Biomedical subjects

Robert E Ferrell

Publications and source records attributed to Robert E Ferrell.

At least 19 recordsLinked to original sources

PubMed2006

Human adaptive evolution at Myostatin (GDF8), a regulator of muscle growth.

Myostatin (GDF8) is a negative regulator of muscle growth in mammals, and loss-of-function mutations are associated with increased skeletal-muscle mass in mice, cattle, and humans. Here, we show that positive natural selection has acted on human nucleotide variation at GDF8, since the observed ratio of nonsynonymous:synonymous changes among humans is significantly greater than expected under the neutral model and is strikingly different from patterns observed across mammalian orders. Furthermore, extended haplotypes around GDF8 suggest that two amino acid variants have been subject to recent positive selection. Both mutations are rare among non-Africans yet are at frequencies of up to 31% in sub-Saharan Africans. These signatures of selection at the molecular level suggest that human variation at GDF8 is associated with functional differences.

Adaptation, Physiological↗

PubMed2006

CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses.

Age-related maculopathy (ARM) is an important cause of visual impairment in the elderly population. It is of crucial importance to identify genetic factors and their interactions with environmental exposures for this disorder. This study was aimed at investigating the CFH, ELOVL4, PLEKHA1 and LOC387715 genes in independent cohorts collected using different ascertainment schemes. The study used a case-control design with subjects originally recruited through the Cardiovascular Health Study (CHS) and the Age-Related Eye Disease Study (AREDS). CFH was significantly associated with ARM in both cohorts (P</=0.00001). A meta-analysis confirmed that the risk allele in the heterozygous or homozygous state (OR, 2.4 and 6.2; 95% CI, 2.2-2.7 and 5.4-7.2, respectively) confers susceptibility. LOC387715 was also significantly associated with ARM in both cohorts (P</=0.00001) and a meta-analysis confirmed that the risk allele in the heterozygous and homozygous state (OR, 2.5 and 7.3; 95% CI, 2.2-2.9 and 5.7-9.4, respectively) confers susceptibility. Both CFH and LOC387715 showed an allele-dose effect on the ARM risk, individuals homozygous at either locus were at more than two-fold risk compared to those heterozygous. PLEKHA1, which is closely linked to LOC387715, was significantly associated with ARM status in the AREDS cohort, but not the CHS cohort and ELOVL4 was not significantly associated with ARM in either cohort. Joint action of CFH and LOC387715 was best described by independent multiplicative effect without significant interaction in both cohorts. Interaction of both genes with cigarette smoking was insignificant in both cohorts. This study provides additional support for the CFH and LOC387715 genes in ARM susceptibility via the evaluation of cohorts that had different ascertainment schemes regarding ARM status and through the meta-analyses.

Aged↗

PubMed2006

Identifying genetic susceptibilities to diabetes-related complications among individuals at low risk of complications: An application of tree-structured survival analysis.

The authors hypothesized that genetic predisposition to diabetes complications would be more evident among low-risk individuals and aimed to identify genes related to developing complications (confirmed distal symmetric polyneuropathy, overt nephropathy, or coronary artery disease) in low-risk groups. Participants in the Pittsburgh, Pennsylvania, Epidemiology of Diabetes Complications Study of childhood-onset type 1 diabetes, first seen in 1986-1988 (mean age, 28 years; diabetes duration, 19 years), were reexamined biennially for 10 years. For each complication, subgroups with the lowest disease risk were identified by using tree-structured survival analysis, and 15 candidate genes were compared between subjects with and without complications. In the group with the lowest incidence of confirmed distal symmetric polyneuropathy (n = 123), confirmed distal symmetric polyneuropathy risk increased fivefold for those with the eNOS GG genotype (p < 0.05). In the group with the lowest risk of overt nephropathy (n = 340), the ACE D polymorphism increased overt nephropathy risk twofold (p = 0.05), whereas a protective effect was observed for the LIPC CC genotype (p < 0.05). In the group with the lowest incidence of coronary artery disease (n = 331), the MTHFR CC genotype increased coronary artery disease risk threefold (p < 0.05). Tree-structured survival analysis may help identify genetic predispositions among individuals who, despite low risk, develop diabetes-related complications.

