Biethnic Comparisons of Autosomal Genomic Scan for Loci Linked to ...

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The Journal of Clinical Endocrinology & Metabolism 89(11):5772–5778 Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2004-0640

Biethnic Comparisons of Autosomal Genomic Scan for Loci Linked to Plasma Adiponectin in Populations of Chinese and Japanese Origin LEE-MING CHUANG, YEN-FENG CHIU, W. HUEY-HERNG SHEU, YI-JEN HUNG, LOW-TONE HO, JOHN GROVE, BEATRIZ RODRIGUEZ, THOMAS QUERTERMOUS, YII-DER I. CHEN, CHAO A. HSIUNG, AND TONG-YUAN TAI, FOR THE STANFORD ASIA-PACIFIC PROGRAM OF HYPERTENSION AND INSULIN RESISTANCE STUDY GROUP Department of Internal Medicine (L.-M.C., T.-Y.T.), National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Clinical Medicine (L.-M.C.), National Taiwan University, Taipei, Taiwan; Division of Biostatistics and Bioinformatics (Y.-F.C., C.A.H.), National Health Research Institutes, Taipei, Taiwan; Department of Education and Research (W.H.-H.S.), Taichung Veterans General Hospital, Taichung, Taiwan; Division of Endocrinology and Metabolism (Y.-J.H.), Tri-Service General Hospital, Taipei, Taiwan; Department of Medical Research and Education (L.-T.H.), Taipei Veterans General Hospital, Taipei, Taiwan; University of Hawaii (J.G.), Honolulu, Hawaii; Hawaii Center for Health Research (B.R.), Honolulu, Hawaii; Division of Cardiovascular Medicine (T.Q.), Stanford University School of Medicine, Stanford, California; and Departments of Medicine and Obstetrics/Gynecology (Y.-D.I.C.), Cedars Sinai Medical Center and University of California at Los Angeles, Los Angeles, California Adiponectin is secreted by adipocytes and is thought to have insulin-sensitizing and antiatherogenic effects. Two previous genome scans for plasma adiponectin have identified different regions for European and Pima Indian populations. We here present multipoint linkage analysis of adiponectin levels using a variance-components model for 1007 siblings (from 360 nuclear families) of Chinese origin and 352 siblings (from 147 nuclear families) of Japanese origin. We found heritability for adiponectin concentrations was 0.70 for Chinese and 0.48 for Japanese. Autosomal genome scan was performed using microsatellite markers span at an interval of approximately10 cM. Suggestive linkage of adiponectin, after adjusting for age

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DIPONECTIN, ONE OF the adipocytokines (1), is a 244-amino-acid protein encoded by the gene APM1 mapped on human chromosome 3q27 (2). Despite being solely expressed and secreted from adipose tissue in humans, the plasma level of adiponectin is paradoxically reduced in obesity (3). Studies have demonstrated that subjects with insulin resistance, type 2 diabetes and coronary artery disease are associated with decreased levels of plasma adiponectin (4 – 6). We have previously demonstrated that adiponectin concentration was lower in the subjects with most or all phenotypes of metabolic syndrome. We found a stepwise decrease in adiponectin concentrations in groups of subjects with an increasing number of risk factors for coronary artery disease (7). More importantly, adiponectin has been shown to be involved in the pathogenesis of atherosclerosis (8, 9). In animal models, administration of adiponectin has been Abbreviations: BMI, Body mass index; QTL, quantitative trait locus; SAPPHIRe, Stanford Asia-Pacific Program of Hypertension and Insulin Resistance; S.I., support interval(s). JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

