Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain.
We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis.
In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD.
The current evidence linking common mtDNA variations with AD is not compelling.
Host genetic factors exert significant influences on differential susceptibility to many infectious diseases. In addition, population structure of both host and parasite may influence disease distribution patterns. In this study, we assess the effects of population structure on infectious disease in two populations in which host genetic factors influencing susceptibility to parasitic disease have been extensively studied. The first population is the Jirel population of eastern Nepal that has been the subject of research on the determinants of differential susceptibility to soil-transmitted helminth infections. The second group is a Brazilian population residing in an area endemic for Trypanosoma cruzi infection that has been assessed for genetic influences on differential disease progression in Chagas disease. For measures of Ascaris worm burden, within-population host genetic effects are generally more important than host population structure factors in determining patterns of infectious disease. No significant influences of population structure on measures associated with progression of cardiac disease in individuals who were seropositive for T. cruzi infection were found.
population structure; genetics of infectious disease susceptibility; intestinal worms; Chagas disease
Rad50 ABC-ATPase complex with Mre11 nuclease is essential for dsDNA break repair, telomere maintenance, and ataxia telangiectasia mutated kinase checkpoint signaling. How Rad50 affects Mre11 functions, and how ABC-ATPases communicate nucleotide binding and ligand states across long distances and among protein partners, has remained obscure. Here, structures of Mre11–Rad50 complexes define the Mre11 2-helix Rad50 binding domain (RBD) that forms a 4-helix interface with Rad50 coiled-coils adjoining the ATPase core. Newly identified effector and basic-switch helix motifs extend the ABC-ATPase signature motif to link ATP-driven Rad50 movements to coiled-coils binding Mre11, implying a ~30 Å pull on the linker to the nuclease domain. Both RBD and basic-switch mutations cause clastogen sensitivity. Collective results characterize flexible ATP-dependent Mre11 regulation, defects in cancer-linked RBD mutations, conserved superfamily basic-switches and motifs effecting ATP-driven conformational change, and a unified comprehension of ABC-ATPase activities.
Objective: To examine the current attitudes towards the prevention of venous thromboembolism among a cohort of surgeons.
Design: A postal survey, comprising a questionnaire covering various aspects of venous thromboembolism prophylaxis was sent to all (n=84) consultant general surgeons in Wales.
Results: Replies were received from 57 surgeons (68%), all of whom routinely used prophylaxis, the most frequent modalities used being heparin (100%) and graded compression stockings (79%). A combination of physical and pharmacological methods was used by over 89% of surgeons, with 60% starting prophylaxis more than two hours before operation. All surgeons continued prophylaxis after surgery, 53% until patients were mobile, 45% until they were discharged, and one surgeon continued prophylaxis for seven days after discharge. The thrombosis risk factors considered most important by surgeons when deciding about prophylaxis were (i) a previous history of venous thromboembolism, (ii) hypercoagulability, and (iii) malignancy.
Conclusions: This study confirms that Welsh surgeons conform to standard methods, but also highlights some uncertainties that are present in current surgical practice. Those who responded all routinely used prophylaxis, the timing of which was variable. The main risk factors identified when considering prophylaxis were previous history of deep vein thrombosis/pulmonary embolism, hypercoagulability, and the presence of malignancy. Suggestions for future practice are made.
Aim—To determine interobserver and intra-observer agreement in the assessment of cytological grade and intraduct necrosis in pure duct carcinoma in situ (DCIS) of the breast.
Methods—Sixty unselected cases with illustrated diagnostic criteria were circulated to 19 practising histopathologists.
Results—Overall agreement was moderate for cytological grade in three categories: 71% agreement; weighted κ (κw), 0.36; intraduct necrosis in three categories (absent, present, extensive): 76% agreement; κw, 0.57; and the Van Nuys classification system: 73% agreement; κw, 0.48. Agreement was no better among observers participating in the National External Quality Assurance Programme. Intra-observer agreement for cytological assessment (69.6% agreement; κw, 0.52) and intraduct necrosis (68.3% agreement; κw, 0.48) was moderate, suggesting that individual variation rather than precision of criteria contributes to the lack of agreement.
Conclusions—Moderate agreement on observations can be achieved by non-specialist pathologists, with better agreement on necrosis than cytological grade. There was evidence of consistent individual bias towards over or under scoring cytological grade, which could be corrected with adequate and prompt feedback.
