymorphism alone and in combination with specific HPV 16 E6 variants with risk of developing squamous intraepithelial cervical lesion has been investigated in low and high-grade squamous intraepithelial lesions and in HPV-negative controls from an Italian population. The data obtained showed statistically significant different distribution of p53 genotypes between healthy controls and precursor lesions, with the p53 arginine homozygous increased in high-grade squamous intraepithelial lesions. The T350G HPV 16 variant was the most frequent variant observed in the analyzed group of Italian women, showing a slight decreasing with the severity of the lesion. At the same time, the number of the prototype T350 slightly increased with the severity of the cytological lesions. In conclusion, p53 arginine homozygous was found to be increased in high-grade lesions, supporting the results of previous investigations indicating that HPV-positive patients with p53 Arg/Arg have an increased risk of developing pre-cancerous lesions. In addition, T350G HPV 16 variant was over-represented in p53 Arg homozygous women with cervical lesions. When p53 genotype and HPV 16 variants are considered together, no difference emerges between cases and controls so is not possible to assess that the oncogenic effect of HPV 16 T350G variant may be influenced by the p53 genotype.

The relationship between estrogen receptor gene polymorphism and mammographic density in postmenopausal women

ABSTRACTObjective To assess the relationship between the presence of PVUII and XBAI polymorphisms in the estrogen receptor α gene and mammographic density in postmenopausal women.Methods For the present analysis, 189 postmenopausal women who had never used hormonal therapy and who did not have clinical or mammographic features were selected. Based on the ACR-BIRADS® 2003 classification, the mammographic density was determined by three independent readers (two subjective ratings and one computerized). Blood samples were available to extract DNA according to KIT GFX® protocol. PCR-RFLP was then used to identify the polymorphisms.Results There was a high degree of agreement among the three readers to determine the mammographic density (κ > 0.75). Sixty women (32%) had dense breasts and 129 (68%) had non-dense breasts. The PVUII polymorphism was found in 132 (69.8%) of 189 women, while the XBAI polymorphism was found in 135 (71.4%) women. Parity (p = 0.02) and body mass index (p < 0.0001) were associated with mammographic density. It was observed that, for the XBAI polymorphism, women with two mutated alleles were approximately 2.5 times more likely to be classified in the dense breasts group (p = 0.003) and the presence of both wild alleles was associated with fibroglandular tissue replacement by fat (p = 0.02).Conclusions There was no significant association of the PVUII polymorphism in the estrogen receptor α gene with mammographic density (p = 0.34). However, the XBAI polymorphism was observed at a higher mutated homozygous frequency in women with dense breasts and there was an increased frequency of wild-type homozygous and heterozygous women with fat-replaced breasts (p = 0.01).

Homozygous factor V Leiden and double heterozygosity for factor V Leiden and prothrombin mutation

The most common forms of familial thrombophilia are factor V Leiden (FVL) and prothrombin mutation (PTM). Homozygous FVL and PTM have long been feared conditions thought to cause high rates of morbidity and mortality. To analyse clinical features in patients with homozygous FVL and PTM, as well as patients with double heterozygosity for FVL and PTM. All patients with homozygous FVL, PTM or double heterozygosity in the MATS database of 1465 consecutive unselected patients were analysed regarding age at inclusion venous thromboembolism (VTE), age at first thrombosis, recurrence, clinical course and acquired risk factors. We found 36 patients homozygous for FVL. Patients homozygous for FVL were younger than controls at group level (56±18 vs. 63±17, p<0.02). Homozygous women were younger than female controls (50±19 vs. 63±18, p<0.002). No difference was observed when comparing male subjects. Women were younger than men at inclusion thrombosis (50±19 vs. 65±14, p<0.02) and at first thrombosis (47±19 vs. 64±14, p<0.01). Deep venous thrombosis (DVT) was seen in 33 patients (92%), 6 (17%) had pulmonary embolism (PE) and 3 (8%) had combined DVT and PE. PE was less frequent in homozygous FVL women compared to female controls (p<0.03). VTE recurred in 3 subjects during the duration of the study. Odds ratio for VTE in homozygous FVL patients compared to controls was 13.9 (95% CI 9.9-19.7). We found no subjects with homozygous PTM. Double heterozygosity for FVL and PTM was seen in 12 subjects. There was no difference in age at inclusion VTE between double heterozygotes and controls (59±16 vs. 63±17, ns.). DVT was seen in 92% at inclusion, 8% had PE. Mean age at first VTE was 52±17 (27-82). Consecutive homozygous FVL patients had a higher age at first thrombosis than previously described. Homozygous females are affected at an earlier age than homozygous men and female controls. It seems that thrombi in homozygous FVL have a different pattern compared to controls i.e. more prone for thrombosis in the lower extremity. The odds ratio for thrombosis among homozygous FVL seems to be lower than previously described.