and sex, was found on chromosome 15 at 39 cM (maximal LOD score ⴝ 3.19, P ⴝ 6.3 ⴛ 10ⴚ5) for Chinese; and on chromosome 18 at 28 cM (maximal LOD score ⴝ 2.40, P ⴝ 4.4 ⴛ 10ⴚ4) for Japanese. There were tentative loci of weak linkage on chromosomes 3, 18, and 20 in Japanese. We provide novel loci on chromosomes 15, 18, and 20 and confirm a region on chromosome 3 as reported in Pima Indians, which may influence differentially on circulating adiponectin concentrations in Chinese and Japanese populations. Further fine mapping of these regions will help to identify the gene(s) that might affect adiponectin levels. (J Clin Endocrinol Metab 89: 5772–5778, 2004)

shown to increase insulin sensitivity in liver, skeletal muscle, and adipose tissues (10, 11). Others and we have found that the plasma levels were also up-regulated under weight reduction and pharmacological treatment for diabetes (4, 12, 13). We found that the increase of the plasma levels of adiponectin correlated with the increase in insulin sensitivity measured with a modified insulin suppression test (12), consistent with a previous report that showed plasma levels of adiponectin were strongly correlated with insulin sensitivity evaluated by glucose disposal rate (14). Interestingly, adiponectin level might serve as a trait of insulin resistance linked to the future development of type 2 diabetes (15). Plasma levels of adiponectin are under complex regulation. Adiponectin expression and/or secretion is increased by IGF-I and ionomycin and decreased by TNF-␣, glucocorticoids, ␤-adrenergic agonists, and cAMP (16, 17). Research on the limited number of candidate genes, such as PPAR␥ and APM1, has suggested a genetic background that might regulate adiponectin gene expression (18, 19). Further studies with whole genome scans have mapped chromosomal regions for adiponectin levels in two different populations (20, 21). These analyses revealed a quantitative trait locus (QTL) on chromosome 5p for a northern European popula-

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Chuang et al. • Genome Mapping for Plasma Adiponectin Levels

J Clin Endocrinol Metab, November 2004, 89(11):5772–5778

tion (20), and on chromosome 9p for a Pima Indian population living in Arizona (21). There are some smaller signals on chromosomes 2, 3, and 10 for Pima Indians and on chromosome 14 for a European population. These data suggest that there is a great ethnic heterogeneity to the genetic influence on plasma adiponectin levels. Therefore, we decided to conduct a genome-wide scan to identify QTLs influencing adiponectin concentrations in two populations recruited in the same Stanford Asia-Pacific Program of Hypertension and Insulin Resistance (SAPPHIRe), namely a Chinese population living in Taiwan and a Japanese population living in Hawaii. Subjects and Methods Subjects and phenotypes All participants were recruited for the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance, the SAPPHIRe, a program designed to investigate the genetics of hypertension (22, 23) and insulin resistance as intermediate phenotypes (24, 25). The characteristics of the study population and the inclusion and exclusion criteria of the SAPPHIRe study were detailed in several previous publications (22–25). Notably, diagnosed diabetic subjects based on the World Health Organization criteria were excluded. For this report, individuals were selected who: 1) had taken part in the genome-wide scan; and 2) had a determination of fasting plasma adiponectin level with a RIA (LINCO Research, Inc., St. Charles, MO). In this study, a total of 1359 subjects from 507 families were analyzed. The institutional review board of each participating center approved the protocols. All subjects received a clear description of the protocol and consented to participate in the study.

Genotyping Whole blood was obtained from all consenting family members for DNA extraction. DNA was prepared using commercial kits (Puregene, Gentra Systems, Minneapolis, MN). Genotyping was performed at the Marshfield Medical Research Foundation (Marshfield, WI) using the Weber screening set 9 (Research Genetics, Inc., Huntsville, AL). This procedure used 376 autosomal markers representing short tandem reTABLE 1. Number of families by sibship size in this study cohort Chinese Sibship size

1 2 3 4 5 6 7 Total

Hawaiian Japanese

No. of families

Total siblings

Sibship size

No. of families

Total siblings

46 126 101 46 29 7 5 360

46 252 303 184 145 42 35 1007

1 2 3 4 5 6 7 Total

31 54 44 11 6 0 1 147

31 108 132 44 30 0 7 352

peat polymorphisms (22) and yielded an average map density of 10 cM. Genotyping quality was monitored by typing 30 samples in duplicate. We estimated an error rate of approximately 1% based on these duplicate samples. All markers were inspected for mendelian errors, and genetic distances between markers were determined.

