The Magnificent VWF SNPs and Where to Find Them: A Journey in Exon 28 of the Hispanic Population

2019 ◽  
Vol 152 (Supplement_1) ◽  
pp. S16-S17
Author(s):  
Mohammad Barouqa ◽  
Jui Choudhuri ◽  
Roger Fecher ◽  
Jack Jacob ◽  
Saed Sadeghi ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Wide Spectrum ◽  
Von Willebrand Disease ◽  
High Rate ◽  
Coagulation Disorder ◽  
Hispanic Population ◽  
Protein Ratio ◽  
A1 Domain

Abstract von Willebrand disease (VWD) is a common coagulation disorder with a prevalence of 0.1% to 1.0% manifesting as a wide spectrum of bleeding symptoms. Type 1 is diagnosed by confirming a quantitative decrease in VWF level, while type 3 has undetectable levels of VWF. Type 2 VWD variants are characterized by functional and binding defects. Initial diagnosis and follow-up depend mainly on measuring VWF protein and VWF activity and calculating the activity to protein ratio. Ristocetin cofactor activity (VWF:RCo) is the most widely used and gold standard activity assay. In our institute, we use a cutoff of VWF:RCo/VWF:Ag <0.7 to screen for possible type 2 VWD. However, the use of this ratio is flawed by the presence of specific SNPs (I1380V, N1435S, and D1472H) in the A1 domain, especially in African Americans. These SNPs lead to a decrease in ristocetin binding to VWF and hence decreased VWF:RCo/VWF:Ag ratio. In this retrospective study, we analyzed the levels of VWF:AG and VWF:RCo based on patients’ ethnicity using an in-house data mining software from 2011 to 2016. Then, we validated several exon 28 primers, kindly provided by Dr. Montgomery (Blood Center of Wisconsin), used to detect type 2 mutations and SNPs in African Americans. We excluded cases diagnosed as positive for VWD and included only cases rendered nondiagnostic of VWD following a comprehensive panel including multimers, collagen binding, and molecular studies when indicated. In our Hispanic population (n = 936), VWF:Ag was 138.9% and 117% (average and median) and VWF:RCo was 110.5% and 93.0% (average and median); 43.2% of Hispanics had VWF:RCo/VWF:Ag <0.7. In our African American population (n = 664), VWF:Ag was 163.0% and 138.5% (average and median) and VWF:RCo was 108.5% and 92.0% (average and median); 50.6% of the African American patients had VWF:RCo/VWF:Ag <0.7. Patients from Caucasian origins (n = 242) had VWF:Ag of 149.6% and 113.0% (average and median) and VWF:RCo of 137.6% and 116.0% (average and median), respectively; 30.9% of Caucasian patients had VWF:RCo/VWF:Ag of less than 0.7. We then selected four random Hispanic cases with VWF:RCo/VWF:Ag <0.5 as part of the validation study of exon 28 sequencing. Using a Sanger sequence assay, we found multiple benign/likely benign single-nucleotide polymorphisms (SNPs) at exon 28 that code for VWF antigen A1 domain. All four cases showed P.Thr1381Ala and P.Thr1547 = [OC1] polymorphism, three showed p.Val1565Leu polymorphism, and two showed p.Ala1555 = polymorphism. The statistical analysis of VWF:Ag/VWF:RCo levels from Hispanics shows a similar trend to African Americans with a high rate of cases with VWF:RCo/VWF:Ag <0.7 in comparison to Caucasians. However, the finding of SNPs and absence of known African American polymorphisms suggest that these SNPs may be the cause of decreased ristocetin binding in Hispanics. This study calls for ethnic-based considerations in VWD workflows.

