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1.
Genome-wide linkage scans were carried out using a multipoint variance components method in white and black families of the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study to identify quantitative trait loci (QTLs) for pancreatic beta-cell function and insulin sensitivity estimated through the newly released nonlinear computer version of homeostasis model assessment 2. Participants fasting <8 h, with diagnosed type 2 diabetes, or taking blood glucose or blood lipid-lowering medications were excluded. Both phenotypes were adjusted separately by race and sex for the effects of age, BMI, and field center before linkage scans using 370 microsatellite markers were performed. A total of 685 white families (1,180 sibpairs) and 773 black families (775 sibpairs) were evaluated as well as subsets including 267 obese white families (757 sibpairs) and 427 obese black families (599 sibpairs) identified through tree-linkage analyses using interacting covariates of age, sex, and BMI. For beta-cell function in the obese white families, significant (logarithm of odds [LOD] score >3.6) evidence supporting linkages was detected on chromosome 8q24 at D8S1179 (135 cM, LOD score 4.2, empirical P = 0.002) and at D8S1128 (140 cM, LOD score 3.7, empirical P = 0.003). In addition, two regions supported linkage for insulin sensitivity index in the obese black families on chromosome 7q11 at D7S3046 (79 cM, LOD score 3.0, empirical P = 0.018) and on chromosome 6q26 at D6S1277 (173 cM, LOD score 3.0, empirical P = 0.018). Reducing clinical heterogeneity using obesity data and improved estimates of beta-cell function and insulin sensitivity may have permitted identification of a QTL on chromosome 8q24 for beta-cell function in the presence of estimated insulin resistance and a QTL on chromosome 7q11 for insulin sensitivity. These regions replicate previous reports for type 2 diabetes-associated traits.  相似文献   

2.
A genome scan for all-cause end-stage renal disease in African Americans.   总被引:1,自引:1,他引:0  
BACKGROUND: In an attempt to map the genes predisposing to the common, complex aetiologies of end-stage renal disease (ESRD), we performed a genome-wide scan in 1023 individuals with chronic kidney disease (946 dialysis dependent and 77 with advanced chronic renal failure) from 483 African American families. METHODS: The study sample comprised 563 ESRD-affected sibling pairs, with nephropathy attributed to diabetes mellitus, chronic glomerular disease or hypertension. Multipoint non-parametric linkage (NPL) analysis methods were employed. RESULTS: NPL regression provided modest evidence of linkage to 13q33.3 near D13S796 [log of the odds (LOD) = 1.72], 9q34.3 near D9S1826 (LOD = 1.22), 4p15.32 near D4S2639 (LOD = 1.11) and 1q25.1 near D1S1589 (LOD = 1.01). Adjusting for the evidence of linkage at the other loci using NPL regression analysis provided evidence for linkage to 4p15.32, 9q34.3 and 13q33.3. NPL regression interaction and ordered subset analysis (OSA) suggested that the evidence for linkage to ESRD significantly increased with higher body mass index (BMI) at 13q33.3 (LOD = 4.94 in 61% of families with the highest BMI). Additionally, OSA suggested that linkage significantly improved in the 13% of families with earliest age at ESRD onset (LOD = 3.05 at 2q32.1) and in the 16% of families with latest age at ESRD onset (LOD = 2.47 at 10q26.3). CONCLUSIONS: Multipoint single-locus linkage analysis provided modest evidence of linkage to all-cause ESRD in African Americans on 13q33.3, and NPL regression and OSA suggested that evidence for linkage in this region markedly increased in obese families. This region, as well as 9q34.3, 4p15.32 and 1q25.1, should receive priority in the search for loci contributing to ESRD susceptibility in African Americans.  相似文献   