Genome-wide multipoint linkage analyses The genome-wide scans on logarithm-transformed adiponectin, with adjustments for age and gender and with or without the additional adjustment for body mass index (BMI), were carried out for subjects of Chinese and Japanese origins separately, using a variance-components approach as implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer package. The variance-components model partitions the variability of a trait into components for a QTL, the residual polygenic component, and the random environmental component (26). Likelihood-ratio tests were used to test for the null hypothesis of no linkage (i.e. the variance component due to the QTL being 0). The likelihood ratio was derived by dividing the likelihood of the estimated variance component due to the QTL by the likelihood of this variance component being zero. Twice the logarithm of the likelihood ratio yields a test statistic that is asymptotically distributed as a 1⁄2:1⁄2 mixture of a ␹12 and a point mass at zero, denoted by ␹02. LOD scores were calculated as logarithm to base 10 of the likelihood ratios. A LOD score exceeding 3.3 was considered to be of genome-wide significance for evidence of linkage, whereas a LOD score greater than 1.9 was suggestive evidence for linkage (27). One-unit LOD support intervals (S.I.) were obtained by identifying the peak for the maximum LOD score on the plot of the linkage results, dropping down one LOD unit and finding the chromosomal region defined by the shoulders of the curve (28). To verify the findings from the multipoint linkage analyses, we conducted a simulation study to examine the false-positive rates in our analyses using the Simulation module implemented in the MERLIN computer package (29). One hundred datasets that mimicked the original data in terms of marker informativeness, spacing, and missing data patterns were simulated. Marker data were simulated under the null hypothesis of no linkage to adiponectin levels. Phenotypic measurements, including age, sex, and adiponectin values, were preserved. The multipoint variance-components approach was then applied to these data sets; empirical false positive rates in a genome-wide scan were derived.

Results Demographic and metabolic characteristics

There were a total of 1007 siblings (constituting 1205 sibpairs) from 360 nuclear families of Chinese, and a total of 352 siblings (constituting 333 sibpairs) from 147 nuclear families of Hawaiian Japanese recruited in this study (Table 1). Nuclear families with at least two siblings were informative for linkage analysis. Among the 360 Chinese families, 24.7% have one parent genotyped, and 4.4% have both parents genotyped. In Japanese families, 60.5% of the families have one parent genotyped, and 10.9% of them have both parents

TABLE 2. Baseline characteristics and plasma adiponectin levels in study subjects according to ethnicity and gender Ethnicity Variable

Chinese Gender

n

(A) Baseline characteristics separated by ethnicity and gender Gender Male 463 Female 544 Age (yr) Male 463 Female 544 2 Male 388 BMI (kg/m ) Female 458 (B) Adiponectin level by ethnicity and gender Adiponectin (␮g/ml) Male Female

463 544

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Mean ⫾

Hawaiian Japanese SD

or %

n

Mean ⫾

SD

or %

45.98% 54.02% 48.58 ⫾ 8.78 49.09 ⫾ 9.22 25.73 ⫾ 3.30 24.53 ⫾ 3.47

136 216 136 216 121 182

38.64% 61.36% 54.34 ⫾ 7.80 54.53 ⫾ 8.67 27.11 ⫾ 3.86 26.06 ⫾ 4.25

5.02 ⫾ 3.22 7.12 ⫾ 3.95

136 216

5.15 ⫾ 4.17 7.65 ⫾ 4.10

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genotyped. There was no significant difference in gender distribution, but the age and BMI were higher for the Hawaiian Japanese population (P ⬍ 0.0001, using the Generalized Estimating Equations method, results not shown). Mean levels of adiponectin were higher (P ⬍ 0.0001, results not displayed) in females in both Chinese and Hawaiian Japanese populations, yet no significant difference (P ⫽ 0.13, results not shown) in adiponectin concentrations was observed between ethnic groups (Table 2B). The genetic heritability of adiponectin concentrations was different between these two ethnic populations, i.e. 0.64 for Chinese and 0.47 for Hawaiian Japanese, respectively, when adjusted for age and sex (Table 3). But, the difference in heritability was not significant between these two populations (P ⫽ 0.25, by 2-sided z test). Further adjustment for BMI TABLE 3. Heritability (h2) of plasma adiponectin levels by ethnicity Chinese