Fourteen Percent of Healthy African Americans Participating In the Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCB VWD) Are Heterozygous for the VWF Gene Mutation H817Q Associated with Type 2N Von Willebrand Disease

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 239-239
Author(s):  
Kenneth D Friedman ◽  
Daniel B. Bellissimo ◽  
Pamela A. Christopherson ◽  
Veronica H Flood ◽  
Joan Cox Gill ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Racial Differences ◽  
Healthy Subjects ◽  
Von Willebrand Disease ◽  
Compound Heterozygous ◽  
Healthy Controls ◽  
Clinical Biology ◽  
A1 Domain ◽  
Von Willebrand

Abstract Abstract 239 Von Willebrand disease (VWD) is a common hereditary bleeding disorder caused by reduced concentration or abnormal structure/function of von Willebrand Factor (VWF). Most published studies of normal VWF have been carried out in European or North American subjects without regard to racial differences. In the process of studying healthy controls in the Zimmerman Program for the Molecular and Clinical Biology of VWD (ZPMCB-VWD), we identified a common polymorphism (D1472H) in the VWF A1-domain in African Americans that affects the measurement of VWF function by ristocetin cofactor (VWF:RCo) but does not appear associated with increased bleeding risk. We therefore explored whether other polymorphisms or mutations were identified more frequently in African Americans. VWF sequencing was performed on 191 healthy controls including 66 that were self-identified as African American. European Bleeding Score was obtained and normal in all healthy subjects. Among the African Americans, 9 individuals were heterozygous for the reported type 2N H817Q mutation and one was homozygous. Factor VIII binding to VWF (VWF:F8B) was determined with a standard FVIII binding assay using the subject's plasma VWF and recombinant FVIII. The VWF:F8B was significantly reduced in H817Q heterozygotes when compared to 10 healthy study subjects without the H817Q mutation (65 ± 11 versus 108 ± 11, p=0.003). The VWF:F8B was further reduced to 37 using the plasma VWF from the homozygous H817Q subject. However, the observed VWF:F8B in these individuals with H817Q are still considerably higher that that observed in patients enrolled in ZPMCB-VWD that are either homozygous or compound heterozygous with the common R854Q type 2N VWD (VWF:F8B < 13). Of the 116 self-identified Caucasian healthy subjects, none had the H817Q mutation, but 3 were heterozygous for the R854Q mutation; their mean plasma VWF:F8B was reduced to 51. While the homozygous R854Q patients had reduced plasma FVIII levels (mean FVIII=24 IU/dL), none of the sequenced healthy control subjects had plasma FVIII levels below 53 IU/dL, Some have advocated FVIII/VWF:Ag ratios as a screen for type 2N VWD. The subject with homozygous H817Q had only a mildly reduced FVIII/VWF:Ag ratio (0.59), while the heterozygous H817Q were not reduced (mean=0.90), thereby demonstrating that the VWF:F8B assay has greater sensitivity for type 2N VWF binding defects than the FVIII/VWF:Ag ratio. Since the previously reported A1-domain D1472H polymorphism was common in African Americans, we explored the prevalence of this polymorphism in the healthy subjects with the H817Q mutation. All H817Q heterozygous subjects were either homozygous (4) or heterozygous (5) for the D1472H polymorphism. The one individual who was H817Q homozygous was also D1472H homozygous, suggesting that there may be an extended haplotype present in African Americans. In summary, an H817Q type 2N mutation is commonly found in healthy African American subjects with an allele frequency of 0.083, predicting that approximately 7 in 1,000 African Americans would be homozygous for the H817Q type 2N mutation. Our data, and the rarity of diagnosis of type 2N VWD in African Americans suggests that while mutation H817Q may interfere with the interaction of FVIII with VWF, this mutation appears to confer little or no clinical symptoms. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Evidence for the Misfolding of the A1 Domain within Multimeric von Willebrand Factor in Type 2 von Willebrand Disease

2020 ◽  
Vol 432 (2) ◽  
pp. 305-323 ◽  
Author(s):  
Alexander Tischer ◽  
Maria A. Brehm ◽  
Venkata R. Machha ◽  
Laurie Moon-Tasson ◽  
Linda M. Benson ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Identification of Type 2 von Willebrand Disease in Previously Diagnosed Type 1 Patients: a Reappraisal Using Phenotypes, Genotypes and Molecular Modelling