Adult↗

PubMed2006

Human choline transporter gene variation is associated with corticolimbic reactivity and autonomic-cholinergic function.

BACKGROUND: Our previous work has shown genetic variation in the human choline transporter gene (CHT1) to be associated with depressive symptoms and autonomic cardiac (cholinergic) dysregulation. Here, functional magnetic resonance imaging (fMRI) was used to examine the relation between a single nucleotide polymorphism (SNP) in CHT1 on regional brain reactivity relevant to autonomic (cholinergic) function. METHODS: Thirty-two participants of European ancestry (18 men, 14 women; age: 33-54 years) completed an fMRI protocol using corticolimbic reactivity and prefrontal inhibitory control paradigms. Resting cholinergic function, as measured by heart rate variability (HRV), was quantified from electrocardiogram. Subjects were genotyped for a CHT1 G/T SNP. RESULTS: GG homozygotes had greater right (R) dorsal amygdala (p < .008), bilateral anterior cingulate (p < .009), and R caudate reactivity (p < .015) than T-allele carriers. Heart rate variability was related to R frontal cortex (Brodmann Areas 6, 9, and 46), R hippocampal formation, bilateral caudate, and bilateral anterior cingulate reactivity (p's < .007). CONCLUSIONS: CHT1 variation is related to differences in a distributed corticolimbic circuitry mediating behavioral and physiologic arousal. These relations may contribute to a biological mechanism by which genetic variation in cholinergic neurotransmission affects cognition, mood, and autonomic cardiac function.

Adult↗

PubMed2006

Peroxisome proliferator-activated receptor-gamma polymorphism, body mass and prostate cancer risk: evidence for gene-environment interaction.

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-gamma has been implicated in prostate cancer. In the present case-control study, we tested if a common Pro12Ala polymorphism in PPAR-gamma is associated with the risk of prostate cancer. METHODS: Ninety-one adult Caucasians with prostate cancer were recruited between 1994 and 1998. Blood samples were also obtained from 237 community-based Caucasian men without prostate cancer. RESULTS: Twenty-six percent of cases and 19% of controls carried at least one Ala allele (p = 0.16). There was a significant interaction between the PPAR-gamma polymorphism and body mass index (BMI) in age-adjusted analyses (p < 0.05). Among the subgroup of men with BMI above 27.2 kg/m2 (median in controls), carriers of the Ala allele had over 2-fold greater risk of prostate cancer compared to those with the Pro12Pro genotype (odds ratio, OR: 2.77; 95% confidence interval, CI: 1.25-6.16). No association was observed between the PPAR-gamma genotype and prostate cancer among men with BMI below the median (OR: 0.68; 95% CI: 0.23-1.97). CONCLUSIONS: Our results suggest a novel gene-environment interaction between the PPAR-gamma Pro12Ala polymorphism and body mass in prostate cancer. Further research, particularly prospective studies, is needed to confirm these findings and to clarify the underlying mechanisms involved.

Adult↗

PubMed2006

AMPD1 gene polymorphism and the vasodilatory response to ischemia.

Peripheral vasculature resistance can play an important role in affecting blood pressure and the development of cardiovascular disease. A better understanding of the genes that encode vasodilators, such as adenosine, will provide insight into the mechanisms underlying cardiovascular disease. We tested whether the adenosine monophosphate deaminase-1 (AMPD1) C34T gene polymorphism was associated with the vasodilatory response to ischemia in Caucasian females aged 18-35 years. Blood samples (n = 58) were analyzed for the C34T variant and resulted in the following genotype groups: CC (n = 45) and CT (n = 13). Mean blood pressure (MBP), heart rate, and forearm blood flow (FBF) measured by venous occlusion plethysmography were measured at baseline and at 1 (peak FBF), 2 and 3 min of vasodilation during reactive hyperemia following 5 min of arm ischemia. To control for interindividual variability in baseline FBF and forearm vascular resistance (FVR) the percent change in FBF and FVR were calculated for each min. The percent decrease in FVR was significantly greater in the CT compared to the CC genotype group (-40+/-4% vs. -24+/-3%, P = 0.01) during the 2nd min of reactive hyperemia. The percent increase in FBF tended to be greater in the CT compared to the CC genotype group (+69+/-9% vs. +42+/-9%, P = 0.07) during the 2nd min of reactive hyperemia after adjustment for percent body fat. Consistent with previous findings of increased production of adenosine during exercise in individuals carrying a T allele, our findings suggest that the AMPD1 C34T polymorphism is associated with vasodilatory response to ischemia in the peripheral vasculature because individuals with the T allele had a greater vasodilatory response to ischemia.