Ethnicity

Hawaiian Japanese

Covariate

Sex, age, and BMI

Sex and age

Sex, age, and BMI

Sex and age

Heritability

0.70 0.082 ⬍0.0001

0.64 0.072 ⬍0.0001

0.48 0.14 0.0001

0.47 0.13 ⬍0.0001

SE

P value


increased heritability in these two populations with only a small effect (Table 3). Linkage analyses

A total of 376 microsatellite markers spread at every 10 cM across the genome were genotyped. The results of genomewide multipoint linkage analyses for adiponectin concentrations for each population were shown in Fig. 1. With adjustment for age and sex, a single peak with a maximum LOD of 3.19 at 39 cM of chromosome 15 was found in Chinese, whereas a smaller peak with a maximum LOD of 2.40 at 38 cM on chromosome 18 was noted in Hawaiian Japanese (solid line in Fig. 1.). With further adjustment for age, sex, and BMI, the maximum LOD scores declined substantially in Chinese, but this phenomenon was not observed in Hawaiian Japanese (dotted line in Fig. 1). The 1-LOD S.I. for the suggestive locus on chromosome 15 for the Chinese population was between 31 and 48 cM, with a maximal LOD of 3.19 at 39 cM (Table 4A). There were three markers, AFM248vc5, ACTC, and GATA63A03, across this region, with LOD scores of 1.61, 2.19, and 2.98, respectively (Table 5A). Further adjustment of the trait for BMI resulted in a remarkable reduction in the magnitude of the evidence for linkage (LOD ⫽ 1.31; Fig. 2A and Table 4B).

FIG. 1. Results of genome-wide scan for multipoint linkage analysis of plasma adiponectin levels for Chinese (A) and Hawaiian Japanese (B). The chromosomal location is represented on the x-axis, and the LOD scores are shown on the y-axis. Multipoint LOD scores are depicted by solid lines where age and sex were adjusted and by dotted lines where age, sex, and BMI were adjusted.



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The 1-LOD S.I. for the suggestive locus on chromosome 18 in the Hawaiian Japanese population was between 16 and 41 cM, with a maximal LOD of 2.40 at 28 cM (Table 4A). There were two markers, ACT1A01 and GATA11A06, across this region, with a LOD score of 2.40 and 1.58, respectively (Table 5B). Further adjustment of the trait for BMI showed similar results for the region on chromosome 18 (Fig. 2B), a strikingly different effect of BMI on the LOD scores compared with that seen in the Chinese population. Interestingly, when adjusted for age, sex, and BMI for Hawaiian Japanese, there were more peaks found with weak LOD scores of approximately 1.5–1.9 on chromosomes 3 and 20 (Fig. 1B, Table 5B).

a maximum LOD score of 3.19 or greater was 0.01 in the genome scan. The chance of observing a maximum LOD score greater than 2 in the genome-scan in the absence of linkage was 0.17. For Japanese, the false-positive rates of observing maximum LOD scores greater than 3 or 2 were 0.02 and 0.26, respectively. These simulation results suggested that distributional irregularities in adiponectin that may result in violation of the assumption of the variance-components method have not resulted in a gross inflation of the type I error rate.