2000 ◽  
Vol 84 (12) ◽  
pp. 998-1004 ◽  
Author(s):  
Ioana Nitu-Whalley ◽  
Anne Riddell ◽  
K. Pasi ◽  
Dale Owens ◽  
M. Enayat ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Correct Diagnosis ◽  
Von Willebrand Disease ◽  
Single Amino Acid ◽  
Elisa Assay ◽  
Modelling Analysis ◽  
A1 Domain ◽  
Von Willebrand

SummaryIn order to investigate the possibility that qualitative type 2 defects in von Willebrand factor (VWF) occurred in patients previously diagnosed with quantitative type 1 von Willebrand disease (VWD), the phenotypes and genotypes were reanalysed in 30 patients who exhibited discrepant VWF activity/VWF:Ag ratios of less than 0.7. The capacity of VWF to bind to glycoprotein Ib (GpIb) was reassessed using the ristocetin co-factor activity (VWF:RiCo) assay compared to an in-house and a commercial ELISA assay (based on a mAb directed against the GpIb binding site on VWF). This was supplemented by multimeric analysis and the amplification and sequencing of a 936 bp fragment of exon 28 of the VWF gene with the aim of identifying mutations in the A1 domain. On reappraisal, using the VWF:RiCo assay all patients demonstrated a disproportionately reduced VWF:RiCo/VWF:Ag ratio, indicative of a qualitative defect, while abnormal ratios were detected in only seven kindreds using the in-house ELISA assay and in only one kindred with the commercial ELISA assay. Eight single amino acid substitutions were found in nine kindreds, four of which were novel candidate VWF mutations and four previously described in association with type 2 VWD. In agreement with the phenotype, the novel VWF mutations were located in the VWF-A1 crystal structure at positions that corresponded to potential type 2M defects. This study underlines the difficulties of correct diagnosis of the subtype of VWD and emphasises the importance of using sensitive phenotypic assays, the relevance of the VWF:RiCo/ VWF:Ag ratio, multimeric analysis and molecular modelling analysis.

Molecular Background of “Smeary” von Willebrand Factor Multimers.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2711-2711
Author(s):  
Reinhard Schneppenheim ◽  
Olivier Marggraf ◽  
Heike Eckert ◽  
Tobias Obser ◽  
Florian Oyen ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Disulfide Bonds ◽  
Von Willebrand Disease ◽  
Molecular Testing ◽  
Functional Deficits ◽  
Intermolecular Disulfide Bonds ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Multimer analysis of von Willebrand factor (VWF) is a most important technique to classify patients with von Willebrand disease (VWD) type 2. Besides “classical” multimer patterns a “smeary” appearance of individual VWF oligomers is increasingly observed and has previously been regarded as a pre-analytical artifact. Objective: To phenotypically and genotypically assess the molecular background of “smeary” VWF multimers. Patients and methods: Samples of 8 VWD patients were analyzed in our reference lab (UB) for further classification and molecular testing. Multimer profiles were assessed by intermediate resolution gels. VWF:CB and VWF:GpIb binding were used as functional assays. VWF gene mutation analysis was performed in all index cases (IC). The causal relationship between genotype and phenotype was studied by analyzing recombinant mutants in comparison to wildtype VWF. Results: In all IC the phenotype correlated with particular mutations in the VWF D3 domain (G1172D), the A1 domain (R1315C, R1374S, R1374C, R1399C), the D4 domain (C2257R), the C1 domain (R2464C) and in the region close to the CK domain (C2671Y), respectively. The multimer patterns of recombinant mutant VWF was of a “smeary” appearance and closely resembled those of mutant plasma VWF. Mutations in the A1 domain additionally correlated with severe GpIb binding deficiency. Conclusions: Our data suggest a molecular cause of the “smeary” multimer structure rather than pre-analytical artifacts. Most of the mutations identified involved cysteine residues suggesting an influence on the VWF secondary structure which is determined by intra- and intermolecular disulfide bonds. This could explain the peculiar multimer appearance. The functional deficits, however, seem to depend on the location of the mutations with a significant impact on GpIb binding of mutants in the A1 domain.

