A common promoter variant of the leptin gene is associated with changes in the relationship between serum leptin and fat mass in obese girls.

Abstract

Mutations in the leptin gene lead to rare obese syndromes of Mendelian inheritance in humans and rodents. However, no relevant mutations are found in the coding region of leptin gene DNA in patients with common multifactorial obesity. These obese patients tend to have an elevation of serum leptin proportional to their adiposity but with a rather wide dispersion of leptin levels for a given body fat content, which in part is attributable to sexual dimorphism. The current study, performed in two independent Caucasian cohorts of obese girls, shows that a frequent promoter variant of the leptin gene is associated with changes in the relationship between serum leptin and body fatness. Girls of comparable adiposity have different circulating leptin levels, depending on their genotype at this locus. Girls with the -/-Lep -2,549 genotype have 25% lower mean leptin levels than the girls with other genotypes, as reflected by differences in the regression slopes of leptin-to-fat mass. Therefore, genetic factors related to the leptin gene may be important in defining the set point of obese individuals (i.e., the circulating leptin level for a given degree of body fatness). This definition may be of both physiological and therapeutic relevance, although a phenotypic association with an individual single-nucleotide polymorphism is not sufficient to assign function to this particular nucleotide site. Diabetes 49:2196-2200, 2000 R are massive obesity syndromes are associated with mutations of the leptin gene in humans (1,10) and several animals models (2,3,11). No mutations are found, however, in the coding region of this gene in patients with more common forms of obesity (4)(5)(6)(12)(13)(14). Obese patients have elevated levels of leptin in serum and of leptin gene mRNA in white adipocytes (7-9,15), the major leptin-producing cells. Circulating leptin levels correlate with body fat according to a well-established linear relationship (7-9). This relationship is of physiological importance, because it allows leptin to act as a quantitative endocrine signal that ensures that target cells (mainly in hypothalamic areas) are informed of the amount of fat stored in adipose tissue.Because of hyperleptinemia, most humans with multifactorial obesity, including our young patients (9), are considered resistant to leptin (16,17). Of obese humans, however, 5-10% have relatively low leptin levels (7-9). Based on results in a transgenic mouse model (18), it has been postulated that a decreased production of leptin by the adipose tissue can cause the obese state in these "low-leptin" individuals (18).To address the question of underlying individual differences in the regulation of circulating of leptin levels in humans, we studied Caucasian girls in the dynamic phase of early-onset obesity, spanning a wide range of body fat content. These obese children underwent measurement of fasting serum leptin and were genotyped for a single-nucleotide polymorphism (SNP) within the 5Ј untranslated region (UTR) of the leptin gene, as described by Mammès e...

Non-Hodgkin's lymphoma, obesity and energy homeostasis polymorphisms

“…Using LEP 19GG as the referent group, the recalculated FL risk estimate for the LEP 19AA genotype is 0.6 (95% CI 0.3 -1.3), similar to the OR of 0.5 (95% CI 0.3 -0.8) presented here. As has been observed elsewhere, the BMIs of our controls were not correlated with LEP 19G4A (r ¼ 0.014, P ¼ 0.70) (Karvonen et al, 1998;Lucantoni et al, 2000), LEP À2548G4A (r ¼ À0.013, P ¼ 0.72) (Mammes et al, 1998;Le Stunff et al, 2000), LEPR 223Q4R (r ¼ À0.008, P ¼ 0.83) (Gotoda et al, 1997;Rosmond et al, 2000;Wauters et al, 2001) or APM1 276G4T (r ¼ À0.024, P ¼ 0.51) (Menzaghi et al, 2002;Fumeron et al, 2004). Moreover, this and the previous report by Skibola et al found little evidence that risks associated with BMI varied by genotype.…”

Study of leptin levels and gene polymorphisms in patients with central precocious puberty

“…and LEPR polymorphism Q223R (17,27). Higher leptin levels in the CPP group might also associate with SNPs in the LEP promoter (G-2548A) and/or the LEPR genes.…”

“…An SNP (G>A variant) in the promoter region of the leptin gene at nt-2548 is associated with higher leptin levels in obese girls (17) and extreme obesity in overweight Europeans and Taiwanese aborigines (18). On the basis of these associations, we hypothesized that the frequency of the G>A variant in the leptin promoter at nt-2548 (rs7799039) or the SNPs in the leptin receptor Q223R (rs1137101) or K109R (rs1137100) may be more frequent in girls with CPP.…”

Genetics of Obesity and Type 2 Diabetes

“…Adolescents with recent and severe obesity suit this purpose. Their metabolic features have been characterized (48,59,60). According to epidemiology, their risk of future IGT and type 2 ODDM is important (61).…”

“…Trying to relate candidate genes bearing common variants to proximal phenotypes is an attempt to make sense of what is going on between the top and the bottom. We used this approach for association studies between insulin levels and insulin gene polymorphisms (47), leptin levels and leptin gene (48), insulin sensitivity, and IRS1 and IRS2 polymorphisms (49). The research work then proceeds by involving genes in low-level phenotypes (50), then attempts to relate the phenotypes studied with higher-level phenotypes.…”