Computer simulations for the empirical P values from genome-wide scans

Adiponectin is one of the adipocytokines that are produced by adipocytes and possess insulin-sensitizing and antiatherogenic properties (1, 30). Linkage analyses of adiponectin have been performed previously in European Caucasians and Pima Indians in Arizona (20, 21). The results are, however, different for these two populations, indicating a strong genetic heterogeneity in influencing circulating adiponectin levels. Using the same protocol in recruiting a Chinese population living in Taiwan and a Japanese population in Hawaii, we further investigated the genetic control of adiponectin, with special emphasis on ethnic heterogeneity. We found a great difference in the genetic heritability of

Discussion

The false-positive rates of multipoint LOD scores from a genome-wide scan, using the variance-components approach based on the random autosomal chromosomes that were unlinked to the adjusted transformed adiponectin level, were derived by a simulation of 100 replicates. Significant linkage is the statistical evidence expected to occur 0.05 times in a genome scan (that is, with a probability of 0.05), whereas suggestive linkage would be expected to occur one time at random in a genome scan (27). For Chinese, under the null hypothesis of no linkage, the false positive rate of observing TABLE 4. Genome scans for adiponectin concentrations Population

Chromosome

(A) Covariate: sex and age Chinese 15 Japanese

18

(B) Covariate: sex, age, and BMI Chinese 15

Japanese

18

Maximum LOD score

P valuea

Map distance (cM)

1-LOD S.I. (cM)

3.19

0.000063

39

[31, 48]

2.40

0.00044

28

[16, 41]

1.31

0.0070

46

[27, 64]

2.23

0.00068

29

[15, 46]

Markers within 1-LOD S.I.

GATA63A03 ACTC ACT1A01 GATA11A06 ACTC GATA63A03 GATA50G06 GATA151F03 ACT1A01 GATA11A06

Regions with the maximum multipoint LOD scores are reported by population and adjusted covariates. P-values were derived from the one-sided mixture ␹2 distribution of 0.5␹02 ⫹ 0.5␹12, where ␹02 is a point mass at zero.

a

TABLE 5. Genome scans for adiponectin concentrations

(A) Chinese population Covariate: Sex and age Suggestive linkage (LOD: 2.0 –2.9): Weak linkage (LOD: 1.5–1.9): (B) Hawaiian Japanese Covariate: Sex and age Suggestive linkage (LOD: 2.0 –2.9): Covariate: Sex, age, and BMI Suggestive linkage (LOD: 2.0 –2.9): Weak linkage (LOD: 1.5–1.9):

Chr

Marker

15 15 15

GATA63A03 ACTC AFM248vc5

18

ACT1A01

18 3 3 18 20 20 20

ACT1A01 GATA128c02 GATA68D03 GATA11A06 AFM077xd3 GATA51D03 AFM218yb5

Location (cM)

LOD score

P-value

43 31 20

2.98 2.19 1.61

0.00011 0.00075 0.0032

28

2.40

0.00044

28 112 119 41 2 12 25

2.23 1.72 1.55 1.58 1.67 1.79 1.50

0.00068 0.0024 0.0038 0.0035 0.0028 0.0020 0.0043

Chr, Chromosome. Regions with LOD score ⱖ 1.5 from multipoint linkage analysis were reported for different ethnic groups.

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FIG. 2. Multipoint linkage analysis for adiponectin concentrations on chromosome 15 for Chinese (A) and chromosome 18 for Hawaiian Japanese populations (B). The chromosomal markers are represented on the x-axis, and the LOD scores are shown on the y-axis. Multipoint LOD scores are depicted by solid lines where age and sex were adjusted and by dotted lines where age, sex, and BMI were adjusted.