Common VWF Haplotypes in Normal African-Americans and Caucasians Recruited into the ZPMCB-VWD and Their Impact on VWF Laboratory Testing.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 714-714
Author(s):  
Veronica H. Flood ◽  
B.C. Kautza ◽  
C.A. Miller ◽  
B.R. Branchford ◽  
J.C. Gill ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Gene Sequencing ◽  
Von Willebrand Disease ◽  
Control Group ◽  
Healthy Controls ◽  
Significant Difference ◽  
The Mean ◽  
Bleeding Score ◽  
Von Willebrand

Abstract Von Willebrand disease (VWD) is a common bleeding disorder that has been reported to affect up to 1% of the population. Diagnostic testing for VWD relies on specific tests of von Willebrand factor (VWF) that include VWF antigen (Ag) and VWF ristocetin cofactor activity (RCo). Variability in these tests, especially in the RCo, has the potential to affect diagnosis of VWD. Clinically, the RCo/Ag ratio is used to identify patients with type 2M VWD, of which 35% of our local type 2M index cases were of African-American descent. As part of the ZPMCB-VWD, a large study of both healthy controls and patients with VWD, we evaluated VWF Ag, RCo, multimers, EU bleeding score, and VWF gene sequencing to look for mutations and/or common polymorphisms (SNPs) that might contribute to RCo measurement. Healthy controls completed a computerized version of the EU bleeding score and provided blood for clinical VWF testing. Since platelet VWF binding primarily involves the A1 domain of VWF, exon 28 gene sequencing was analyzed and common SNPs were identified, particularly in African-Americans (AA) with altered RCo/Ag ratios. Statistical comparisons were performed using t-tests. For the AA control group, the presence of specific exon 28 SNPs, including I1380V, N1435S, and D1472H, correlated with a low RCo/Ag. In controls, the 3 SNPs occurred together in 22% of AA and 1.5% of Caucasians. For AA controls with all 3 SNPs, the mean Ag was 155, RCo 115, and RCo/Ag 0.77, while for AA without the 3 SNPs, the mean Ag was 129, RCo 129, and RCo/Ag 1.01. The difference in RCo/Ag ratio was significant (p<0.001). In comparison, the Caucasian controls without the 3 SNPs had a mean Ag of 108, RCo of 115, and RCo/Ag of 1.08. When only D1472H was considered, a significant difference in RCo/Ag ratio was noted for both African-American and Caucasian controls with D1472H (present in 63% of AA and 24% of Caucasian controls). For AA controls with D1472H, the mean RCo/Ag ratio was 0.82 (range 0.42–1.16) compared to 1.01 for those without the SNP (p<0.001). The Caucasian controls with D1472H had a mean ratio of 0.87 (range 0.57–1.17) compared to 1.08 for those without the SNP (p<0.001). EU Bleeding Score was not significantly affected by either race or SNP status. All Caucasian controls with D1472H were heterozygous, while 14% of the African-American controls were homozygous. The mean RCo/Ag for the homozygous controls was 0.71, compared to 0.86 for the AA heterozygous controls (p<0.025). In order to determine if the exon 28 SNPs intrinsically altered the measurement of VWF, the 3 SNPs were engineered into recombinant VWF and expressed in HEK293T cells. VWF Ag and RCo were performed on the purified expressed VWF. The RCo/Ag ratios for the recombinant expressed VWF were decreased for 1380V and 1472H, while the construct containing all 3 SNPs showed an even lower ratio (59% of wild-type RCo/Ag ratio). These data suggest that specific exon 28 SNPs may contribute to low RCo/Ag ratios, especially in the African-American population. Since the RCo assay involves ristocetin binding to VWF, mutations (and polymorphisms) in VWF may affect the measurement of “VWF activity” by this assay and might not reflect true hemorrhagic risk.

