Using HbA1c to improve efficacy of the American Diabetes Association fasting plasma glucose criterion in screening for new type 2 diabetes in American Indians. The Strong Heart Study

WSTĘP. Celem badania jest określenie optymalnej krytycznej linii FPG-HbA1c, umożliwiającej rozpoznanie cukrzycy w grupie chorych z nieprawidłowym stężeniem glukozy na czczo (IFG, impaired fasting glucose) i poprawa skuteczności oznaczenia glikemii na czczo (FPG, fasting plasma glucose), stosowanego jako samodzielne badanie przesiewowe w kierunku cukrzycy u Indian amerykańskich. MATERIAŁ I METODY. Analizowano oznaczenia stężenia glukozy na czczo i 2 godziny po doustnym obciążeniu glukozą (2hPG) oraz HbA1c w grupie 2389 Indian amerykańskich w wieku 45-74 lat, którzy dotychczas nie byli leczeni z powodu cukrzycy, u których wcześniej nie rozpoznawano cukrzycy, a których poddano wyjściowej i powtórnej ocenie w ramach badania SHS (Strong Heart Study). Zgodnie z kryteriami American Diabetes Association cukrzycę rozpoznawano, gdy stężenie glukozy na czczo było równe lub wyższe niż 126 mg/dl lub gdy wartość 2hPG wynosiła 200 mg/dl lub więcej. Nieprawidłowe stężenie glukozy na czczo rozpoznawano, gdy mieściło się ono w przedziale 110 Ł FPG < 126 mg/dl, a jako wartość prawidłową (NFG, normal fasting glucose) przyjęto stężenie glukozy na czczo niższe niż 110 mg/dl. Do rozpoznawania cukrzycy w grupie badanych z IFG (2hPG ł 200 mg/dl) zastosowano modele regresji logistycznej. Najlepszy model wybrano na podstawie porównania pól pod krzywymi ROC (receiver operating characteristic) utworzonymi w oparciu o różne modele regresji logistycznej. Do wyznaczenia optymalnych wartości krytycznych użyto funkcji przydatności opartej na najlepszym modelu oraz współczynniku koszt/korzyść. Dane z drugiego badania wykorzystano do oceny wpływu czasu, jaki upłynął pomiędzy dwoma kolejnymi badaniami przesiewowymi, zarówno na kryterium FPG, jak i na optymalną krytyczną linię FPG-HbA1c. WYNIKI. W grupie chorych z nowo rozpoznaną cukrzycą, u 37% w badaniu wyjściowym oraz u 55,2% w badaniu powtórnym stwierdzono wartości 2hPG większe bądź równe 200 mg/dl, przy wartościach FPG mniejszych niż 126 mg/dl. Zarówno w wyjściowym, jak i w drugim oznaczeniu u znacznej części pacjentów z IFG rozpoznano cukrzycę (odpowiednio: 19,3 i 22,9%). Porównanie pól pod krzywymi ROC dla poszczególnych modeli regresji logistycznej wykazało, że największa wartość pola odpowiada łącznemu oznaczeniu FPG i HbA1c. Wartość ta była znamiennie wyższa od wartości pola dla oznaczenia FPG (p = 0,0008). Dla współczynnika koszt/korzyść = 0,23888 optymalna linia krytyczna o największej użyteczności miała wartość równą 0,89 × HbA1c + 0,11 × FPG = 17,92. U chorych, u których wartości FPG i HbA1c znajdowały się na tej linii lub powyżej, zalecano wykonanie doustnego testu tolerancji glukozy (OGTT, oral glucose tolerance test) w celu rozpoznania lub wykluczenia cukrzycy. Optymalne wartości krytyczne w badaniu powtórzonym po 4 latach były mniejsze. WNIOSKI. Według kryteriów American Diabetes Association cukrzycę rozpoznaje się, gdy wartość FPG jest większa lub równa 126 mg/dl albo gdy wartość 2hPG wynosi 200 mg/dl lub więcej. Wykonanie badania FPG jest proste i zaleca się je jako badanie przesiewowe. Natomiast stosowanie w praktyce OGTT w celu uzyskania wartości 2hPG jest kłopotliwe, szczególnie u chorych, u których stwierdza się wartość FPG poniżej 126 mg/dl. Wykonywanie OGTT jako badania przesiewowego u każdego pacjenta również jest niepraktyczne. Uzyskane dane wskazują, że u 37% osób z nowo wykrytą cukrzycą w badaniu wyjściowym i u 55,2% w oznaczeniu drugim stężenie glukozy w OGTT wynosiło 200 mg/dl lub więcej, podczas gdy wartość FPG była niższa niż 126 mg/dl. W takich wypadkach, na podstawie oznaczenia wyłącznie FPG jako badania przesiewowego, cukrzyca nie zostałaby rozpoznana. Mimo że odsetek chorych na cukrzycę w grupie NFG jest mały i może zostać zignorowany (4,7% w pierwszym