AMP Deaminase↗

PubMed2006

Simple tandem repeat (TTTA)n polymorphism in CYP19 (aromatase) gene and breast cancer risk in Nigerian women.

BACKGROUND: Breast cancer is the most common cancer and the leading cause of cancer related deaths in women worldwide. The incidence of the disease is increasing globally and this increase is occurring at a faster rate in population groups that hirtherto enjoyed low incidence. This study was designed to evaluate the role of a simple tandem repeat polymorphism (STRP) in the aromatase (CYP19) gene in breast cancer susceptibility in Nigerian women, a population of indigenous sub-Saharan African ancestry. METHODS: A case-control study recruiting 250 women with breast cancer and 250 women without the disease from four University Teaching Hospitals in Southern Nigeria was carried out between September 2002 and April 2004. Participants were recruited from the surgical outpatient clinics and surgical wards of the Nigerian institutions. A polymerase chain reaction (PCR)-based assay was employed for genotyping and product sizes were detected with an ABI 3730 DNA Analyzer. RESULTS: Conditional logistic regression analysis revealed that harboring the putative high risk genotypes conferred a 29% increased risk of breast cancer when all women in the study were considered (Odds ratio [OR] = 1.29, 95% confidence interval [CI] 0.83-2.00), although this association was not statistically significant. Subgroup analysis based on menopausal status showed similar results among premenopausal women (OR = 1.35, 95% CI 0.76-2.41 and postmenopausal women (OR = 1.27, 95% CI 0.64-2.49). The data also demonstrated marked differences in the distribution of (TTTA)n repeats in Nigerian women compared with other populations. CONCLUSION: This study has shown that harboring 10 or more repeats of the microsatellite (TTTA)n repeats of the CYY19 gene is associated with a modest increased risk of breast cancer in Nigerian women.

Journal Article↗

PubMed2006

Decreased STAT1 expression by promoter methylation in squamous cell carcinogenesis.

BACKGROUND: Dysregulation of signal transducers and activators of transcription (STATs) is associated with many cancers, but no role of STAT1 in human tumor progression has been demonstrated. METHODS: We compared STAT1 protein expression in squamous cell carcinoma of the head and neck (SCCHN) tumors (n = 28) and normal oropharyngeal mucosa samples (n = 10) from patients without cancer as assessed by immunoblotting. Stable clones were established from SCCHN 1483 cells that were transfected with a STAT1 expression construct; cell growth and cisplatin-induced apoptosis of the clones and vector control-transfected 1483 cells were compared using trypan blue exclusion and Annexin V staining and expression of the cyclin-dependent kinase inhibitor p21 was assayed by immunoblotting. The growth of STAT1-overexpressing SCCHN 1483 xenograft tumors was compared with that of xenograft tumors derived from cells transfected with vector control DNA. DNA from SCCHN tumors (n = 16) and paired peripheral blood lymphocytes were analyzed for STAT1 mutations and promoter methylation using methylation-specific polymerase chain reaction and bisulfite sequencing. SCCHN cell lines (PCI-15b, 1483, and UM-22B) were treated with the demethylating agent azacytidine alone or in combination with the cytotoxic drug cisplatin, and expression of STAT1 and p21 were monitored by immunoblotting. All statistical tests were two-sided. RESULTS: STAT1 levels were statistically significantly lower in the SCCHN tumors than normal mucosa (median = 0.8 relative units versus 2.4, difference = 1.6, 95% confidence interval [CI] = 1.3 to 2.0, P < .001). Overexpression of STAT1 abrogated the growth of SCCHN cells and xenograft tumors and increased p21 expression. STAT1 expression levels of the tumors with STAT1 promoter methylation (n = 12) were lower than those of tumors (n = 4) without promoter methylation of STAT1 (P = .008). Azacytidine treatment increased expression of STAT1 and p21 in SCCHN cell lines and increased apoptosis in cisplatin-treated 1483 cells compared with cisplatin treatment alone (mean = 61.3% versus 25.8%, difference = 35.5%, 95% CI = 24.5% to 43.4%; P = .028). CONCLUSION: STAT1 can function as a tumor suppressor in SCCHN cells. Silencing of the STAT1 gene via promoter methylation may contribute to SCCHN tumor cell growth.