Key Words: classification • duct carcinoma in situ • breast • intraduct necrosis
OBJECTIVES: To describe the presentation, pathology, and outcome of biopsy proved renal disease in HIV infected patients at a central London HIV unit from 1992 to 1996. METHODS: Retrospective review of a computerised database and case notes to identify patients with renal disease confirmed by antemortem percutaneous renal biopsy or necropsy. RESULTS: 17 patients were identified, 13 had biopsy and four necropsy confirmed renal disease. Abnormalities included HIV associated nephropathy (HIVAN) in seven (41%) patients, membranous glomerulonephritis (GN) in four (23%), haemolytic uraemic syndrome (HUS) in two (12%), and interstitial nephritis, rhabdomyolysis, IgA nephropathy, and membranoproliferative GN in one patient each. Although renal disease was the first presentation of HIV disease in six (35%) patients the majority had advanced HIV disease (median CD4 count 40 x 10(6)/l). The commonest presentation was acute renal failure (ARF) in 10 (59%) patients, chronic renal failure (CRF) in five (29%), and proteinuria alone in two (12%). Although the majority of patients died during the study period (9/13) only three deaths were attributable to their renal disease. Survival ranged in those with HIVAN from 0 to 31 (median 10) months and, in those with membraneous GN from 1 to 46 (median 29) months. CONCLUSIONS: HIVAN was the commonest renal disease found in this group of patients; however, a variety of other pathologies were seen with variable outcomes. All cases of HIVAN were in patients of African or Afro-Caribbean origin and for the majority this was their first presentation of HIV disease. Nephrologists need to be aware of the possibility of HIV infection in patients presenting with renal disease.
Technetium labelled, negatively charged, unilamellar liposomes were given by intravenous injection to patients with rheumatoid arthritis and the joints scanned 20-22 hours later. Positive scintigraphy was obtained in all six patients with active disease, and, with the exception of the small interphalangeal joints, all clinically involved joints could be visualised.
BACKGROUND AND PURPOSE
Excess morbidity/mortality in rheumatoid arthritis (RA) is associated with increased incidence of cardiovascular disease. In this ‘proof-of-concept’ study, vascular function was characterized in the murine collagen-induced arthritis (mCIA) model, the benchmark choice for evaluation of the pathological processes and assessment of new therapies.
Mice in the very early stages of arthritis development [and appropriate naïve (non-immunized) age-matched controls] were used in the study. Blood pressure was measured using tail cuff plethysmography. Vascular function in rings of isolated aorta was studied with isometric tension myography. Levels of NO metabolites (NOx), MMP-9 protein and IL-1β in plasma and MMP-9 protein in aortic homogenates were quantified.
Impaired vascular contractile responses in arthritis were unaffected by ex vivo inhibition of NOS (endothelial/neuronal and inducible) or COX activities. Endothelium-dependent and -independent relaxation, plasma NOx and blood pressure were unaffected by arthritis. Plasma and aortic homogenate MMP-9 protein levels were increased significantly in arthritis. Incubation of aortic tissues from naïve control animals with exogenous MMP-9 impaired subsequent contractile responses, mirroring that observed in arthritis. A role for IL-1β in perpetuating contractile dysfunction and increasing aortic MMP-9 was excluded.
CONCLUSIONS AND IMPLICATIONS
These data identify for the first time a relationship between early arthritis and contractile dysfunction and a possible role for MMP-9 therein, in the absence of overt endothelial dysfunction or increased NO production. As such, MMP-9 may constitute a significant target for early intervention in RA patients with a view to decreasing risk of cardiovascular disease.
arthritis; cardiovascular disease; aorta: contractile dysfunction; matrix metalloproteinase 9
The relationship between the TCR repertoires of natural regulatory T (nTreg) and conventional T (Tconv) cells capable of responding to the same antigenic epitope is unknown. Here, we used TCRβ-chain transgenic mice to generate polyclonal nTreg and Tconv cell populations specific for a foreign antigen. CD4+ T cells from immunized 3.L2β+/− TCRα+/−
Foxp3EGFP mice were re-stimulated in culture to yield nTreg cells (EGFP+) and Tconv cells (EGFP−) defined by their antigenic reactivity. Relative to Tconv cells, nTreg cell expansion was delayed, although a higher proportion of viable nTreg cells had divided after 72 hours. Spectratype analysis revealed that both the nTreg and Tconv cell responses were different and characterized by skewed distributions of CDR3 lengths. CDR3 sequences from nTreg cells displayed a divergent pattern of Jα usage, minimal CDR3 overlap (3.4%), and less diversity than CDR3 sequences derived from Tconv cells. These data indicate that foreign antigen-specific nTreg and Tconv cells are clonally distinct, and that foreign antigen-specific nTreg cells populations are constrained by a limited TCR repertoire.
