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Clinical Chemistry 50: 647-650, 2004; 10.1373/clinchem.2003.025858
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(Clinical Chemistry. 2004;50:647-650.)
© 2004 American Association for Clinical Chemistry, Inc.

Technical Briefs

Association of Interleukin-1ß Gene Polymorphism with Body Mass Index in Women

Jae-Young Um1, Hwan-Suck Chung1, Mi-Yeon Song2, Hyun-Dae Shin2 and Hyung-Min Kim1,a

Departments of1 Pharmacology and 2 Oriental Rehabilitation Medicine, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, South Korea

aauthor for correspondence: fax 82-2-968-1085, e-mail hmkim{at}khu.ac.kr

Although environmental factors are clearly important determinants of obesity, heredity may contribute to the etiology of obesity (1)(2). The inheritance of obesity does not, however, follow the classic Mendelian patterns that are characteristic of single-gene disorders. Multiple regions of the genome are likely to contain susceptibility genes for obesity and associated phenotypes (3)(4).

Cytokines appear to be major regulators of adipose tissue metabolism. The effects of cytokines within adipose tissue include actions that might be characterized as metabolic. The cytokine tumor necrosis factor-{alpha} (TNF-{alpha}) is expressed primarily in adipocytes and modulates the expression of several genes in adipose tissue (5)(6). In obese individuals, increased TNF-{alpha} correlates strongly with hyperinsulinemia (6). A polymorphism upstream of the transcription start site of TNF-{alpha} (G to A at position -308) has been associated with obesity in several European populations (7)(8). In Swedes, the polymorphism influences body fat content only in homozygous individuals (9). Interleukin-1ß (IL-1ß), like TNF-{alpha}, suppresses adipose differentiation and lipoprotein lipase expression and activity (10). IL-1ß stimulates lipolysis and inhibits lipogenesis by inhibiting the expression of fatty acid transport protein and fatty acid translocase in adipose tissue (11). IL-1ß is significantly more potent than TNF-{alpha} and other cytokines in inducing anorexia when administered into the brain (12)(13). These studies suggest that IL-1ß may be protectively involved in the onset and progression of weight gain.

Most genes coding for the IL-1 family of proteins and clustered on the 2q12-q21 locus (IL-1{alpha}, IL-1ß, and the IL-1 receptor antagonist) are polymorphic in multiple loci (14). Three diallelic polymorphisms in IL-1ß, all representing C-to-T base transitions, have been reported at positions -511, -31, and +3953 bp from the transcriptional start site (15)(16)(17). For the IL-1ß +3953 C/T polymorphism, individuals homozygous for the T allele have a fourfold increase in the production of IL-1ß compared with individuals homozygous for the C allele (17)(18). We hypothesized that the increased expression of IL-1ß as a consequence of the polymorphism can be protective against obesity. We therefore designed this study to investigate whether the IL-1ß +3953 C/T polymorphism is associated with obesity in Korean women and to examine the impact of this variant on changes in body mass index (BMI).

The participants were recruited consecutively from the hospital’s obesity clinic to an ongoing project to investigate candidate genes for obesity among the Korean population. All were nonsmokers and had no evidence of cancer, liver, renal, or hematologic diseases or metabolic disorders other than obesity. A total of 257 women met all study criteria and were enrolled into the study. Ages were limited to those between 18 and 47 years, and postmenopausal women were excluded. BMI ranged from 19.2 to 39.1 kg/m2. To obtain a better separation among phenotypes, the participants were divided into three BMI groups according to the WHO definitions, with minor modifications: lean (BMI <25.0 kg/m2), overweight (BMI, 25.0–29.9 kg/m2), and obese (BMI, 30.0–40.0 kg/m2). All participants (all Korean) gave informed consent before participating in the research protocol, which was approved by the ethics committee of the hospital.

Genomic DNA was extracted (19) from the whole blood stored at -20 °C. Genotyping for the IL-1ß +3953 C/T polymorphism was conducted essentially according to previous studies (20) with small modifications. Plasma IL-1ß was measured by a modified ELISA (21).

The significance of genotype differences among groups was tested by the {chi}2 test. Odds ratios were determined by the Mantel–Haenszel method. All statistical analyses were performed with SPSS, Ver. 10.00 (SPSS Inc.). P <0.05 was considered statistically significant.

The clinical characteristics of all of the participants are provided in Table 1 of the Data Supplement that accompanies the online version of this Technical Brief at http://www.clinchem.org/content/vol50/issue3/. A total of 26% of the participants were classified as lean (n = 67), 51% were classified as overweight (n = 131), and 23% were classified as obese (n = 59). As expected, the values for weight, fat mass, percentage body fat, and waist-to-hip ratio differed among the three BMI groups.

The genotype distribution of the IL-1ß +3953 C/T polymorphism was in Hardy–Weinberg equilibrium. The frequencies of the C and T alleles were 0.95 and 0.05 in all participants, which was similar to the distribution in Japanese (22).

We assessed the relationships of the variant alleles with physical and clinical characteristics (Table 2 of the online Data Supplement). Carriers of the T allele in the heterozygous or homozygous form had comparable decreases in total cholesterol, triglycerides, fat mass, BMI, and waist-to-hip ratio, although the differences were not statistically significant.