3.
Genetic and environmental determinants play critical roles in insulin resistance and beta-cell function. A model of the complex feedback system for maintenance of glucose tolerance has been developed that reflects the constraint of glycemia within narrow physiologic limits. The "glucose homeostasis" model is described by insulin sensitivity (S(I)), glucose disposition (S(G)), acute insulin response to glucose (AIR(G)), and disposition index (DI). Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes and atherosclerotic cardiovascular disease. A genome scan for glucose homeostasis phenotypes in nondiabetic subjects has been carried out in African-American (n = 21) and Hispanic (n = 45) extended families as part of the IRAS Family Study. In African-American families, there was significant evidence for linkage of DI between D11S2371 and D11S2002 (logarithm of odds [LOD] = 3.21) at 81 cM, and in the combined sample of African-American and Hispanic families, there was evidence at GATA117D01 (140 cM) on chromosome 11 (LOD = 2.21). Evidence of linkage was also observed for S(I) in Hispanic (LOD = 2.28, between D15S822 and GTTTT001) and AIR(G) in African-American families (LOD = 2.73, between D4S1625 and D4S1629; and LOD = 2.56 at PAH (phenylalanine hydroxylase) on chromosome 12). These results provide impetus for future positional cloning of quantitative trait loci (QTLs). Identifying genes in these regions should provide insight into the nature of the metabolic syndrome and diabetes, and facilitate the development of more effective therapies for prevention and treatment of diabetes and other diseases associated with disordered glucose metabolism.  相似文献   

4.
Genome-wide linkage analyses were performed using a multipoint variance components method in eight study groups from four multicenter networks (whites and blacks in GenNet; whites, blacks, and Mexican Americans in GENOA; whites and blacks in HyperGEN; and Asians in SAPPHIRe) that comprise the National Heart, Lung, and Blood Institute Family Blood Pressure Program (FBPP), in order to identify quantitative trait loci (QTLs) influencing fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR). These study populations were enriched with subjects who had elevated blood pressure. Participants fasting <8 h, those with a history of type 2 diabetes, or those on antidiabetic medications were excluded from the current investigation. These three phenotypes were suitably transformed to approximate normal distributions. Each phenotype was adjusted for the effects of age, BMI, and field center separately by sex within each of the eight network ethnicity groups before genetic analysis. A total of 8,664 subjects comprising 5,923 sibpairs from 4,043 families with 365 markers were available for conducting a meta-analysis using a modified Fisher's method of combining the P values from each of the eight scans. Evidence of linkages was found on chromosome 7q36 at 163 cM, with a logarithm of odds (LOD) score of 3.21 for HOMA-IR, and on chromosome 19q13 at 88 cM, with a LOD score of 3.33 for fasting glucose. We also found suggestive linkages (LOD score >/=2.2) on chromosome 7q36 at 163 cM, with LOD scores of 2.31 for fasting glucose and 2.26 for fasting insulin (versus the LOD score of 3.21 for HOMA-IR at this locus). In conclusion, QTLs were identified on chromosomes 7q36 and 19q13 for fasting glucose, insulin, and insulin resistance in large and multiple-ethnicity populations in the FBPP with good replications across several other independent studies for relevant traits. Follow-up dense mapping and association studies are warranted.  相似文献   