The clinical course and eventual outcome, or prognosis, of complex diseases varies enormously between affected individuals. This variability critically determines the impact a disease has on a patient’s life but is very poorly understood. Here, we exploit existing genome-wide association study data to gain insight into the role of genetics in prognosis. We identify a noncoding polymorphism in FOXO3A (rs12212067: T > G) at which the minor (G) allele, despite not being associated with disease susceptibility, is associated with a milder course of Crohn’s disease and rheumatoid arthritis and with increased risk of severe malaria. Minor allele carriage is shown to limit inflammatory responses in monocytes via a FOXO3-driven pathway, which through TGFβ1 reduces production of proinflammatory cytokines, including TNFα, and increases production of anti-inflammatory cytokines, including IL-10. Thus, we uncover a shared genetic contribution to prognosis in distinct diseases that operates via a FOXO3-driven pathway modulating inflammatory responses.
•Reanalysis of GWAS data identifies a SNP associated with outcome in Crohn’s disease•This SNP modulates inflammatory responses in monocytes via a FOXO3-driven pathway•The mild disease-associated allele reduces TNFα and increases IL-10 production•Prognosis in RA and malaria (also TNFα-related diseases) is also linked to this SNP
An analysis of GWAS data of patients with Crohn’s disease distinguishes SNPs associated with disease risk from those associated with outcome. Functional studies indicate that a noncoding SNP associated with FOXO3A influences a cytokine inflammatory pathway that impacts outcome, not only in Crohn’s but also other diseases such as rheumatoid arthritis and malaria.
Aldosterone (ALDO), a critical regulator of sodium homeostasis, mediates its effects via activation of the mineralocorticoid receptor (MR) through mechanisms that are not entirely clear. Striatin, a membrane associated protein, interacts with estrogen receptors in endothelial cells.
We studied the effects of MR activation in vitro and in vivo on striatin levels in vascular tissue.
We observed that dietary sodium restriction was associated with increased striatin levels in mouse heart and aorta and that striatin and MR are present in the human endothelial cell line, (EA.hy926), and in mouse aortic endothelial cells (MAEC). Further, we show that MR co-precipitates with striatin in vascular tissue. Incubation of EA.hy926 cells with ALDO (10−8 mol/l for 5–24 h) increases striatin protein and mRNA expression, an effect that was inhibited by canrenoic acid, an MR antagonist. Consistent with these observations, incubation of MAEC with ALDO increased striatin levels that were likewise blocked by canrenoic acid. To test the in vivo relevance of these findings, we studied two previously described mouse models of increased ALDO levels. Intraperitoneal ALDO administration augmented the abundance of striatin protein in mouse heart. We also observed that in a murine model of chronic ALDO-mediated cardiovascular damage following treatment with NG-nitro-L-arginine methyl ester plus angiotensin II an increased abundance of striatin protein in heart and kidney tissue.
Our results provide evidence that increased striatin levels is a component of MR activation in the vasculature and suggest that regulation of striatin by ALDO may modulate estrogen’s nongenomic effects.