Antineoplastic Agents↗

PubMed2006

The PANE1 gene encodes a novel human minor histocompatibility antigen that is selectively expressed in B-lymphoid cells and B-CLL.

Minor histocompatibility antigens (mHAg's) are peptides encoded by polymorphic genes that are presented by major histocompatibility complex (MHC) molecules and recognized by T cells in recipients of allogeneic hematopoietic cell transplants. Here we report that an alternative transcript of the proliferation-associated nuclear element 1 (PANE1) gene encodes a novel human leukocyte antigen (HLA)-A(*)0301-restricted mHAg that is selectively expressed in B-lymphoid cells. The antigenic peptide is entirely encoded within a unique exon not present in other PANE1 transcripts. Sequencing of PANE1 alleles in mHAg-positive and mHAg-negative cells demonstrates that differential T-cell recognition is due to a single nucleotide polymorphism within the variant exon that replaces an arginine codon with a translation termination codon. The PANE1 transcript that encodes the mHAg is expressed at high levels in resting CD19(+) B cells and B-lineage chronic lymphocytic leukemia (B-CLL) cells, and at significantly lower levels in activated B cells. Activation of B-CLL cells through CD40 ligand (CD40L) stimulation decreases expression of the mHAg-encoding PANE1 transcript and reciprocally increases expression of PANE1 transcripts lacking the mHAg-encoding exon. These studies suggest distinct roles for different PANE1 isoforms in resting compared with activated CD19(+) cells, and identify PANE1 as a potential therapeutic target in B-CLL.

Alternative Splicing↗

PubMed2006

Lipoprotein subclass and particle size differences in Afro-Caribbeans, African Americans, and white Americans: associations with hepatic lipase gene variation.

Despite a higher prevalence of coronary heart disease risk factors, men of African origin have less coronary atherosclerosis, as measured by coronary calcification, than whites. In part, this is thought to be because of the less atherogenic lipoprotein profile observed in men of African origin, characterized by lower triglycerides and higher high-density lipoprotein (HDL) cholesterol. We hypothesized that the -514C>T polymorphism in the hepatic lipase gene (LIPC) plays a significant role in determining a less atherogenic lipoprotein profile observed in men of African origin. Previously conducted studies of the LIPC -514C>T polymorphism in African Americans may have been confounded by a higher level of European admixture; in addition, the results from these studies do not necessarily apply to other African populations because gene-environment interactions may differ. Thus, we compared nuclear magnetic resonance spectroscopy-measured lipoprotein subclass patterns and LIPC -514C>T genotypes in population-based samples of older white American (n = 532) and African American (n = 97) men from the Cardiovascular Health Study to those among older, less admixed, Afro-Caribbean men (n = 205) from the Tobago Health Study. Men of African origin had a more favorable lipoprotein profile than whites. In addition, levels of low-density lipoprotein cholesterol, total cholesterol, and triglyceride, and large and small very low-density lipoprotein, small low-density lipoprotein, as well as very low-density lipoprotein particle size, were remarkably lower in Afro-Caribbean men than in either African American or white men. The frequency of the LIPC -514T allele was much higher in Afro-Caribbeans (0.57) and in African Americans (0.49) than in whites (0.20). The -514T allele in both populations of African origin, but not in whites, was associated with elevated large HDL and greater HDL size. Our findings indicate that the higher frequency of the LIPC -514T allele found in men of African origin living in different environments significantly contributes to the more favorable distribution of HDL subclasses compared with whites.