i 6,5% w drugim oznaczeniu), to częstość przypadków cukrzycy stwierdzonych w grupie IFG w trakcie niniejszego badania (ok. 20%) wymaga uwzględnienia w dyskusji na temat metody badań przesiewowych. Wydaje się, że u części chorych z nieprawidłowym stężeniem glukozy na czczo, wybranych na podstawie optymalnych krytycznych wartości FPG-HbA1c, warto wykonać OGTT. Wyznaczenie optymalnej linii krytycznej i odstępu między kolejnymi testami przesiewowymi wymaga dalszych badań.INTRODUCTION. To find an optimal critical line in the fasting plasma glucose (FPG)-HbA1c plane for identifying diabetes in participants with impaired fasting glucose (IFG) and thereby improve the efficacy of using FPG alone in diabetes screening among American Indians. RESEARCH DESIGN AND METHODS. We used FPG, 2-h postload glucose (2hPG), and HbA1c measured in the 2,389 American Indians (aged 45&#8211;74 years, without diabetes treatment or prior history of diabetes) in the Strong Heart Study (SHS) baseline (second) examination. Participants were classified as having diabetes if they had either FPG &#163; 126 mg/dl or 2hPG &#8805; 200 mg/dl, as having IFG if they had 110 &#163; FPG < 126 mg/dl, and as having normal fasting glucose (NFG) if they had FPG < 110, according to the American Diabetes Association (ADA) definition. Logistic regression models were used for identifying diabetes (2hPG &#8805; 200 mg/dl) in IFG participants. The areas under the receiver operating characteristic (ROC) curves generated by different logistic regression models were evaluated and compared to select the best model. A utility function based on the best model and the cost-to-benefit ratio was used to find the optimal critical line. The data from the second examination were used to study the effect of the time interval between the successive diabetes screenings on both the FPG criterion and the optimal critical line. RESULTS. A total of 37% of all subjects with new diabetes at baseline and 55.2% of those in the second exam had 2hPG &#8805; 200 but FPG < 126. There was a very large portion of IFG participants with diabetes (19.3 and 22.9% in the baseline and second exam, respectively). Among the areas under the ROC curves, the area generated by the logistic regression model on FPG plus HbA1c is the largest and is significantly larger than that based on FPG (P = = 0.0008). For a cost-to-benefit ratio of 0.23888, the optimal critical line that has the highest utility is: 0.89 × HbA1c + 0.11 × FPG = 17.92. Those IFG participants whose FPG and HbA1c were above or on the line were referred to take an oral glucose tolerance test (OGTT) to diagnose diabetes. The optimal critical line is lower if a successive diabetes screening will be conducted 4 years after the previous screening. CONCLUSIONS. FPG &#8805; 126 and 2hPG &#8805; 200, as suggested by the ADA, are used in-dependently to define diabetes. The FPG level is easy to obtain, and using FPG alone is suggested for diabetes screening. It is difficult to get physicians and patients to perform an OGTT to get a 2hPG level because of the many drawbacks of the OGTT, especially in those patients who already have FPG < 126. It is also impractical to conduct an OGTT for everyone in a diabetes screening. Our data show that 37% of all subjects with new diabetes in the SHS baseline exam and 55.2% of those in the second exam have 2hPG &#8805; 200 but FPG < 126. These cases of diabetes cannot be detected if FPG is used alone in a diabetes screening. Therefore, although the small portion of diabetes in the NFG group (4.7% in the base-line and 6.9% in the second exam) may be ignored, those cases of diabetes among IFG participants (~20% in our data) need further consideration in a diabetes screening. It may be worthwhile for those IFG participants identified by the optimal critical line to take an OGTT. The optimal critical line and time interval between successive diabetes screenings need further study

