Braj Pandey

Methylenetetrahydrofolate reductase (MTHFR) polymorphism A1298C (Glu429Ala) predicts decline in renal function over time in the African-American Study of Kidney Disease and Hypertension (AASK) Trial and Veterans Affairs Hypertension Cohort (VAHC)

BACKGROUND Hyperhomocysteinemia is associated with increased venous thrombosis and cardiovascular disease (CVD). Mutations in the human methylenetetrahydrofolate reductase (MTHFR) gene have been associated with increased homocysteine levels and risks of CVD in various populations including those with kidney disease. Here, we evaluated the influence of MTHFR variants on progressive loss of kidney function. METHODS We analyzed 821 subjects with hypertensive nephrosclerosis from the longitudinal National Institute of Diabetes and Digestive and Kidney Diseases African-American Study of Kidney Disease and Hypertension (AASK) Trial to determine whether decline in glomerular filtration rate (GFR) over ∼4.2 years was predicted by common genetic variation within MTHFR at non-synonymous positions C677T (Ala222Val) and A1298C (Glu429Ala) or by MTHFR haplotypes. The effect on GFR decline was then supported by a study of 1333 subjects from the San Diego Veterans Affairs Hypertension Cohort (VAHC), followed over ∼4.5 years. Linear effect models were utilized to determine both genotype [single-nucleotide polymorphism (SNP)] and genotype (SNP)-by-time interactions. RESULTS In AASK, the polymorphism at A1298C predicted the rate of GFR decline: A1298/A1298 major allele homozygosity resulted in a less pronounced decline of GFR, with a significant SNP-by-time interaction. An independent follow-up study in the San Diego VAHC subjects supports that A1298/A1298 homozygotes have the greatest estimated GFR throughout the study. Haplotype analysis with C677T yielded concurring results. CONCLUSION We conclude that the MTHFR-coding polymorphism at A1298C is associated with renal decline in African-Americans with hypertensive nephrosclerosis and is supported by a veteran cohort with a primary care diagnosis of hypertension. Further investigation is needed to confirm such findings and to determine what molecular mechanism may contribute to this association.

The VA Hypertension Primary Care Longitudinal Cohort: Electronic medical records in the post-genomic era

The Veterans Affairs Hypertension Primary Care Longitudinal Cohort (VAHC) was initiated in 2003 as a pilot study designed to link the VA electronic medical record system with individual genetic data. Between June 2003 and December 2004, 1,527 hypertensive participants were recruited. Protected health information (PHI) was extracted from the regional VA data warehouse. Differences between the clinic and mail recruits suggested that clinic recruitment resulted in an over-sampling of African Americans. A review of medical records in a random sample of study participants confirmed that the data warehouse accurately captured most selected diagnoses. Genomic DNA was acquired non-invasively from buccal cells in mouthwash; ~ 96.5 per cent of samples contained DNA suitable for genotyping, with an average DNA yield of 5.02 ± 0.12 micrograms, enough for several thousand genotypes. The coupling of detailed medical databases with genetic information has the potential to facilitate the genetic study of hypertension and other complex diseases.

Common Charge-Shift Mutation Glu65Lys in K+ Channel β1-Subunit KCNMB1: Pleiotropic Consequences for Glomerular Filtration Rate and Progressive Renal Disease

Background: Glomerular filtration rate (GFR) is a heritable trait, and hyperfiltration (GFR increment in remnant nephrons) may accelerate renal functional decline in chronic kidney disease (CKD). Mesangial and vascular smooth myocytes control GFR by contraction, dependent on voltage-gated Ca2+ influx, which is controlled by the regulatory β1-subunit (KCNMB1) of large-conductance heteromeric K+ (‘BK’) channels. KCNMB1 gain-of-function variant Glu65Lys results in generalized vasorelaxation and thus protection against systemic hypertension. Here we asked whether the Glu65Lys variant influences GFR, in the basal state or during progressive renal decline. Methods: We explored Glu65Lys effects on GFR in three populations spanning two ethnicities and two diseases (hypertension and nephrosclerosis). GFR was either estimated (eGFR from serum creatinine) or directly measured (iothalamate clearance). Results: The 65Lys variant was relatively common, occurring on ∼5–10% of chromosomes in different biogeographic ancestry groups, and 65Lys carriers exhibited higher eGFR in two primary care populations: extreme BP values in Kaiser clinics (p = 0.029, accounting for ∼0.2% of trait variance), or treated hypertensives in VA clinics (p = 0.017, accounting for ∼0.9% of trait variance). In blacks with progressive renal disease (NIDDK AASK), 65Lys carriers displayed a steeper slope in GFR chronic decline (p = 0.030, accounting for ∼0.4% of trait variance), and Glu65Lys genotype also predicted time of onset of renal failure (log rank p = 0.019). Conclusions: Common KCNMB1 gain-of-function variant Glu65Lys influences GFR, and 65Lys carriers exhibit not only elevated baseline GFR, but also more rapid GFR decline (and consequent development of renal failure) in CKD. The results suggest that profiling patients at Glu65Lys can assist in gauging renal prognosis as well as selection of rational therapy in hypertension with progressive renal disease.