Functional Characterization of Three VWF- A1 Domain Mutations Causing Type 2 Von Willebrand Disease.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1305-1305
Author(s):  
Maha Othman ◽  
Rouzbeh Chegeni ◽  
Linda M Vickars ◽  
Emmanuel J Favaloro ◽  
David Lillicrap
Keyword(s):  
Functional Characterization ◽  
Von Willebrand Disease ◽  
Site Directed Mutagenesis ◽  
Missense Mutations ◽  
Binding Studies ◽  
Disease Subtype ◽  
Platelet Binding ◽  
The Media ◽  
A1 Domain

Abstract Abstract 1305 Poster Board I-327 Through the Canadian Platelet-Type VWD Project (www.pt-vwd.org), we have identified 3 novel candidate mutations within the A1 domain of VWF gene in 5 patients that were provisionally diagnosed as type 2 VWD. These mutations are: L1460F (2 related patients), Y1363C (1 patient), E1389K (2 related patients). The VWF:Ag ranged from 0.19 – 0.54 IU/mL, VWF:RCo ranged from 0.19- 0.21 IU/mL and platelet count ranged from 206-254 × 103/ mm3. High Molecular weight multimers of VWF were absent in the plasma of the patient with the 1460 aa change. These substitutions have not been previously reported in the literature or in the International VWF Mutation Database. All three mutations were created by site-directed mutagenesis in the full-length huVWF cDNA and transiently transfected in the HEK293T/17 cell line. The VWF protein secreted in the media was collected and quantified by ELISA before proceeding with Functional VWF-platelet binding studies. Quantification of the mutant rVWF proteins in the media and cell lysates and multimer analysis of the proteins showed normal secretion and multimer distributions. To determine the GpIb binding properties of the putative mutants, the VWF recombinant protein (0.25 ug) from each of the WT and three mutants was incubated with lyophilized platelets (1 × 108) for 10 minutes at 25°C with different concentrations of ristocetin between 0-1 mg/mL. The platelets were then pelleted by centrifugation at 1200 g and the resulting supernatant was tested for the remaining unbound VWF by ELISA. Compared to the WT VWF protein, only the L1460F mutant showed increased platelet binding under lower concentration of ristocetin. Ristocetin-induced platelet agglutination (RIPA) assays performed using these recombinant proteins confirmed enhanced ristocetin responsiveness for L1460F, and that Y1363C and E1389K alternatively showed reduced responsiveness. Based on these data, a type 2B VWD diagnosis can only be made with respect the L1460F and not the other two A1 domain missense mutations. These data confirm once again that the assignment of the phenotype on clinical and laboratory basis is useful prior to genetic analysis and mutation identification. However, in some situations both will be ultimately required to understand the clinical presentation and to assign a disease subtype. Disclosures Vickars: Novartis Canada: Honoraria, Research Funding.

scholarly journals Role of plasma adiponectin /C-reactive protein ratio in obesity and type 2 diabetes among African Americans

2017 ◽  
Vol 17 (1) ◽  
pp. 99 ◽  
Author(s):  
Preetha Anna Abraham ◽  
Selasi Attipoe ◽  
Josh B. Kazman ◽  
Stacey Anne Zeno ◽  
Merrily Poth ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
African Americans ◽  
C Reactive Protein ◽  
Protein Ratio ◽  
Plasma Adiponectin ◽  
Reactive Protein

scholarly journals Family Legacy of Diabetes-Related Behaviors: An Exploration of the Experiences of African American Parents and Adult Children

2019 ◽  
Vol 6 ◽  
pp. 233339361985234 ◽  
Author(s):  
Brianna Routh ◽  
Tera Hurt ◽  
Donna Winham ◽  
Lorraine Lanningham-Foster
Keyword(s):  
African American ◽  
African Americans ◽  
Health Care Professionals ◽  
Cultural Norms ◽  
Family Interactions ◽  
Generational Cohort ◽  
Parental Gender ◽  
The Life Course ◽  
Intergenerational Patterns