adiponectin level and the chromosomal loci for influencing adiponectin concentrations in these two study populations. The physiological and molecular control of adiponectin expression is not fully elucidated (16, 19). The adiponectin gene (APM1) promoter region contains consensus sequences for both peroxisome proliferator-activated receptor and glu-

cocorticoid receptor (31, 32). Interestingly, we have demonstrated a significant interaction between the genotypes of APM1 and PPAR␥ in determining insulin sensitivity in these populations (25). Whether the genotypes of the two genes affect the circulating level of adiponectin remains to be seen. However, a number of previous studies have examined the


association of polymorphisms of the PPAR␥ gene with circulating concentrations of adiponectin and metabolic diseases, with inconsistent results (33, 34). This suggests that other potentially causal genes might contribute to the adiponectin levels in the circulating blood. In this study, we have examined linkage to QTLs of adiponectin in two populations. A significant linkage on chromosome 15 was found in Chinese; a smaller peak indicative of linkage on chromosome 18 was found in Hawaiian Japanese. After adjustment for BMI, in addition to age and sex, we found that in Chinese, the LOD score of the region on chromosome 15 declined remarkably from 3.19 to 1.31, suggesting that the effect of this locus is partially mediated by obesity. The LOD score for BMI on the same region is 0; the peak of LOD scores for BMI is 2.73 at 73 cM on chromosome 12 (our unpublished observations). Nevertheless, the same QTL on chromosome 15 showed evidence for other metabolic phenotypes, such as high-density lipoprotein cholesterol (our unpublished observations). How these putative QTLs for various traits interact needs further investigation. On the contrary, the LOD score of the region on chromosome 18 for Japanese did not decline significantly (from 2.40 to 2.23) when adjusted for age, sex, and BMI, indicating that the effect of chromosome 18 locus is independent of obesity. More interestingly, when further adjusted for age, sex, and BMI, peaks on chromosomes 3, 18, and 20 were identified in Hawaiian Japanese. These additional loci were not observed in the Chinese population. Our findings that different loci are mapped for adiponectin levels in Chinese and Japanese, together with previous genome scans for Caucasians and Pima Indians, indicate a great genetic heterogeneity in control of adiponectin levels among different ethnic groups. The major peaks that we found on chromosome 15 and 18 were not seen in the previous analysis (20, 21), suggesting that the set of genes controlling the expression/secretion of adiponectin are different in each population. The only linkage found on chromosome 3 (112 and 119 cM) found in this study might be similar to the previous studies (20, 21). The adiponectin gene itself might be excluded because it lies at approximately 200 cM on chromosome 3. The estimates derived from the present analyses suggest that the loci on chromosomes 15 and 18 account for 35.1% and 50.7% of the variation in age/sex-adjusted adiponectin levels in the Chinese and Japanese population, respectively. It is worthy to note that the estimated heritability of adiponectin levels in Hawaiian Japanese is lower, though not significantly so, than in Chinese (0.48 vs. 0.70). But the mapped locus, which is independent of obesity, accounts for a larger portion of variation in adiponectin levels. This estimate must be interpreted with caution, however, because the multiple testing involved in a genome-wide scan will produce an upward bias, the magnitude of which is difficult to quantify (35). Given the stochastic variability in linkage studies, our finding of potential heterogeneity across populations in the genetic control of adiponectin should be interpreted with caution. A more convincing case for heterogeneity might be made by exclusion mapping. On the other hand, there are some consistent findings in chromosome 3, with evidence of linkage to plasma adiponectin level in the previous two scans (20, 21) and ours in this study. However, the peaks of linkage


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are different among these studies [Comuzzie et al. (20), 201 cM; Lindsay et al. (21), 124 cM; this study, 112 and 119 cM]. Further fine mapping of this region might be of help to confirm and localize the QTL for adiponectin in the future. There are many possible explanations for the failure of the current study to replicate the previous results, including differences in study design, sample size (in particular, the small sample size for Japanese in this study), or racial composition. However, with the same study design for SAPPHIRe, we here present evidence that novel regions on chromosomes 15, 18, and 20 may be important in influencing circulating levels of adiponectin in populations of Chinese and Japanese descent, in addition to a region on chromosome 3 that has been reported previously in other populations. Further fine mapping of these regions might help to identify the candidate genes that might control the expression and blood level of adiponectin in different populations. Acknowledgments The authors thank Ms. Chia-Ling Chao and Mr. Fu-Shiung Lin for their technical assistance, and particularly Ms. Suyun Liu for her computing assistance. We thank patients and their families for participating in this study. Received April 5, 2004. Accepted July 30, 2004. Address all correspondence and requests for reprints to: Lee-Ming Chuang, M.D., Ph.D., Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan. E-mail: [email protected]. This work was supported, in part, by a grant (BS-090-pp-01) from National Health Research Institutes and a grant from the Program for Promoting University Academic Excellence (89-B-FA01–1-4), Ministry of Education, Taiwan.