Fatty acids linked to cardiovascular mortality are associated with risk factors

Background. Although saturated fatty acids (FAs) have been linked to cardiovascular mortality, it is not clear whether this outcome is attributable solely to their effects on low-density lipoprotein cholesterol (LDL-C) or whether other risk factors are also associated with FAs. The Western Alaskan Native population, with its rapidly changing lifestyles, shift in diet from unsaturated to saturated fatty acids and dramatic increase in cardiovascular disease (CVD), presents an opportunity to elucidate any associations between specific FAs and known CVD risk factors. Objective. We tested the hypothesis that the specific FAs previously identified as related to CVD mortality are also associated with individual CVD risk factors. Methods. In this community-based, cross-sectional study, relative proportions of FAs in plasma and red blood cell membranes were compared with CVD risk factors in a sample of 758 men and women aged ]35 years. Linear regression analyses were used to analyze relations between specific FAs and CVD risk factors (LDL-C, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, systolic blood pressure, diastolic blood pressure, heart rate, body mass index, fasting glucose and fasting insulin, 2-hour glucose and 2-hour insulin). Results. The specific saturated FAs previously identified as related to CVD mortality, the palmitic and myristic acids, were adversely associated with most CVD risk factors, whereas unsaturated linoleic acid (18:2n-6) and the marine n-3 FAs were not associated or were beneficially associated with CVD risk factors. Conclusions. The results suggest that CVD risk factors are more extensively affected by individual FAs than hitherto recognized, and that risk for CVD,MI and stroke can be reduced by reducing the intake of palmitate, myristic acid and simple carbohydrates and improved by greater intake of linoleic acid and marine n-3 FAs

Research with Arctic peoples: Unique research opportunities in heart, lung, blood and sleep disorders. Working group summary and recommendations

Arctic peoples are spread over eight countries and comprise 3.74 million residents, of whom 9% are indigenous. The Arctic countries include Canada, Finland, Greenland (Denmark), Iceland, Norway, Russia, Sweden and the United States. Although Arctic peoples are very diverse, there are a variety of environmental and health issues that are unique to the Arctic regions, and research exploring these issues offers significant opportunities, as well as challenges. On July 28-29, 2004, the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research co-sponsored a working group entitled Research with Arctic Peoples: Unique Research Opportunities in Heart, Lung, Blood and Sleep Disorders . The meeting was international in scope with investigators from Greenland, Iceland and Russia, as well as Canada and the United States. Multiple health agencies from Canada and the United States sent representatives. Also attending were representatives from the International Union for Circumpolar Health (IUCH) and the National Indian Health Board. The working group developed a set of ten recommendations related to research opportunities in heart, lung, blood and sleep disorders; obstacles and solutions to research implementation; and ways to facilitate international comparisons. These recommendations are expected to serve as an agenda for future research

Diabetes-specific genetic effects on obesity traits in American Indian populations: the Strong Heart Family Study

<p>Abstract</p> <p>Background</p> <p>Body fat mass distribution and deposition are determined by multiple environmental and genetic factors. Obesity is associated with insulin resistance, hyperinsulinemia, and type 2 diabetes. We previously identified evidence for genotype-by-diabetes interaction on obesity traits in Strong Heart Family Study (SHFS) participants. To localize these genetic effects, we conducted genome-wide linkage scans of obesity traits in individuals with and without type 2 diabetes, and in the combined sample while modeling interaction with diabetes using maximum likelihood methods (SOLAR 2.1.4).</p> <p>Methods</p> <p>SHFS recruited American Indians from Arizona, North and South Dakota, and Oklahoma. Anthropometric measures and diabetes status were obtained during a clinic visit. Marker allele frequencies were derived using maximum likelihood methods estimated from all individuals and multipoint identity by descent sharing was estimated using Loki. We used variance component linkage analysis to localize quantitative trait loci (QTLs) influencing obesity traits. We tested for evidence of additive and QTL-specific genotype-by-diabetes interactions using the regions identified in the diabetes-stratified analyses.</p> <p>Results</p> <p>Among 245 diabetic and 704 non-diabetic American Indian individuals, we detected significant additive gene-by-diabetes interaction for weight and BMI (<it>P </it>< 0.02). In analysis accounting for QTL-specific interaction (<it>P </it>< 0.001), we detected a QTL for weight on chromosome 1 at 242 cM (LOD = 3.7). This chromosome region harbors the adiponectin receptor 1 gene, which has been previously associated with obesity.</p> <p>Conclusion</p> <p>These results suggest distinct genetic effects on body mass in individuals with diabetes compared to those without diabetes, and a possible role for one or more genes on chromosome 1 in the pathogenesis of obesity.</p