African Americans are at higher risk of developing type 2 diabetes mellitus (T2DM), and this risk may be influenced by familial experiences and cultural norms throughout the life course. This led us to conduct this study of 20 African American families with strong histories of T2DM to explore familial complexities that prevent or help manage diabetic symptoms. Experiences were analyzed inductively through individual family profiles created using content-analytic summaries. When profiles were further analyzed for emerging and theoretically informed data patterns, two themes emerged: (a) family interactions characterized by T2DM-related actions and communication patterns, and (b) intergenerational patterns of openness characterized by variations in approach within generational cohort and parental gender. Through inquiries related to intergenerational experiences with T2DM, nursing and health care professionals may be better able to tailor and promote success for prevention and management of behaviors among high-risk African Americans.

scholarly journals Plasma FGF23 and Calcified Atherosclerotic Plaque in African Americans with Type 2 Diabetes Mellitus

2015 ◽  
Vol 42 (6) ◽  
pp. 391-401 ◽  
Author(s):  
Barry I. Freedman ◽  
Jasmin Divers ◽  
Gregory B. Russell ◽  
Donald W. Bowden ◽  
J. Jeffrey Carr ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Type 2 Diabetes ◽  
African American ◽  
Coronary Artery ◽  
African Americans ◽  
Kidney Function ◽  
Vascular Calcification ◽  
Atherosclerotic Plaque ◽  
Mineral Density

Background: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial. Methods: Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aortoiliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, gender, African ancestry proportion, body mass index, diabetes duration, hemoglobin A1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate. Results: The sample was 56.7% female with a mean (SD) age of 55.6 (9.6) years, diabetes duration of 10.3 (8.2) years, eGFR 90.9 (22.1) ml/min/1.73 m2, urine albumin:creatinine ratio (UACR) 151 (588) (median 13) mg/g, plasma FGF23 161 (157) RU/ml, and CAC 637 (1,179) mg. In fully adjusted models, FGF23 was negatively associated with eGFR (p < 0.0001) and positively associated with UACR (p < 0.0001) and CAC (p = 0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after a mean of 5.1 years follow-up. Conclusions: Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not between FGF23 and bone mineral density, in African Americans lacking advanced nephropathy.

scholarly journals Relationship of Insulin Receptor Substrate-1 and -2 Genotypes to Phenotypic Features of Polycystic Ovary Syndrome

2002 ◽  
Vol 87 (9) ◽  
pp. 4297-4300 ◽  
Author(s):  
David A. Ehrmann ◽  
Xu Tang ◽  
Issei Yoshiuchi ◽  
Nancy J. Cox ◽  
Graeme I. Bell
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
African American ◽  
African Americans ◽  
Polycystic Ovary Syndrome ◽  
Polycystic Ovary ◽  
Insulin Receptor Substrate ◽  
Ovary Syndrome ◽  
Glucose Levels

Insulin resistance is a key component in the pathogenesis of polycystic ovary syndrome (PCOS) and type 2 diabetes. Polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, IRS-1 (Gly972Arg) and IRS-2 (Gly1057Asp), influence susceptibility to type 2 diabetes. This study was undertaken to assess the influence of these polymorphisms on insulin resistance, glucose tolerance, and androgen levels in nondiabetic PCOS women. We studied 227 PCOS subjects including 126 and 48 nondiabetic white and African-American subjects, respectively. The IRS-1 Gly972Arg allele frequencies were identical in whites and African-Americans [0.95 (Gly) and 0.05 (Arg)]. The IRS-2 Gly1057Asp allele frequencies were 0.85 (Gly) and 0.15 (Asp) in African-Americans and 0.59 (Gly) and 0.41 (Asp) in whites. There was no association of IRS-1 genotype with any clinical or hormonal measure in nondiabetic white or African-American PCOS subjects. However, nondiabetic subjects with the IRS-2 Gly/Gly genotype had significantly higher 2-h oral glucose tolerance test glucose levels compared with those with Gly/Asp and Asp/Asp genotypes in whites or Gly/Asp genotype in African-Americans (there were no Asp/Asp subjects in our modest size African-American sample). These results suggest that the IRS-2 Gly1057Asp polymorphism influences blood glucose levels in nondiabetic white and African-American women with PCOS. Thus, individuals with the common IRS-2 Gly/Gly genotype may be at increased risk of developing type 2 diabetes.

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