Apolipoprotein E gene (APOE) genotype in Wilson’s disease: Impact on clinical presentation

BackgroundWilson’s disease (WD), an inherited copper metabolism disorder that leads to pathological tissue copper accumulation and secondary organ damage, is caused by mutations in the ATP-ase 7B gene (ATP7B). The apolipoprotein E gene (APOE) alleles ε2, ε3, and ε4 produce three different apoE isoforms with different biological effects, which can determine risks of many human diseases, including neurodegenerative and liver disease. This study aimed to evaluate the impact of APOE genotype on the variability of WD phenotypic expression. MethodsWe analyzed data on 383 WD consecutive patients in the WD registry. The APOE genotypes (APOE ε3/ε3 (wild-type), APOE ε2-positive, and APOE ε4-positive) were determined and the APOE genotype effect on the phenotypic WD presentation was assessed in all symptomatic WD patients, as well as in patient subgroups divided according to sex and ATP7B genotype. ResultsAPOE genotype had no impact on WD presentation in the general population of symptomatic patients. However, APOE ε4-positive women tended to present WD symptoms earlier than women possessing the wild-type APOE ε3/ε3 genotype (24.2 vs. 27.9 years; p = 0.08). The effect of the APOE ε4-positive genotype was more pronounced in ATP7B p.H1069Q homozygous women, in whom disease symptoms started almost 6 years earlier (23.6 vs. 29.9 years; p < 0.05) than in APOE ε3/ε3 women. ConclusionsIn women, APOE ε4-positive genotype is associated with earlier onset of WD symptoms, particularly among ATP7B p.H1069Q homozygous patients. Further studies are needed to understand the mechanisms of these gender-dependent phenotypic effects.

P4-02-10: The Relationship between Estrogen Receptor Gene Polymorphism and Mammographic Density in Postmenopausal Women.

Abstract Background Assess the relation between the presence of PVUII and XBAI polymorphisms in the estrogen receptor alpha gene and mammographic density in postmenopausal women. Methods For the present analysis, 189 postmenopausal women who had never used hormonal therapy and who did not have clinical or mammographic features were selected. Based on the ACR-BIRADSâ 2003 classification, the mammographic density was determined by three independent readers (two subjective ratings and one computerized - Adobe Photoshop â 7.0 software). Blood samples were available to extract DNA according to KIT GFX â protocol. PCR-RFLP (Polymerase Chain Reaction - Restriction Fragment Length Polymorphism) was then used to identify the polymorphisms. Results There was a high degree of agreement among the three readers to determine the mammographic density (Kappa&amp;gt;0.75). Sixty women (32%) had dense breasts and 129 (68%) had non-dense breasts. The PVUII polymorphism was found in 132 (69.8%) of 189 women, while the XBAI was found in 135 (71.4%) of women. Parity (p=0.02) and body mass index (p&amp;lt;0.0001) were associated with mammographic density. It was observed that for the XBAI polymorphism, women with two mutated alleles were approximately 2.5 times more likely to be classified in dense breasts group (p=0.003) and the presence of both wild alleles was associated with fibroglandular tissue replacement by fat (p=0.02). Conclusions There was no significant association of the PVUII polymorphism in the estrogen receptor alpha gene with mammographic density (p=0.34). However, the XBAI polymorphism was observed at a higher mutated homozygous frequency in women with dense breasts and there was an increased frequency of wild-type homozygous and heterozygous women with fat-replaced breasts (p=0.01). Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-02-10.

CHEK2*1100delC homozygosity is associated with a high breast cancer risk in women

BackgroundMutations in the CHEK2 gene confer a moderately increased breast cancer risk. The risk for female carriers of the CHEK2*1100delC mutation is twofold increased. Breast cancer risk for carrier women...