Adult↗

PubMed2006

C-reactive protein genotype affects exercise training-induced changes in insulin sensitivity.

An etiologic role for chronic inflammation in the development of insulin resistance has been hypothesized. We determined whether the -732A/G and +219G/A C-reactive protein (CRP) gene variants affect insulin and glucose measures and whether these variants affect training-related changes in insulin sensitivity and glucose measures. Men and women 50 to 75 years old (n = 61) underwent baseline testing that included glucose tolerance, maximal oxygen consumption, body composition, CRP levels, and genotyping assessments. Tests were repeated after 24 weeks of aerobic exercise training. In bivariate analyses, CRP -732A/G G allele carriers had significantly lower baseline postprandial plasma glucose and after-training CRP levels. After exercise training, the -732A/G G allele carriers had approximately 28% increase in insulin sensitivity index (ISI) and approximately 26% reduction in insulin area under the curve (AUC), compared with the approximately 7% increase in ISI and approximately 15% reduction in insulin AUC in the A allele homozygotes (P = .03). The significant enhancement of ISI in -732A/G G allele carriers remained evident in analyses limited to those with normal glucose tolerance. Multivariate analyses adjusted for demographic and biologic variables confirmed the significant enhancement of training-induced improvement in ISI by the CRP gene variant. In addition, the CRP -732A/G and +219G/A haplotype significantly associated with training-induced improvements in ISI and insulin AUC in separate multivariate models. In conclusion, the CRP -732A/G variant modulates exercise training-related improvements in ISI and glucose AUC, and the haplotype of the CRP -732A/G and +219G/A variants significantly affected training-induced changes in ISI and insulin AUC.

Aged↗

PubMed2006

Effects of exercise on mitochondrial content and function in aging human skeletal muscle.

Skeletal muscle mitochondria are implicated with age-related loss of function and insulin resistance. We examined the effects of exercise on skeletal muscle mitochondria in older (age = 67.3 +/- 0.6 years) men (n = 5) and women (n = 3). Similar increases in (p <.01) cardiolipin (88.2 +/- 9.0 to 130.6 +/- 7.5 microg/mU creatine kinase activity [CK]) and the total mitochondrial DNA (1264 +/- 170 to 1895 +/- 273 copies per diploid of nuclear genome) reflected increased mitochondria content. Succinate oxidase activity, complexes 2-4 of the electron transport chain (ETC), increased from 0.13 +/- 0.02 to 0.20 +/- 0.02 U/mU CK (p <.01). This improvement was more pronounced (p <.05) in subsarcolemmal (127 +/- 48%) compared to intermyofibrillar (56 +/- 12%) mitochondria. NADH oxidase activity, representing total ETC activity, increased from 0.51 +/- 0.09 to 1.00 +/- 0.09 U/mU CK (p <.01). In conclusion, exercise enhances mitochondria ETC activity in older human skeletal muscle, particularly in subsarcolemmal mitochondria, which is likely related to the concomitant increases in mitochondrial biogenesis.

Aged↗

PubMed2006

Functional single nucleotide polymorphism haplotypes in the human equilibrative nucleoside transporter 1.

The human equilibrative nucleoside transporter 1 gene (hENT1) is the primary nucleoside transporter for cytosine arabinoside (AraC), a deoxycytidine analog used for treatment of acute leukemias and lymphomas. We screened approximately 1.6 kb upstream of the transcription initiation site of hENT1 for single nucleotide polymorphisms (SNPs) that affect gene expression. We identified one SNP at position -706G>C with a frequency of 21% in whites and 5% in African-Americans. In African-Americans, we observed two SNPs at positions -1345C>G and -1050G>A with allele frequencies of 8% and 19%, respectively. TRANSFAC analysis suggested that -1345C>G and -706G>C may alter transcription factor binding sites. Four naturally occurring haplotypes (CGG, CAG, CGC and GAG) were cloned into a luciferase expression plasmid, transfected into Cos-1 cells, and reporter activity measured at 24 and 48 h. Three haplotypes, CAG, CGC and GAG, respectively, showed average expression that was approximately two-fold (P<0.05), 1.4-fold (P<0.05) and 1.1-fold (P>0.05) higher than lowest expression haplotype CGG at 48 h. When reanalysed as single SNPs, the differences in expression were significant for -1345C>G and -1050G>A genotypes, and not for -706G>C. However, the magnitude of difference was reduced, suggesting that no single SNP completely accounts for the expression differences observed at the haplotype level. By real-time quantitative reverse transcriptase-polymerase chain reaction assay, individuals with CGG/CGC haplotypes showed 1.37-fold higher median expression of hENT1 transcript than those with common CGG/CGG haplotypes. Although not statistically significant (P=0.12), this difference is in the direction predicted by the in vitro data. hENT1 promoter region haplotypes may influence gene expression and alter AraC chemosensitivity.