References 1. Matsuzawa Y, Funahashi T, Nakamura T 1999 Molecular mechanism of metabolic syndrome X contribution of adipocytokines adipocyte-derived bioactive substances. Ann NY Acad Sci 892:146 –154 2. Vasseur F, Lepretre F, Lacquemant C, Froguel P 2003 The genetics of adiponectin. Curr Diab Rep 3:151–158 3. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79 – 83 4. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y 2000 Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 20:1595–1599 5. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA 2001 Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930 –1935 6. Kumada M, Kihara S, Sumitsuji S, Kawamoto T, Matsumoto S, Ouchi N, Arita Y, Okamoto Y, Shimomura I, Hiraoka H, Nakamura T, Matsuzawa Y 2003 Association of hypoadiponectinemia with coronary artery disease in men. Arterioscler Thromb Vasc Biol 23:85– 89 7. Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY, Chuang LM 2002 Plasma adiponectin levels in overweight and obese Asians. Obes Res 10:1104 –1110 8. Matsuda M, Shimomura I, Sata M, Arita Y, Nishida M, Marda N, Kumada M, Okamoto Y, Nagaretani H, Nishizawa H, Kishida K, Komuro R, Ouchi N, Kihara S, Nagai R, Funahashi T, Matsuzawa Y 2002 Role of adiponectin in preventing vascular stenosis: the missing link of adipo-vascular axis. J Biol Chem 277:37487–37491 9. Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Fuahashi T, Matsuzawa Y 2002 Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 26:2767–2770 10. Fruebis J, Tsao TS, Javorshci S, Ebbets-Reed D, Erickson MRS, Yen FT,

5778

11.

12.

13.

14.

15. 16. 17. 18.

19.

20.

21.


Bihain BE, Lodish HF 2001 Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 98:2005–2010 Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T 2001 The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946 Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY, Chuang LM 2001 Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein adiponectin. J Clin Endocrinol Metab 86:3815–3819 Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, Matsuzawa Y, Wang JP, Chen CL, Tai TY, Chuang LM 2002 Synthetic peroxisome proliferators-activated receptor-␥ agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes Care 25:376 –380 Stefan N, Vozarova B, Funahashi T, Matsuzawa Y, Weyer C, Lindsay RS, Youngren JF, Havel PJ, Pratley RE, Bogardus C, Tataranni PA 2002 Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration and low plasma concentration precedes a decrease in whole body insulin sensitivity in humans. Diabetes 51:1884 –1888 Lindsay RS, Funahashi T, Hanson RL, Matsuzawa Y, Tanaka S, Tataranni PA, Knowler WC, Krakoff J 2002 Adiponectin and development of type 2 diabetes in the Pima Indian population. Lancet 360:57–58 Guerre-Millo M 2002 Adipose tissue hormones. J Endocrinol Invest 25: 855– 861 Stefan N, Stumvoll M 2002 Adiponectin—its role in metabolism and beyond. Horm Metab Res 34:469 – 474 Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y 2001 PPAR␥ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50:2094 –2099 Yang WS, Tsou PL, Lee WJ, Tseng DL, Chen CL, Peng CC, Lee KC, Chen MJ, Huang CJ, Tai TY, Chuang LM 2003 Allele-specific differential expression of a common adiponectin gene polymorphism related to obesity. J Mol Med 81:428 – 434 Comuzzie AG, Funahashi T, Sonnenberg G, Martin LJ, Jacob HJ, Black AE, Maas D, Takahashi M, Kihara S, Tanaka S, Matsuzawa Y, Blangero J, Cohen D, Kissebah A 2001 The genetic basis of plasma variation in adiponectin, a global endophenotype for obesity and the metabolic syndrome. J Clin Endocrinol Metab 86:4321– 4325 Lindsay RS, Funahashi T, Krakoff J, Matsuzawa Y, Tanaka S, Kobes S, Bennett PH, Tataranni PA, Knowler WC, Hanson RL 2003 Genome-wide


22.