Aging phenotype and its relationship with IGF-I gene promoter polymorphisms in elderly people living in Catalonia

ObjectivesGenetic variations in the Insulin/IGF-I genes pathway have been related to longevity, dementia, metabolic diseases and cancer. The purpose of the present study was to investigate the 192bp allele of IGF-I gene promoter and its relationship with metabolic syndrome (MS) components, mental and nutritional state, muscle strength and functional capacity in an aged Spanish population. DesignPopulation-based study (Mataró Ageing Study), including 292 subjects (144 men and 148 women, mean age 77.0±5.4). Anthropometric variables, lipid profile, glucose and blood pressure (BP) were measured; mental state (MMSE), nutritional state (MNA) and Barthel scale were performed, and were correlated to the presence of the 192bp allele of IGF-1 gene promoter polymorphisms. ResultsMS (ATP-III criteria) was found in 49.5% (41.4% in men and 57.6% in women). The 192bp allele of IGF-I gene promoter was distributed as: 41.9% homozygous, 44.3% heterozygous and 13.9% were non-carriers of this allele. A lower prevalence of metabolic syndrome was observed in homozygous (41.9% vs 54.9% in heterozygous+non-carriers, p=0.031). Mental state (MMSE), nutritional state (MNA) and Barthel scale were better in homozygous individuals compared to heterozygous and non-carriers (p=0.015, p=0.026 and 0.047, respectively). In men, MNA was better in homozygous with no differences in MMSE and Barthel scales. In homozygous women, BP was lower (p=0.009) and Barthel scale was better (p=0.05) with no differences in MMSE and MNA. ConclusionHomozygosity for the 192bp allele of the IGF-I gene polymorphism suggests a healthier aging condition, with less prevalence of cardiometabolic disturbances, and better mental, nutritional and functional state.

Effects of neuromedin-β on caloric compensation, eating behaviours and habitual food intake

We have previously shown that a missense mutation (p.P73T) located in the neuromedin-β gene, a satiety peptide, was associated with higher levels of disinhibition, susceptibility to hunger, and body weight gain over time. In this study we compare caloric compensation, eating behaviour traits, food intake and adiposity between premenopausal women with (T73T) and without (P73P) mutation. Subjects ( N = 153) were screened to find homozygous women (T73T) that were matched for age, BMI and use of oral contraceptives with 7 women (P73P) not carrying the mutation. Eating behaviour traits were assessed with the Three-Factors Eating Questionnaire and habitual dietary intakes with a 3-day dietary record. A randomized single-blind cross-over design was used to test the effect of p.P73T on caloric compensation. We measured appetite sensations and ad libitum dietary intake following two different energy preloads. We found no difference in eating behaviour traits, adiposity, appetite sensations, ad libitum dietary intake and caloric compensation. However, T73T women had lower habitual energy and carbohydrate intakes than P73P. Differences in carbohydrate intakes disappeared when expressed in percentage of energy. These results suggest that the neuromedin-β p.P73T mutation modulates energy intake without effects on macronutrient. A lack of power resulting from our difficulty to recruit enough T73T women precludes any definitive conclusion regarding the impact of this mutation on caloric compensation.

The predictive value of IL28B gene polymorphism for spontaneous clearance in a single source outbreak cohort is limited in patients carrying the CCR5Δ32 mutation

The CCR5Δ32 mutation has been suspected to adversely affect outcomes of HCV infection, although reports have remained controversial. Here, we investigated the relative genetic contributions of the CCR5Δ32 deletion and the IL28B rs12979860 polymorphisms to spontaneous clearance of hepatitis C in a single-source outbreak. We retrieved 396 Caucasian women (119 women with spontaneous HCV clearance) who had been infected with HCV genotype 1-contaminated anti-D immunoglobulin in 1978, and determined their IL28B and CCR5 alleles. IL28B CC, CT, and TT genotypes were found in 35.4%, 50%, and 14.6% of patients and corresponded to spontaneous clearance rates of 50%, 21.2%, and 12.1% (Chi(2)=38.7, p=5.0×10(-10)), respectively. CCR5 WT/WT, WT/Δ32, and Δ32/Δ32 genotypes were observed in 76%, 22.7%, and 1.3% of patients and corresponded to clearance rates of 33.2%, 21.2%, and 0% (Chi(2)=6.9, p=0.009), respectively. In a stepwise forward-conditional multivariate regression model both CCR5 (OR 2.1, p=0.01 for WT/WT) and IL28B genetic variants (OR 4.3, p=4.6×10(-10) for the C/C genotype) were identified as independent predictors of spontaneous HCV clearance. Importantly, favorable response rates were associated with the IL28B CC genotype only in CCR5 wild-type homozygous women, while HCV clearance in CCR5Δ32 carriers remained poor even in patients with the rs12979860 CC genotype. Both IL28B rs1297860 and CCR5Δ32 allelic variants are independent genetic determinants of spontaneous HCV clearance. The variable relative distribution between IL28B rs1297860 and CCR5Δ32 allelic variants in different populations may have masked the role of the CCR5Δ32 mutation in some studies.