5.
Glucose homeostasis, a defining characteristic of physiological glucose metabolism, is the result of complex feedback relationships with both genetic and environmental determinants that influence insulin sensitivity and beta-cell function. Relatively little is known about the genetic basis of glucose homeostasis phenotypes or their relationship to risk of diabetes. Our group previously published a genome scan for glucose homeostasis traits in 284 African-American subjects from 21 pedigrees in the Insulin Resistance Atherosclerosis Study Family Study (IRASFS) and presented evidence for linkage to disposition index (DI) on chromosome 11q with a logarithm of odds (LOD) of 3.21 at 81 cM flanked by markers D11S2371 and D11S2002 (support interval from 71 to 96 cM). In this study, genotyping and analysis of an additional 214 African-American subjects in 21 pedigrees from the IRASFS yielded independent evidence of linkage to DI. When these two datasets were combined, a DI linkage peak was observed with an LOD of 3.89 at 78 cM (support interval from 67 to 89 cM). Fine mapping with 15 additional microsatellite markers in this 11q region for the entire 42 pedigrees resulted in an LOD score of 4.80 at 80 cM near marker D11S937 (support interval from 76 to 84 cM). In these 42 pedigrees, there was also suggestive evidence for linkage to acute insulin response (AIR) at two separate locations flanking the DI peak (64 cM, LOD 2.77, flanked by markers D11S4076 and D11S981; and 85 cM, LOD 2.54, flanked by markers D11S4172 and D11S2002). No evidence of linkage to the insulin sensitivity index (S(i)) was observed. Nine positional candidate genes were evaluated for association to DI and AIR. Among these candidates, single nucleotide polymorphisms (SNPs) in muscle glycogen phosphorylase showed evidence of association with DI (P < 0.011). In addition, SNPs in the pyruvate carboxylase gene showed evidence of association (P < 0.002) with AIR. Further analysis of these candidate genes, however, did not provide evidence that these SNPs accounted for the evidence of linkage to either DI or AIR. These detailed genetic analyses provide strong evidence of a DI locus on 11q in African-American pedigrees, with additional suggestive evidence of independent AIR loci in the same region.  相似文献   

6.
Li WD  Dong C  Li D  Garrigan C  Price RA 《Diabetes》2004,53(9):2487-2491
Fasting plasma glucose is a multigenic trait related to both diabetes and obesity. We performed a genome scan for quantitative fasting plasma glucose levels in 320 families (1,514 subjects), segregating extreme obesity and normal weight using 382 autosomal microsatellite markers. We found significant linkages on 18q22-23 using family regression (logarithm of odds [LOD] 3.67, P = 0.00002, D18S1371 at 116 cM) and variance components (LOD 4.48, P < 0.00001) methods. Evidence for linkage remained strong when restricted to European Americans (260 families, 1,258 individuals). After an additional 60 families were added, the linkage signal strengthened (LOD 6.59). The result on 18q22-23 remained significant, even after controlling for both BMI and diabetes status. We also found suggestive linkages on chromosomes 2 (LOD 1.58, 216 cM) and 7 (LOD 1.78, 163 cM). Our results suggest that there is a quantitative trait locus in chromosome region 18q22-23 that influences fasting glucose levels and may play a role in the pathogenesis of type 2 diabetes. The strength of the serum glucose results after controlling for BMI suggests that this putative gene does not influence glucose levels merely through an effect on obesity.  相似文献   

7.
Additional information on genetic susceptibility effects relevant to type 2 diabetes pathogenesis can be extracted from existing genome scans by extending examination to related phenotypes such as age at disease onset. In this study, we report the reanalysis of data from 573 U.K. sibships ascertained for multiplex type 2 diabetes, using age at onset (assessed by the proxy measure of age at diagnosis) as the phenotype of interest. Genome-wide evidence for linkage to age at diagnosis was evaluated using both variance components and Haseman-Elston (HECOM) regression approaches, with extensive simulations to derive empirical significance values. There was broad agreement across analyses with six regions of interest (logarithm of odds [LOD] >/==" BORDER="0">1.18) identified on chromosomes 1qter, 4p15-4q12, 5p15, 12p13-12q13, 12q24, and 14q12-14q21. The strongest empirically "suggestive" evidence for linkage comes from regions on chromosome 12. The first region (12p13-12q13), peaking at D12S310 (variance components LOD [LOD(VC)] = 2.08, empirical pointwise P = 0.0007; HECOM LOD [LOD(HECOM)] = 2.58, P = 0.0010) seems to be novel. The second (12q24) peaking between D12S324 and D12S1659 (LOD(VC) = 1.87, P = 0.0016; LOD(HECOM) = 1.93, P = 0.0027) overlaps a region showing substantial prior evidence for diabetes linkage. These data provide additional evidence that genes mapping to these chromosomal regions are involved in the susceptibility to, and/or development of, type 2 diabetes.  相似文献   