Black or African American↗

PubMed2006

Apolipoprotein E polymorphism and preclinical carotid artery disease in untreated hypertensive men.

METHODS: The apolipoprotein E (apoE) polymorphism was evaluated alone, and in interaction with smoking status, in predicting carotid intima-medial thickness and plaque among 182 untreated, hypertensive, white men (mean age 56+/-8.9 years). RESULTS: After covariate adjustment (age, education, smoking, body mass index, systolic and diastolic blood pressure, glucose, total : high-density lipoprotein), apoE genotype (no [epsilon]4 versus any [epsilon]4) predicted mean ([beta]=-0.139, P=0.023) and maximum ([beta]=-0.138, P=0.028) intima-medial thickness, as well as plaque ([beta]=-0.744; P=0.072). Tests of a genotype-x-smoking interaction were non-significant. CONCLUSIONS: Mean intima-medial thickness was greater in men with the 3/3 than [epsilon]4 genotypes (2/4 3/4 4/4), suggesting genetic risk for carotid atherosclerosis may be conferred by the [epsilon]3, rather than the [epsilon]4, allele.

Adult↗

PubMed2006

Paroxetine: population pharmacokinetic analysis in late-life depression using sparse concentration sampling.

AIM: To develop a population pharmacokinetic (PK) model using sparse sampling of long-term treatment with paroxetine in elderly depressed subjects, incorporating CYP2D6 genotype as well as other covariates. METHODS: Elderly subjects (age>or=70 years) with nonpsychotic, nonbipolar major depressive disorder from the inpatient and outpatient clinic were treated with paroxetine in a 5-year clinical trial investigating 'Maintenance Therapies in Late-Life Depression' (MTLD-2). Plasma concentrations were collected during regular visits. CYP2D6 genotype was determined using polymerase chain reaction (PCR) for each individual. A nonlinear mixed-effects model was developed with NONMEM for these subjects who received 10-40 mg day-1 of paroxetine during treatment. One- and two-compartment models with linear and nonlinear elimination (Michaelis-Menten) were evaluated. PK parameters as well as interindividual and residual variability were estimated. The effects of age, weight, sex, race and CYP2D6 genotypes on the pharmacokinetics of paroxetine were evaluated. RESULTS: One hundred and seventy-one subjects with a mean age of 77 years (range 69-95) and a mean weight of 72.0 kg (range 32.9-137.0) were enrolled in the MTLD-2 clinical trial. A total of 1970 paroxetine concentrations were available for population PK analyses. Approximately 10 samples were taken per subject. A two-compartment nonlinear PK model with additive and proportional error provided the best base model for description of the data. Weight and CYP2D6 polymorphisms were found to have a significant effect on maximal velocity (Vm), whereas sex had an effect on volume of distribution of the central compartment. The Vm estimates in each of the CYP2D6 phenotypic groups were: 125 microg h-1 in poor metabolizer (n=1), 182 microg h-1 in intermediate metabolizers (n=28), 454 microg h-1 in extensive metabolizers (n=36) and 3670 microg h-1 in ultra-rapid metabolizers (n=5). CONCLUSIONS: The population PK model adequately described paroxetine data in this elderly depressed population. The data indicate that female and male subjects with different CYP2D6 polymorphisms have different elimination rates and therefore may need to be dosed differently based on metabolizer genotype.

Age Factors↗

PubMed2006

The Khatri Sikh Diabetes Study (SDS): study design, methodology, sample collection, and initial results.