Geno‐ and phenotyping and immunogenicity of HNA‐3

Alloantibodies directed against the human neutrophil alloantigen (HNA)-3a are frequently implicated in severe and fatal transfusion-related acute lung injury (TRALI). The HNA-3a/3b system results from a single-nucleotide exchange (461G>A; Arg154Gln) in the choline transporter-like protein 2 gene. Genotyping may allow identification of blood donors at risk to develop HNA-3a antibodies. A polymerase chain reaction using sequence-specific primers (PCR-SSP) for genotyping of HNA-3a and -3b alleles was designed. Results of genotyping and phenotyping were compared in 40 randomly selected individuals and in blood donors and recipients of six TRALI cases associated with HNA-3a antibodies. Phenotyping was performed by granulocyte immunofluorescence and granulocyte agglutination using typing sera for HNA-3a and two recently found HNA-3b-reactive sera. Immunogenicity of HNA-3a was determined by the rate of HNA-3a alloantibodies in HNA-3b homozygous parous women. Genotyping and phenotyping results correlated to 100% and were in accordance with alloantibody formation and binding in HNA-3a antibody associated TRALI cases. Gene frequencies of HNA-3a and -3b were 0.792 and 0.207 in the German population with 64.1% homozygous individuals for the HNA-3a allele, 5.5% for the HNA-3b allele, and 30.4% heterozygous individuals, in accordance with the Hardy-Weinberg equilibrium and the gene frequencies of 0.819 and 0.181 reported in 1964. Immunization rates were estimated to be of 7% for HNA-3a and 0.5% for HNA-3b. The PCR-SSP method allows reliable determination of the HNA-3a and -3b genotypes; approximately 7% of HNA-3b homozygous women develop antibodies when exposed to the HNA-3a antigen during pregnancy.

A variant in the fibrillin-3 gene is associated with TGF-β and inhibin B levels in women with polycystic ovary syndrome

In an attempt to evaluate the association between allele 8 (A8) of D19S884 in the fibrillin-3 gene and circulating transforming growth factor (TGF) β and inhibin levels in women with polycystic ovary syndrome (PCOS), we studied 120 similarly aged women from families with PCOS and compared 40 women with PCOS who did not have A8 (A8- PCOS) with 40 women with PCOS who had A8 (A8+ PCOS) and 40 normally menstruating women who did not have either PCOS or A8 (A8- Non-PCOS). A8- PCOS is associated with higher levels of TGF-β1 compared with A8+ PCOS or A8- Non-PCOS, similar levels of TGF-β2 compared with A8+ PCOS but lower levels of TGF-β2 compared with A8- Non-PCOS, and lower levels of inhibin B and aldosterone compared with A8+ PCOS.

The G Protein 3 Subunit C825T Polymorphism Is Associated With Microalbuminuria in Hypertensive Women and Cardiovascular Disease in Hypertensive Men

The aim of the study was to examine the association between the G protein β3 subunit C825T polymorphism, associated with cardiovascular risk factors like hypertension (HT) and obesity and microalbuminuria (MA), reflecting the endothelial dysfunction in the atherosclerotic process. Second, we wanted to examine the association between the polymorphism and cardiovascular disease (CVD). In the large population-based, cross-sectional Nord-Trøndelag Health Study, HUNT 1995-1997, a total of 5,755 treated hypertensive individuals attended the MA substudy. A randomly selected sample of 1,000 of these was genotyped. A total of 402 men and 540 women were included in the final analyses. MA was measured as albumin/creatinine ratio (ACR) in three urine samples. Logistic regression was used to calculate odds ratios (ORs) for the association between MA or CVD and the genotype. The study demonstrated a positive association between the TT genotype and MA in women (OR 3.2, 95% confidence interval (CI): 1.1-8.7, P = 0.03), but not in men. The association became stronger with increasing number of positive urine samples and with increasing cutoff value in women with TT genotype compared to the CC genotype. Additionally, there was a positive association between TT genotype and CVD in men and postmenopausal women without hormone therapy. Increased MA in TT homozygous women might be explained by other mechanisms of albuminuria or inflammation than the atherosclerotic process. We postulate that the association between CVD and the genotype are mediated through mechanisms other than the classical risk factors and endothelial dysfunction, reflected by MA, which have to be further investigated.