aldosterone; angiotensin; animal physiology; antagonists; blood pressure; endothelial cells; heart tissue; hypertension; inflammation; L-NAME; mineralocorticoid receptor; RAAS
Aberrant regulation of the erythroblastosis oncogene B (ErbB) family of receptor tyrosine kinases (RTKs) and their ligands is common in human cancers. ErbB3 is required in luminal mammary epithelial cells (MECs) for growth and survival. Since breast cancer phenotypes may reflect biological traits of the MECs from which they originate, we tested the hypothesis that ErbB3 drives luminal breast cancer growth. We found higher ERBB3 expression and more frequent ERBB3 gene copy gains in luminal A/B breast cancers compared with other breast cancer subtypes. In cell culture, ErbB3 increased growth of luminal breast cancer cells. Targeted depletion of ErbB3 with an anti-ErbB3 antibody decreased 3D colony growth, increased apoptosis, and decreased tumor growth in vivo. Treatment of clinical breast tumors with the antiendocrine drug fulvestrant resulted in increased ErbB3 expression and PI3K/mTOR signaling. Depletion of ErbB3 in fulvestrant-treated tumor cells reduced PI3K/mTOR signaling, thus decreasing tumor cell survival and tumor growth. Fulvestrant treatment increased phosphorylation of all ErbB family RTKs; however, phospho-RTK upregulation was not seen in tumors treated with both fulvestrant and anti-ErbB3. These data indicate that upregulation of ErbB3 in luminal breast cancer cells promotes growth, survival, and resistance to fulvestrant, thus suggesting ErbB3 as a target for breast cancer treatment.
To examine family caregiver involvement for long-term care (LTC) residents during the
last month of life. Researchers examined direct (personal care and meals) and indirect
(management and monitoring) types of caregiver involvement and the relationship between
the type of involvement and predisposing, enabling, and need characteristics.
Researchers also examined whether the frequency of involvement changed during the
end-of-life (EOL) period.
Researchers used an expanded version of Andersen’s Behavioral Model to
conceptualize predictors of family involvement for 438 residents in 125 residential
care/assisted living and nursing home settings. Bivariate and multivariate analyses
examined relationships among variables.
More than one-half of family caregivers monitored, managed care and assisted with
meals, and 40% assisted with personal care tasks. The enabling characteristic of days
visited and the need characteristic of caregiver role strain were related to each of the
4 types of involvement. However, the other correlates were distinct to the type of
Families are involved in EOL care in LTC settings. Higher role strain is related to
more involvement in each of the 4 types of involvement, suggesting that whether
involvement is by desire, perceived need, or both, there is cause to more critically
examine the family caregiver’s desired role and need for support.
Long-term care facilities; Family caregiver involvement; End of life.
Microsporidia are obligate intracellular parasites with the smallest known eukaryotic genomes. Although they are increasingly recognized as economically and medically important parasites, the molecular basis of microsporidian pathogenicity is almost completely unknown and no genetic manipulation system is currently available. The fish-infecting microsporidian Spraguea lophii shows one of the most striking host cell manipulations known for these parasites, converting host nervous tissue into swollen spore factories known as xenomas. In order to investigate the basis of these interactions between microsporidian and host, we sequenced and analyzed the S. lophii genome. Although, like other microsporidia, S. lophii has lost many of the protein families typical of model eukaryotes, we identified a number of gene family expansions including a family of leucine-rich repeat proteins that may represent pathogenicity factors. Building on our comparative genomic analyses, we exploited the large numbers of spores that can be obtained from xenomas to identify potential effector proteins experimentally. We used complex-mix proteomics to identify proteins released by the parasite upon germination, resulting in the first experimental isolation of putative secreted effector proteins in a microsporidian. Many of these proteins are not related to characterized pathogenicity factors or indeed any other sequences from outside the Microsporidia. However, two of the secreted proteins are members of a family of RICIN B-lectin-like proteins broadly conserved across the phylum. These proteins form syntenic clusters arising from tandem duplications in several microsporidian genomes and may represent a novel family of conserved effector proteins. These computational and experimental analyses establish S. lophii as an attractive model system for understanding the evolution of host-parasite interactions in microsporidia and suggest an important role for lineage-specific innovations and fast evolving proteins in the evolution of the parasitic microsporidian lifecycle.
Microsporidia are unusual intracellular parasites that infect a broad range of animal cells. In comparison to their fungal relatives, microsporidian genomes have shrunk during evolution, encoding as few as 2000 proteins. This minimal molecular repertoire makes them a reduced model system for understanding host-parasite interactions. A number of microsporidian genomes have now been sequenced, but the lack of a system for genetic manipulation makes it difficult to translate these data into a better understanding of microsporidian biology. Here we present a deep sequencing project of Spraguea lophii, a fish-infecting microsporidian that is abundantly available from environmental samples. We use our sequence data combined with germination protocols and complex-mix proteomics to identify proteins released by the cell at the earliest stage of germination, representing potential pathogenicity factors. We profile the RNA expression pattern of germinating cells and identify a set of highly transcribed hypothetical genes. Our study provides new insight into the importance of uncharacterized, lineage-specific and/or fast evolving proteins in microsporidia and provides new leads for the investigation of virulence factors in these enigmatic parasites.