8.
Nephropathy is a complex disorder, with predisposition influenced by the interplay of both genetic and environmental factors. As part of an effort to map genes that predispose to ESRD, a genome scan was performed in 264 black pedigrees that contained 296 ESRD-affected sibling pairs using multipoint nonparametric linkage analysis methods. The cause of ESRD in index cases was consistent with hypertension-associated ESRD. Nonparametric linkage (NPL) regression provided modest evidence of linkage to 9p21.3 near D9S1121 (logarithm of odds [LOD] = 2.03), 1q25.1 near D1S1589 (LOD = 1.62), and 13q33.3 near D13S796 (LOD = 1.02). Adjusting for the evidence of linkage at the other loci through the NPL regression analysis provided evidence for linkage to 1q25.1, 6p23, and 9p21.3. The NPL regression and ordered subset analyses suggest that the evidence for linkage significantly increased with early onset of ESRD (2q32.1 LOD = 3.89, 13q13.1 LOD = 3.90), increased BMI (8p22 LOD = 3.37, 13q33.3 LOD = 5.20, 18p11.3 LOD = 2.38), early onset of hypertension (14q21.1 LOD = 3.19, 20q13.2 LOD = 2.32), and late onset of hypertension (4q13.1 LOD = 3.44, 5p15.33 LOD = 2.82). Multipoint single-locus linkage analysis provided modest evidence of linkage to nondiabetic ESRD on 9p21.3, 1q25.1 (in the region of the podocin gene), and 13q33.3. NPL regression and ordered subset analyses also identified loci on 13q13.1 and 13q33.3 as contributing to early-onset ESRD and ESRD in the presence of increased BMI, respectively. These regions should receive priority in the search for loci that contribute susceptibility to nondiabetic nephropathy.  相似文献   

9.
Plasma insulin and glucose concentrations are important quantitative phenotypes related to diabetes and the metabolic syndrome. Reports purporting to identify quantitative trait loci (QTLs) that contribute to the variation in fasting insulin and glucose concentrations are discrepant. As part of the Insulin Resistance Atherosclerosis Study (IRAS) Family Study, a genome scan was performed in African-American (n = 42) and Hispanic (n = 90) extended families to identify regions that may contain positional candidate genes for fasting insulin and fasting glucose (n = 1,604 subjects). There was significant evidence for linkage of fasting insulin to the short arm of chromosome 17 (logarithm of odds [LOD] = 3.30; 54 cM between D17S1294 and D17S1299, P = 1.0 x 10(-4)). The strongest evidence for linkage over all pedigrees for fasting glucose was also observed in this region (LOD = 1.44; 58 cM, P = 9.9 x 10(-3)). The results of this study provide impetus for future positional cloning of QTLs regulating insulin and glucose levels. Identifying genes in these regions should provide insight into the nature of genetic factors regulating plasma glucose and insulin concentrations.  相似文献   

10.
Mutations in hepatocyte nuclear factor (HNF)-1alpha (MODY3) account for the largest proportion of maturity-onset diabetes of the young (MODY) cases in the U.S. This form of diabetes is characterized by impaired insulin secretion in response to glucose, but wide variability exists in the severity of hyperglycemia and in the age at which it becomes clinically manifest. We have previously shown that the age at onset of diabetes in MODY3 families is influenced by familial factors (including modifying genes) and exposure to diabetes in utero. To identify genes influencing the onset of MODY3, we conducted a genome scan in 13 extended MODY families in which diabetes segregates with an HNF-1alpha mutation. Linkage with age at onset of diabetes was assessed by genetic variance component analysis using SOLAR. The locus with the strongest evidence of linkage was on chromosome 14q24 (D14S588; logarithm of odds [LOD] = 2.58, P = 0.0004). This location overlaps with IDDM11 and includes SEL1L, a negative regulator of the Notch pathway that may control islet development. Linkage evidence also supported loci on 5p15 (D5S817; LOD = 2.44, P = 0.0004) and 9q22 (D9S910; LOD = 2.02, P = 0.0018). The latter matches a region linked to 2-h insulin levels in Pima Indians. Less strong linkage evidence was observed at three other regions: chromosomes 3p24 (LOD = 1.44), 7q21 (1.20), and 16q23 (1.51). Our data are consistent with the existence of multiple loci that contribute to the expression of the MODY3 phenotype. Identification of these genes will offer new insights into the pathophysiology of MODY that may, in turn, increase our understanding of the cellular events underlying more common forms of diabetes.  相似文献   