Paraoxonase 1 (PON1) C/T-108 Association With Longitudinal Mean Arterial Blood Pressure

BACKGROUND Blood pressure is a complex quantitative trait with a strong genetic component. In this study, we leveraged the Veterans Affairs electronic medical record system to explore the relationship between Paraoxonase 1 (PON1)-108 C/T (rs705379) and mean arterial blood pressure (MAP). METHODS Outpatient blood pressure data over an approximate 8-year period was collected from the Veterans Affairs Hypertensive Cohort (N = 1,302). Association between genotype and longitudinal MAP was further explored using a random effects model controlling for age, ancestry, renal function, and other determinants of blood pressure. To control for population stratification, principal component groupings based on ancestry informative markers in this dataset were included as covariates (in addition to self-identified ancestry). Data from the African American Study of Kidney Disease and Hypertension (AASK, N = 857) was used to confirm significant findings in an independent cohort. RESULTS There was a significant interaction between PON1-108 C/T genotype and follow-up age group. At a younger age (<50 years), there was an estimated 2.53 mm Hg (95% confidence interval: 1.06, 4.00) increase in MAP with each additional C-allele. At the older age groups, there were no significant associations between PON1-108 C/T genotype and MAP. Using data from the AASK trial, the C-allele at PON1-108 C/T was significantly associated with a higher MAP (P = 0.005) but only among younger participants (<54 years). CONCLUSIONS The PON1-108 polymorphism may be associated with MAP in an age-dependent manner.

A Simple Dietary Questionnaire Correlates With Formal Dietitian Evaluation and Frequently Identifies Specific Clinical Interventions in an Outpatient Gastroenterology Clinic.

Background: The spectrum of gastroenterology-related diseases related to obesity is growing. Few clinical tools exist to aid in clinician-guided dietary counseling. Goals: (1) Develop and validate a 1-page diet history form that would provide information on dietary factors that can contribute to gastrointestinal (GI) illness and to assess adherence to the Mediterranean diet; and (2) evaluate the form in a general GI clinic to determine its potential utility as a clinical tool. Study: A 1-page diet history form was developed and underwent qualitative and quantitative validation in comparison to a formal diet evaluation by a registered dietitian. The form was then evaluated in consecutive patients attending a general GI clinic, and analyzed for overall diet content, compliance with a Mediterranean diet, and presence of high-risk (red flag) dietary behaviors. Results: The form was evaluated in 134 patients. In a validation cohort (n=30) the qualitative dietary components measured were highly concordant with a formal dietary interview. Total daily calorie intake correlated with formal dietary review (R=0.61), but tended to underestimate total calories due to less precision in portion size. The prospective cohort (n=104) patients had a mean body mass index of 29.8. Overall, 52.9% were obese, 50% had metabolic syndrome, and 51% had a primary GI illness directly impacted by dietary factors (gastroesophageal reflux, irritable bowel, fatty liver). Overall, 85.6% of patients documented red flag behaviors. Patients with obesity trended for more red flags than overweight or normal body mass index groups. Conclusion: A 1-page diet questionnaire correlated well with formal dietary assessment and identified clinically relevant dietary interventions in a high percentage of GI patients.

Embolic stroke complicating Staphylococcus aureus endocarditis circumstantially linked to rectal trauma from foreign body: a first case report

BackgroundDiagnostic and therapeutic instrumentation of the lower gastrointestinal tract has been reported to result in bacteremia and endocarditis. No such case has been reported in persons with a history of rectal foreign body insertion despite its potential for greater trauma.Case presentationA 58-year-old male was admitted with confusion and inability to speak. His past history was notable for hospitalization to extract a retained plastic soda bottle from the rectosigmoid two years prior. On examination, he was febrile, tachycardic and hypotensive. There was an apical pansystolic murmur on cardiac examination. He had a mixed receptive and expressive aphasia, and a right hemiparesis. On rectal examination he had perianal erythema and diminished sphincter tone. Magnetic resonance imaging of the brain showed infarction of the occipital and frontal lobes. Transesophageal Echocardiography of the heart revealed vegetations on the mitral valve. All of his blood culture bottles grew methicillin sensitive Staphylococcus aureus. He was successfully treated for bacterial endocarditis with intravenous nafcillin and gentamicin. The rectum is frequently colonized by Staphylococcus aureus and trauma to its mucosa can lead to bacteremia and endocarditis with this organism.In the absence of corroborative evidence such as presented here, it is difficult to make a correlation between staphylococcal endocarditis and anorectal foreign body insertion due to patients being less than forthcomingConclusionThere is a potential risk of staphylococcal bacteremia and endocarditis with rectal foreign body insertion. Further studies are needed to explore this finding. Detailed sexual history and patient counseling should be made a part of routine primary care.

Hyperventilation and vomiting due to posterior circulation stroke

Central neurogenic hyperventilation has been reported in brainstem infiltration by tumors1 but seldom with acute posterior stroke. Vomiting is frequent with such strokes2 but usually not associated with hyperventilation. We describe a patient with acute occlusive posterior stroke in whom the combination of hyperventilation and vomiting delayed diagnosis. A 54-year-old man with diabetes mellitus and hypertension had nausea and vomiting for 1 day. Clinical examination was normal except for elevation of blood pressure (189/95 mm Hg) and respiratory rate (20/min). Laboratory tests showed blood glucose level of 213 mg/dL and white blood count of 15,800/mm3 with 83% neutrophils. Chest and abdominal radiographs were negative. He was given IV saline and sent home with a diagnosis of gastroenteritis. The patient returned the next day with persistent vomiting, difficulty breathing, blurred vision, fever, and malaise. His respiration was 26/min. He was mentally alert but dysarthric. He had normal cranial nerves, normal motor examination, diminished pedal sensation and slowed hand coordination. Laboratory tests …