To further evaluate the association between the IL-1ß +3953 C/T polymorphism and BMI, participants were grouped according to BMI range (Table 1 ). The difference in the distribution of the T-allele carriers among groups was significant ({chi}2 = 9.246; df = 2; P = 0.010). Of interest, the T-allele frequency was significantly decreased in the overweight group (BMI, 25.0–29.9 kg/m2) compared with the lean group [BMI <25.0 kg/m2; odds ratio, 0.202 (confidence interval, 0.07–0.61; P = 0.004]. In obese women (BMI, 30.0–40.0 kg/m2), only a trend was observed for the frequency of the T allele to be decreased compared with lean women.


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  		Table 1. Frequencies of IL-1ß genotypes according to BMI in females.

To investigate whether the observed association has any physiologic (pathophysiologic) relevance, we measured plasma IL-1ß in the three groups (lean vs overweight vs obese). From the 257 participants, a subset of 29 was recalled for measurement of plasma IL-1ß (lean, n = 7; overweight, n = 14; obese, n = 8). We found a significant increase in circulating IL-1ß concentrations in the overweight [mean (SE), 3.2 (1.21) ng/L; P <0.05] and obese [3.5 (1.14) ng/L; P <0.001] groups compared with the lean group [0.09 (0.03) ng/L; Fig. 1 ].



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  		Figure 1. Comparison of plasma IL-1ß concentrations in three BMI groups: lean (BMI <25.0 kg/m2; n = 7), overweight (BMI, 25.0–29.9 kg/m2; n = 14), and obese (BMI, 30.0–40.0 kg/m2; n = 8).

Circulating IL-1ß concentrations were significantly increased in the overweight [3.2 (1.21) ng/L] and obese [3.5 (1.14) ng/L] groups compared with the lean group [0.09 (0.03) ng/L]. The result for each group represents the mean (SE) of duplicate determinations from three independent experiments. *, P <0.05; **, P <0.001 compared with the lean group.

Although the absence of men in our study precluded separate analysis, other studies have indicated sex differences in the phenotypes and genotypes of obesity. Men often have upper-body obesity, whereas peripheral obesity is the most common form among women. Several of the polymorphisms have a different impact on body fat in men than in women. The Trp64Arg polymorphism in the ß3-adrenoceptor is associated with obesity only in women (23). The Gln27Glu polymorphism in the ß2-adrenoceptor was linked to obesity in women but not in men in a Swedish population (24). The A/G (-308) polymorphism in the TNF-{alpha} gene was associated with excess body fat in women but not in men in a Swedish study (9). Further studies are needed to investigate the association of the IL-1ß gene polymorphism with obesity in males.

The mechanism by which the IL-1ß gene polymorphisms influence obesity is unknown. Pociot and coworkers (17)(18) reported that homozygosity for the IL-1ß (+3953) T allele was associated with a fourfold increase in the production of IL-1ß compared with those homozygous for the C allele. However, it seems premature to ascribe the polymorphism at position +3953 of the IL-1ß gene a key role in obesity. Indeed, it is possible that the IL-1ß gene polymorphism has no direct effect on obesity, but instead is an indirect risk factor for adipose tissue metabolism. IL-1ß is released by human adipose cells (25), and it is regulated by TNF-{alpha} production in obesity. Increased TNF-{alpha} production in obesity may act on adipose tissue to increase the expression and release of IL-1ß, which in turn regulates lipid metabolism and synergizes with other effects of TNF-{alpha} (26).

The effect of IL-1ß on leptin production and release is of particular interest because leptin is known to be an important regulator of appetite and energy expenditure in rodents and humans, probably through central pathways (27). Bruun et al.(28) demonstrated that TNF-{alpha} and IL-1ß are able to regulate the production and release of leptin from human adipose tissue fragments in vitro. In particular, IL-1ß can induce an acute increase in leptin in plasma as well as in leptin gene expression in adipose tissue (29). In addition, Plata-Salaman et al.(13) reported that obese rats show a significantly stronger anorexia in response to the central administration of IL-1ß than do lean controls. These findings support our hypothesis that the increased basal expression of IL-1ß as a consequence of the polymorphism can be protective against being overweight. However, in contrast to these findings, Granowitz (30) reported that incubation of 3T3-L1 adipocytes with IL-1ß attenuated leptin gene expression. Therefore, although the data suggest that the IL-1ß gene is linked to obesity, further studies are needed to clarify this role.

In summary, we found an association between the polymorphism in the IL-1ß gene and obesity in women. We observed a significant decrease for the IL-1ß T allele in the overweight group compared with the lean group. In obese women, only a trend was observed for the frequency of the T allele to be decreased compared with lean women, but this is likely a result of the small sample size. In addition, to investigate whether the observed association has any physiologic (pathophysiologic) relevance, we measured plasma IL-1ß in the three groups (lean vs overweight vs obese). As expected, circulating IL-1ß was significantly increased in overweight and obese women compared with lean women. The decreased frequency of the IL-1ß T allele in overweight women suggests that a genetic variation in IL-1ß may be involved in weight regulation of overweight people, but the present study is small, and the mechanism for such an effect is unclear.


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