11.
We performed a genome scan using BMD data of the forearm and hip on 664 individuals in 29 Mexican-American families. We obtained evidence for QTL on chromosome 4p, affecting forearm BMD overall, and on chromosomes 2p and 13q, affecting hip BMD in men. INTRODUCTION: The San Antonio Family Osteoporosis Study (SAFOS) was designed to identify genes and environmental factors that influence bone mineral density (BMD) using data from large Mexican-American families. MATERIALS AND METHODS: We performed a genome-wide linkage analysis using 416 highly polymorphic microsatellite markers spaced approximately 9.5 cM apart to locate and identify quantitative trait loci (QTL) that affect BMD of the forearm and hip. Multipoint variance components linkage analyses were done using data on all 664 subjects, as well as two subgroups of 259 men and 261 premenopausal women, from 29 families for which genotypic and phenotypic data were available. RESULTS: We obtained significant evidence for a QTL affecting forearm (radius midpoint) BMD in men and women combined on chromosome 4p near D4S2639 (maximum LOD = 4.33, genomic p = 0.006) and suggestive evidence for a QTL on chromosome 12q near locus D12S2070 (maximum conditional LOD = 2.35). We found suggestive evidence for a QTL influencing trochanter BMD on chromosome 6 (maximum LOD = 2.27), but no evidence for QTL affecting the femoral neck in men and women combined. In men, we obtained evidence for QTL affecting neck and trochanter BMD on chromosomes 2p near D2S1780 (maximum LOD = 3.98, genomic p = 0.013) and 13q near D13S788 (maximum LOD = 3.46, genomic p = 0.039), respectively. We found no evidence for QTL affecting forearm or hip BMD in premenopausal women. CONCLUSION: These results provide strong evidence that a QTL on chromosome 4p affects radius BMD in Mexican-American men and women, as well as evidence that QTL on chromosomes 2p and 13q affect hip BMD in men. Our results are consistent with some reports in humans and mice. J Bone Miner Res 2003;18:2245-2252  相似文献   

12.
Type 1 diabetes results from a combination of genetic susceptibility and environmental exposures. Susceptibility loci other than HLA and the insulin gene remain to be identified to account for the degree of familial clustering observed in this disorder. Early genome-wide scans provided suggestive evidence of linkage on chromosome 8q, prompting detailed analysis of this region. A total of 20 microsatellite markers spanning an 88-cM region of 8q11-24 were genotyped in 24 type 1 diabetes pedigrees from Wisconsin that contained 39 affected sib-pairs. Multipoint linkage analyses provided close to suggestive evidence of linkage, with a multipoint logarithm of odds score (MLS) of 2.4 and Genehunter nonparametric logarithm of odds score (NPL) of 2.7 (P = 0.003). There is also evidence of linkage disequilibrium at peak marker D8S1823 for the 217bp allele (P = 0.037) using the pedigree disequilibrium test. Although our sample size was small, the multiple tests were consistent and our preliminary results suggested that 8q24 may harbor a novel population-specific type 1 diabetes susceptibility gene. Continued investigation of this region for a novel type 1 diabetes susceptibility gene appears justified.  相似文献   