Variants in CPT1A, FADS1, and FADS2 are Associated with Higher Levels of Estimated Plasma and Erythrocyte Delta-5 Desaturases in Alaskan Eskimos

The delta-5 and delta-6 desaturases (D5D and D6D), encoded by fatty acid desaturase 1 (FADS1) and 2 (FADS2) genes, respectively, are rate-limiting enzymes in the metabolism of ω-3 and ω-6 fatty acids. The objective of this study was to identify genes influencing variation in estimated D5D and D6D activities in plasma and erythrocytes in Alaskan Eskimos (n = 761) participating in the genetics of coronary artery disease in Alaska Natives (GOCADAN) study. Desaturase activity was estimated by product: precursor ratio of polyunsaturated fatty acids. We found evidence of linkage for estimated erythrocyte D5D (eD5D) on chromosome 11q12-q13 (logarithm of odds score = 3.5). The confidence interval contains candidate genes FADS1, FADS2, 7-dehydrocholesterol reductase (DHCR7), and carnitine palmitoyl transferase 1A, liver (CPT1A). Measured genotype analysis found association between CPT1A, FADS1, and FADS2 single-nucleotide polymorphisms (SNPs) and estimated eD5D activity (p-values between 10−28 and 10−5). A Bayesian quantitative trait nucleotide analysis showed that rs3019594 in CPT1A, rs174541 in FADS1, and rs174568 in FADS2 had posterior probabilities > 0.8, thereby demonstrating significant statistical support for a functional effect on eD5D activity. Highly significant associations of FADS1, FADS2, and CPT1A transcripts with their respective SNPs (p-values between 10−75 and 10−7) in Mexican Americans of the San Antonio Family Heart Study corroborated our results. These findings strongly suggest a functional role for FADS1, FADS2, and CPT1A SNPs in the variation in eD5D activity

Mapping of a blood pressure QTL on chromosome 17 in American Indians of the strong heart family study

Abstract Background Blood pressure (BP) is a complex trait, with a heritability of 30 to 40%. Several genome wide associated BP loci explain only a small fraction of the phenotypic variation. Family studies can provide an important tool for gene discovery by utilizing trait and genetic transmission information among relative-pairs. We have previously described a quantitative trait locus at chromosome 17q25.3 influencing systolic BP in American Indians of the Strong Heart Family Study (SHFS). This locus has been reported to associate with variation in BP traits in family studies of Europeans, African Americans and Hispanics. Methods To follow-up persuasive linkage findings at this locus, we performed comprehensive genotyping in the 1-LOD unit support interval region surrounding this QTL using a multi-step strategy. We first genotyped 1,334 single nucleotide polymorphisms (SNPs) in 928 individuals from families that showed evidence of linkage for BP. We then genotyped a second panel of 306 SNPs in all SHFS participants (N = 3,807) for genes that displayed the strongest evidence of association in the region, and, in a third step, included additional genotyping to better cover the genes of interest and to interrogate plausible candidate genes in the region. Results Three genes had multiple SNPs marginally associated with systolic BP (TBC1D16, HRNBP3 and AZI1). In BQTN analysis, used to estimate the posterior probability that any variant in each gene had an effect on the phenotype, AZI1 showed the most prominent findings (posterior probability of 0.66). Importantly, upon correction for multiple testing, none of our study findings could be distinguished from chance. Conclusion Our findings demonstrate the difficulty of follow-up studies of linkage studies for complex traits, particularly in the context of low powered studies and rare variants underlying linkage peaks