The objectives of this study were to examine the relationship between selected decedent and caregiver characteristics, facility-related perceptions, and emotional and physical health of 434 informal caregivers (94% family) of recently deceased residents of residential care/assisted living facilities and nursing homes. We also examined potential mediating effects of social support (informal, staff, and spiritual).
We analyzed data using linear mixed models.
Among caregivers, younger age, female gender, more education, financial burden, other dependents, poorer perceptions of care, and more care involvement were associated with more emotional strain. More staff support also was associated with more emotional strain and partially mediated the relationship between having a trusted staff member and emotional strain. Characteristics associated with poorer physical health included unemployment, financial burden, poorer physician communication, and trusted staff member. Informal social support was directly related to better physical health and mediated the relationships between physical health and both physician communication and financial burden.
Many characteristics related to end-of-life caregiving outcomes in long-term care are consistent with community-based studies, suggesting that end-of-life caregiving outcomes in long-term care are not markedly different than in other settings. However, the role of staff support may either facilitate or complicate emotional strain and merits additional study.
End of life; Long-term care facilities; Social support; Emotional and physical health
Hypertension represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP).
Animal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type and LSD-1 heterozygote knockout (LSD-1+/−) mice. Clinical relevance was tested by multivariate associations between single nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African-American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American).
LSD1 expression was modified by dietary salt in wild-type mice with lower levels associated with liberal salt intake. LSD-1+/− mice expressed lower LSD-1 protein levels than wild-type mice in kidney tissue. Similar to LSD-1+/− mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP in response to change from low to liberal salt diet (rs671357, p=0.01; rs587168, p=0.005). This association was replicated in the Hispanic (rs587168, p=0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1+/− mice, decreased alpha-EnaC expression in LSD-1+/− mice, and impaired renovascular responsiveness to salt loading in minor allele carriers.
The results of this translational research study support a role for LSD1 in the pathogenesis of salt-sensitive hypertension.
Hypertension; Salt-sensitivity; LSD1; Genetics; Epigenetic
Nurse-led clinics are an increasingly used resource in managing postoperative patients and meeting their clinical needs. Since 2007, St James' University Hospital has run a ward-based nurse-led clinic; providing follow-up and management of patients after thoracic surgery. We aimed to assess patient satisfaction with the clinic's ability to manage their postoperative needs. Data were collected prospectively from patients attending the clinic between July and August 2010 using structured patient questionnaires. We evaluated 83 patient feedback questionnaires. The reasons for clinic attendance were predominantly wound assessment and chest drain review. Fifty-four (65%) patients were managed without seeing a doctor, of whom only four (7%) believed seeing a doctor would have been beneficial. Seventy-three (88%) patients stated their needs were met in the clinic and 82 (99%) patients described the overall care they received as good, very good or excellent. This survey highlights that patients are satisfied with a nurse-led service and will hopefully help encourage the development of such services within thoracic surgery.
Nurse-led clinic; Patient satisfaction; Thoracic surgery
To determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.
Resistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list.
Four hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84–3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P < 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P < 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience.
Viral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.