13.
Ng MC  So WY  Lam VK  Cockram CS  Bell GI  Cox NJ  Chan JC 《Diabetes》2004,53(10):2676-2683
We conducted autosomal genome scans to map loci for metabolic syndrome (MES) and related traits in the Hong Kong Family Diabetes Study. We selected 55 families with 137 affected members (121 affected relative pairs) for nonparametric linkage analysis on MES. We also selected 179 families with 897 members (2,127 relative pairs) for variance component-based linkage analyses on seven MES-related traits: waist circumference, systolic and diastolic blood pressure (BP), triglyceride, HDL cholesterol, fasting plasma glucose, and insulin resistance index (insulin resistance index by homeostasis model assessment [HOMA%IR]). Analyses revealed three regions that showed suggestive linkage for MES and also showed overlapping signals for metabolic traits: chromosome 1 at 169.5-181.5 cM (logarithm of odds [LOD] = 4.50 for MES, 3.71 for waist circumference, and 1.24 for diastolic BP), chromosome 2 at 44.1-57.3 cM (LOD = 2.22 for MES, 2.07 for fasting plasma glucose, and 1.29 for diastolic BP), and chromosome 16 at 45.2-65.4 cM (LOD = 1.75 for MES, 1.61 for HOMA%IR, and 1.25 for HDL cholesterol). Other regions that showed suggestive linkages included chromosome 5q for diastolic BP; 2q, 3q, 6q, 9q, 10q, and 17q for triglyceride; 12p, 12q, and 22q for HDL-C; and 6q for HOMA%IR. Simulation studies demonstrated genome-wide significant linkage of the chromosome 1 region to both MES and waist circumference (P(genome-wide) = 0.002 and 0.019, respectively). In summary, we have found a susceptibility locus on chromosome 1q21-q25 involved in the pathogenesis of multiple metabolic abnormalities, in particular obesity. Our results confirm the findings of previous studies on diabetes and related phenotypes. We also suggest the locations of other loci that may contribute to the development of MES in Hong Kong Chinese.  相似文献   

14.
We conducted a genome scan using a 10-cM map to search for genes linked to type 2 diabetes in 691 individuals from a founder population, the Old Order Amish. We then saturated two regions on chromosomes 1 and 14 showing promising linkage signals with additional markers to produce a approximately 2-cM map for fine mapping. Analyses of both discrete traits (type 2 diabetes and the composite trait of type 2 diabetes and/or impaired glucose homeostasis [IGH]), and quantitative traits (glucose levels during a 75-g oral glucose challenge, designated glucose 0-180 and HbA(1c)) were performed. We obtained significant evidence for linkage to type 2 diabetes in a novel region on chromosome 14q11 (logarithm of odds [LOD] for diabetes = 3.48, P = 0.00005). Furthermore, we observed evidence for the existence of a diabetes-related locus on chromosome 1q21-q24 (LOD for type 2 diabetes/IGH = 2.35, P = 0.0008), a region shown to be linked to diabetes in several other studies. Suggestive evidence for linkage to glucose traits was observed on three other regions: 14q11-q13 (telomeric to that above with LOD = 1.82-1.85 for glucose 150 and 180), 1p31 (LOD = 1.28-2.30 for type 2 diabetes and glucose 120-180), and 18p (LOD = 3.07, P = 0.000085 for HbA(1c) and LOD = 1.50 for glucose 0). In conclusion, our findings provide evidence that type 2 diabetes susceptibility genes reside on chromosomes 1, 14, and 18.  相似文献   