23.

24.

25.

26. 27. 28. 29. 30. 31. 32. 33.

34. 35.

linkage analysis of serum adiponectin in the Pima Indian population. Diabetes 52:2419 –2425 Ranade K, Hinds D, Hsiung CA, Chuang LM, Chang MS, Chen YT, Pesich R, Hebert J, Chen YD, Dzau V, Olshen R, Curb D, Botstein D, Cox DR, Risch N 2003 A genome scan for hypertension susceptibility loci in populations of Chinese and Japanese origins. Am J Hypertens 16:158 –162 Ranade K, Wu KD, Hwu CM, Ting CT, Pei D, Pesich R, Hebert J, Chen YD, Pratt R, Olshen R, Masaki K, Risch N, Cox DR, Botstein D 2001 Genetic variation in the human urea transporter-2 is associated with variation in blood pressure. Hum Mol Genet 10:2157–2164 Ranade K, Wu KD, Risch N, Olivier M, Pei D, Hsiao CF, Chuang LM, Ho LT, Jorgenson E, Pesich R, Chen YD, Dzau V, Lin A, Olshen RA, Curb D, Cox DR, Botstein D 2001 Genetic variation in aldosterone synthase predicts plasma glucose levels. Proc Natl Acad Sci USA 98:13219 –13224 Yang WS, Hsiung CA, Ho LT, Chen YT, He CT, Curb JD, Grove J, Quertermous T, Chen YD, Kuo SS, Chuang LM 2003 Genetic epistasis of adiponectin and PPAR␥2 genotypes in modulation of insulin sensitivity: a familybased association study. Diabetologia 46:977–983 Almasy L, Blangero J 1998 Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:198 –211 Lander E, Kruglyak L 1995 Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11:241–247 Ott J 1991 Analysis of human genetic linkage. Baltimore: Johns Hopkins University Press Abecasis GR, Cherny SS, Cookson WO, Cardon LR 2002 Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101 Funahashi T, Nakamura T, Shimomura I, Maeda K, Kuriyama H, Takahashi M, Arita Y, Kihara S, Matsuzawa Y 1999 Role of adipocytokines on the pathogenesis of atherosclerosis in visceral obesity. Intern Med 3:202–206 Kiyomi S, Takashi T, Shinsei M, Shuichi A, Junichi S, Madoka Y, Yasuko N, Nobuyoshi S, Motowo T 1999 Organization of the gene for gelatin-binding protein (GBP28). Gene 229:67–73 Scha¨ffler A, Langmann T, Palitzsch KD, Scho¨lmerich J, Schmitz G 1998 Identification and characterization of the human adipocyte apM-1 promoter. Biochim Biophys Acta 1399:187–197 Yamamoto Y, Hirose H, Miyashita K, Nishikai K, Saito I, Taniyama M, Tomita M, Saruta T 2002 PPAR (␥) 2 gene Pro12Ala polymorphism may influence serum level of an adipocyte-derived protein, adiponectin, in the Japanese population. Metabolism 51:1407–1409 Thamer C, Machicao F, Fritsche A, Stumvoll M, Ha¨ring H 2003 No influence of the PPAR␥2 Pro12Ala genotype on serum adiponectin concentrations in healthy Europeans. Metabolism 52:798 Goring HH, Terwilliger JD, Blangero J 2001 Large upward bias in estimation of locus-specific effects from a genomewide scan. Am J Hum Genet 69:1357–1369

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