HIV; drug resistance mutations; naive patients; protease inhibitors; virological failure
Thioredoxin glutathione reductase from Schistosoma mansoni (SmTGR) catalyzes the reduction of both thioredoxin and glutathione disulfides (GSSG), thus playing a crucial role in maintaining redox homeostasis in the parasite. In line with this role, previous studies have demonstrated that SmTGR is a promising drug target for schistosomiasis. To aid in the development of efficacious drugs that target SmTGR, it is essential to understand the catalytic mechanism of SmTGR. SmTGR is a dimeric flavoprotein in the glutathione reductase family and it has a head-to-tail arrangement of its monomers; each subunit has the components of both a thioredoxin reductase (TrxR) domain and a glutaredoxin (Grx) domain. However, the active site of the TrxR domain is composed of residues from both subunits: FAD and a redox-active Cys-154/Cys-159 pair from one subunit and a redox-active Cys-596′/Sec-597′ pair from the other; the active site of the Grx domain contains a redox-active Cys-28/Cys-31 pair. Via its Cys-28/Cys-31 dithiol and/or its Cys-596′/Sec-597′ thiol-selenolate, SmTGR can catalyze the reduction of a variety of substrates by NADPH. It is presumed that SmTGR catalyzes deglutathionylation reactions via the Cys-28/Cys-31 dithiol. Our anaerobic titration data suggest that reducing equivalents from NADPH can indeed reach the Cys-28/Cys-31 disulfide in the Grx domain to facilitate reductions effected by this cysteine pair. To clarify the specific chemical roles of each redox-active residue with respect to its various reactivities, we generated variants of SmTGR. Cys-28 variants had no Grx glutathionylation activity whereas Cys-31 variants retained partial Grx glutathionylation activity, indicating that the Cys-28 thiolate is the nucleophile initiating deglutathionylation. Lags in the steady-state kinetics, found when wild-type (WT) SmTGR was incubated at high concentrations of GSSG, were not present in Grx variants, indicating that this cysteine pair is in some way responsible for the lags. A Sec-597 variant was still able to reduce a variety of substrates, albeit slowly, showing that selenocysteine is important but is not the sole determinant for the broad substrate tolerance of the enzyme. Our data show that Cys-520 and Cys-574 are not likely to be involved in the catalytic mechanism.
Previously, we reported that estrogen receptor alpha mRNA (Esr1) or protein (ESR1) overexpression resulting from neonatal exposure to estrogens in rats was associated with infertility and mal-developed penis characterized by reduced length and weight and abnormal accumulation of fat cells. The objective of this study was to determine if mutant male mice overexpressing Esr1 are naturally infertile or have reduced fertility and/or develop abnormal penis. The fertility parameters, including fertility and fecundity indices, numbers of days from the day of cohabitation to the day of delivery, and numbers of pups per female, were not altered from controls, as a result of Esr1 overexpression. Likewise, penile morphology, including the length, weight, and diameter and os penis development, was not altered from controls. Conversely, weights of the seminal vesicles and bulbospongiosus and levator ani (BS/LA) muscles were significantly (P < 0.05) lower as compared to controls; however, the weight of the testis, the morphology of the testis and epididymis, and the plasma and testicular testosterone concentration were not different from controls. Hence, the genetically-induced Esr1 overexpression alone, without an exogenous estrogen exposure during the neonatal period, is unable to adversely affect the development of the penis as well as other male reproductive organs, except limited, but significant, reductions in weights of the seminal vesicles and BS/LA muscles.
Esr1 overexpression; mutant mice; fertility; penis; testis; seminal vesicles
Insulin resistance (IR) is a complex disorder caused by an interplay of both genetic and environmental factors. Recent studies identified a significant interaction between body mass index (BMI) and the rs1800795 polymorphism of the Interleukin-6 (IL-6) gene that influences both IR and onset of type 2 diabetes mellitus (T2DM) with obese individuals homozygous for the C allele demonstrating the highest level of IR and greatest risk for T2DM. Replication of a gene-environment interaction is important to confirm the validity of the initial finding and extends the generalizability of the results to other populations. Thus, the objective of this study was to replicate this gene-environment interaction on IR in a hypertensive population and perform a meta-analysis with prior published results.
Material and Methods
The replication analysis was performed using Caucasian individuals with hypertension (HTN) from the HyperPATH cohort (N=311), genotyped for rs1800795. Phenotype studies were conducted after participants consumed two diets: high sodium (HS) (200mmol/day) and low sodium (LS) (10mmol/day) for 7 days each. Measurements for plasma glucose, insulin, and IL-6 were obtained after 8 hours of fasting. IR was characterized by the homeostatic model assessment (HOMA-IR).
In HyperPATH, BMI was a significant effect modifier of the relationship between rs1800795 and HOMA-IR; higher BMI was associated with higher HOMA-IR among homozygote CC individuals when compared to major allele G carriers (p=0.003). Further, the meta-analysis in 1028 individuals confirmed the result demonstrating the same significant interaction between rs1800795 and BMI on HOMA-IR (p=1.05×10−6).
This rare replication of a gene-environment interaction extends the generalizability of the results to HTN while highlighting this polymorphism as a marker of IR in obese individuals.
Interleukin-6 gene; Hypertension; Obesity; Insulin Resistance