15.
Insulin resistance syndrome (IRS)-related phenotypes, such as hyperinsulinemia, obesity-related traits, impaired glucose tolerance, dyslipidemia, and hypertension, tend to cluster into factors. We attempted to identify loci influencing the factors of IRS-related phenotypes using phenotypic data from 261 nondiabetic subjects distributed across 27 low-income Mexican-American extended families. Principal component factor analyses were performed using eight IRS-related phenotypes: fasting glucose (FG), fasting specific insulin (FSI), BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), HDL cholesterol, ln triglycerides (ln TGs), and leptin (LEP). The factor analysis yielded three factors: factor 1 (BMI, LEP, and FSI), factor 2 (DBP and SBP), and factor 3 (HDL and ln TG). We conducted multipoint variance components linkage analyses on these factors with the program SOLAR using a 10--15 cM map. We found significant evidence for linkage of factor 1 to two regions on chromosome 6 near markers D6S403 (logarithm of odds [LOD] = 4.2) and D6S264 (LOD = 4.9). We also found strong evidence for linkage of factor 3 to a genetic location on chromosome 7 between markers D7S479 and D7S471 (LOD = 3.2). In conclusion, we found substantial evidence for susceptibility loci on chromosomes 6 and 7 that appear to influence the factors representing the IRS-related phenotypes in Mexican-Americans.  相似文献   

16.
A genome-wide scan was performed in a randomly ascertained set of 330 extended families from the population-based Framingham Study to identify chromosomal regions possibly linked to bone mineral density (BMD). A set of 401 microsatellite markers was typed at a 10-centimorgan (cM) average density throughout the genome. BMD was measured at the femoral neck, trochanter, Ward's area, and lumbar spine in 1557 participants of both Framingham cohorts. BMDs were adjusted for age, body mass index (BMI), height, alcohol, caffeine, calcium and vitamin D intakes, smoking, physical activity, and estrogen use in women within each sex and cohort. Strong heritabilities (values between 0.543 and 0.633) were found for the adjusted BMD at all sites. Two-point and multipoint quantitative linkage analyses were performed for each BMD site using the maximum likelihood variance components method. By two-point screening, loci of suggestive linkage were identified on chromosomes 6 and 21, with the maximum log10 of the odds ratio (LOD) scores of 2.34 for the trochanter at D21S1446 and 2.93 for the femoral neck at D6S2427. Lumbar spine BMD had maxima at D6S2427 (LOD = 1.88) and at D12S395 (LOD = 2.08). Multipoint linkage analysis revealed suggestive linkage of trochanteric BMD at a broad (approximately 20 cM) interval on chromosome 21q, with the peak linkage close to D21S1446 (LOD = 3.14). LOD scores were 2.13 at 8q24 with Ward's BMD and 1.92 at 14q21.3 with lumbar spine BMD. This largest genome screen to date for genes underlying normal variation in BMD, adjusted for a large number of covariates, will help to identify new positional candidate genes, otherwise unrecognized.  相似文献   

17.
The beta-3 adrenergic receptor (ADRB3) has been implicated as a regulator of energy expenditure, and a polymorphism in codon 64 of this gene (Trp64Arg) has been associated in some studies with obesity and insulin resistance. However, many studies have failed to detect an effect of this variant, and the importance of the Trp64Arg variant in human obesity remains controversial. We performed a quantitative linkage analysis of the ADRB3 and obesity, using 12 markers (including the intragenic Trp64Arg polymorphism) spanning a 57-cM region of chromosome 8. The study population consisted of 470 individuals from 10 large multigenerational families of Mexican-American ancestry residing in San Antonio, TX. In two-point analysis, logarithm of odds (LOD) scores >1.0 were observed for six markers surrounding ADRB3 in a 33-cM region spanned by markers D8S1477 and D8S1136. The multipoint LOD score was 3.21, occurring between markers D8S1121 and ADRB3, approximately 2-3 cM from ADRB3. Adjusting for the presence of the Arg64 allele or excluding from the analysis the 11 individuals homozygous for the Arg64 allele did not reduce the evidence for linkage. A genome scan was conducted at 10 cM map density to detect other loci influencing variation in BMI. Multipoint LOD scores >1.0 were observed in four other regions, including two on chromosome 17, one on chromosome 6q, and one on chromosome 2p. These data suggest that the ADRB3 should continue to be regarded as a strong candidate gene for obesity even though evidence for an effect of the Trp64Arg polymorphism could not be established. It is also possible that a gene closely linked to ADRB3 may influence susceptibility to obesity.  相似文献   