Non-insulin-dependent diabetes mellitus, or type 2 diabetes (T2DM), has become a major public health problem in India. The high prevalence, relatively young age of onset, and strong familial aggregation of T2DM in some Indian communities remains to be explained. Many of the traditional risk factors established for European populations do not appear to be present in Asian Indians. Phase I of the Sikh Diabetes Study (SDS) was launched to build the population resources required to initiate a large-scale genetic epidemiological study of diabetes in an Asian Indian population. The SDS is focused on the Khatri Sikh population of North India. In all, 1,892 subjects were enrolled to participate in the family-based study; 1,623 of these subjects belong to 324 families, each of which has at least 2 siblings affected with T2DM. The sample included 1,288 individuals affected with T2DM (siblings, parents, or relatives) and 335 unaffected siblings, parents, or relatives. The remaining 269 subjects were unrelated nondiabetic control subjects, including unaffected spouses of probands or siblings. This primarily nonvegetarian, nonsmoking endogamous caste group has presented an unusual clinical picture of uneven distribution of adiposity and a high rate of T2DM with secondary complications. Such well-characterized population isolates may offer unique advantages in mapping genes for common complex diseases.

Adult↗

PubMed2006

Identification of a novel mutation combination in factor XIII deficiency: genetic update to the first reported case in the United States.

A 1967 report described the first known case of congenital factor XIII (FXIII) deficiency in the United States in a male patient with a severe hemorrhagic disorder. The patient's family presented no symptoms of the disorder, but the members were found to have half the normal FXIII activity. Although the molecular basis of the disorder could not be evaluated at the time, the results suggested an autosomal recessive inherited disorder. We sequenced all of the exons and the flanking regions in the genes for the FXIII A and B subunits of the patient, his family, and 18 unrelated individuals. We report the novel combination of an Arg-to-Cys mutation at codon 78 and a G-to-C mutation at the intron 5/exon 6 splice junction in the patient's FXIIIA gene. The missense-splice junction mutation combination appears to have caused the patient's FXIIIA deficiency, because the remaining family members, who present no symptoms and have no clinical diagnoses of FXIII deficiency, have one or the other of the 2 mutations but not both. Additionally, the 18 unrelated individuals are homozygous wild type at these loci. The molecular consequences of these mutations appear to be an abnormality in protein conformation or folding and/or a reduced production of messenger RNA transcripts of varying length that likely result in a nonfunctional, unstable FXIII protein.

Adult↗

PubMed2006

Association of FCgamma receptor IIA (CD32) polymorphism with malarial anemia and high-density parasitemia in infants and young children.

Protective immunity against Plasmodium falciparum is partially mediated through binding of malaria-specific IgG antibodies to Fcgamma receptors. Polymorphic variability in Fcgamma RIIa (H/R-131) is associated with differential binding of IgG subtypes and malaria disease outcomes. However, the role of Fcgamma RIIa-131 variability in conditioning susceptibility to severe malarial anemia, the primary manifestation of severe malaria in holoendemic P. falciparum transmission areas, is largely undefined. Thus, Fcgamma RIIa-H131R polymorphism was investigated in 493 children who came to a hospital with acute malaria. Variation in Fcgamma RIIa-131 was not significantly associated with severe malarial anemia (hemoglobin [Hb] < 6.0 g/dL) or malaria anemia (Hb < 8.0 g/dL). However, relative to the heterozygous genotype, homozygotes for the R131 alleles were protected against high-density parasitemia (>or= 10,000 parasites/microL; odds ratio [OR] = 0.58, 95% confidence interval [CI] = 0.37-0.92, P = 0.02), while homozygotes for the H131 alleles were mildly protective (OR = 0.71, 95% CI = 0.45-1.13, P = 0.14). Additional multivariate analyses showed that infection with human immunodeficiency virus type 1 did not influence the associations between FcgammaRIIa-H131R polymorphism and malaria disease outcomes. Genotypic results presented here parallel data illustrating that parasite density is unrelated to the severity of anemia in children with acute malaria. Thus, although homozygosity for the R131 allele protects against high-density parasitemia, FcgammaRIIa-131 polymorphism does not protect against malaria anemia.

Anemia↗