18.
Elevated serum uric acid level is associated with obesity, insulin resistance, diabetes, nephropathy, and hypertension. Epidemiologic studies suggest that serum uric acid levels are heritable. We sought to identify chromosomal regions harboring quantitative trait loci that influence serum uric acid in Mexican Americans using data from 644 participants in the San Antonio Family Heart Study. Serum uric acid was found to exhibit significant heritability (0.42) in this population (P = 2 x 10(-7)) after accounting for covariate effects. In addition, genetic correlations between serum uric acid and other cardiovascular risk factors, such as body mass index, waist circumference, systolic BP, and pulse pressure, were identified, suggesting that the genes associated with uric acid level are also associated with these phenotypes. Multipoint linkage analysis identified quantitative trait loci with measurable effects on serum uric acid variability. The highest multipoint logarithm of odds score of 3.3 was found at 133 cM on chromosome 6q22-23, a region that also contains genes that seem to influence familial IgA nephropathy, obesity, BP, insulin resistance, and type 2 diabetes. Given the relationship between uric acid level and these conditions, future studies should investigate potential candidate susceptibility genes found in this region.  相似文献   

19.
We investigated whether variability at the insulin receptor substrate (IRS)-2 locus plays a role in the etiology of early-onset autosomal dominant type 2 diabetes. By means of radiation hybrid mapping, we placed the human IRS-2 gene on 13q at 8.6 cRays from SHGC-37358. Linkage between diabetes and two polymorphic markers located in this region (D13S285 and D13S1295) was then evaluated in 29 families with early-onset autosomal dominant type 2 diabetes. Included were 220 individuals with diabetes, impaired glucose tolerance, or gestational diabetes (mean age at diabetes diagnosis 36 +/- 17 years) and 146 nondiabetic subjects. Overall, strongly negative logarithm of odds (LOD) scores for linkage with diabetes were obtained by multipoint parametric analysis (LOD score -45.4 at D13S285 and -40.9 at D13S1295). No significant evidence of linkage was obtained under the hypothesis of heterogeneity or by nonparametric methods. Fourteen pedigrees for which linkage could not be excluded (LOD score > -2.0) were screened for mutations in the IRS-2 coding region by dideoxy fingerprinting. However, no mutations segregating with diabetes could be detected in these families. These data indicate that IRS-2 is not a major gene for early-onset autosomal dominant type 2 diabetes, although a role of mutations in the promoter region cannot be excluded at this time.  相似文献   

20.
We examined the hypothesis that imprinted genes may affect the propensity to type 2 diabetes and obesity in Pima Indians. Multipoint variance component methods were used to assess linkage of BMI (kg/m(2)) and age-adjusted diabetes to loci derived from either father (LOD(FA)) or mother (LOD(MO)) in a genome-wide scan. Tentative evidence of loci where imprinted genes might be acting was found for diabetes with maternally derived alleles on chromosomes 5 (LOD(MO) = 1.5) and 14 (LOD(MO) = 1.6). Evidence of linkage of BMI to maternally derived alleles was found on chromosome 5 (LOD(MO) = 1.7) and to paternally derived alleles on chromosome 10p (LOD(FA) = 1.7). Additional analyses of sibling pairs who were affected by diabetes and younger than 25 years of age showed an increase of sharing of maternally derived alleles on chromosome 6 (LOD(MO) = 3.0). We also examined sites of a priori interest where action of imprinted genes has been proposed in diabetes or obesity. We found no evidence of parent-specific linkage (of either diabetes or BMI) on chromosome 11p, a region that contains several imprinted genes, but observed weak evidence of linkage of diabetes to paternally derived alleles (LOD(FA) = 0.9) in the region of chromosome 6q, believed to contain an exclusively paternally expressed gene or genes that cause transient neonatal diabetes mellitus. In conclusion, we determined regions of interest on chromosomes 5, 6, and 10 where imprinted genes might be affecting the risk of type 2 diabetes or obesity in Pima Indians.  相似文献   

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