Obesity is one of the most significant risk factors for hypertension,
coronary heart disease, and NIDDM (Frayn RN, Coppack SW: Insulin resis
tance, adipose tissue and coronary heart disease. Clin Sci 82:1-8, 199
2; Kaplan NM: The deadly quartet: upper-body obesity, glucose intolera
nce, hypertriglyceridemia, and hypertension. Arch Intern Med 149:1514-
1520, 1989). While family segregation, adoption, and twin studies have
indicated that degree of adiposity has a significant genetic componen
t (Stunkard AJ, Harris JR, Pedersen NL, McClearn GE: The body-mass ind
ex of twins who have been reared apart. N Engl J Med 322:1483-1487, 19
90; Bouchard C, Despres J-P, Mauriege P: Genetic and nongenetic determ
inants of regional fat distribution. Endocr Rev 14:72-93, 1993), the g
enes and predisposing mutations remain poorly understood. This is in c
ontrast to several well-defined genetic models for obesity in rodents,
particularly the mouse obese Cab) gene, in which loss-of-function mut
ations cause severe obesity. Recent studies have demonstrated a substa
ntial reduction in body fat when recombinant ob protein (leptin) is ad
ministered to mice. To test the relevance of these observations to hum
an obesity, the location of the human homologue (OB) was established b
y radiation hybrid mapping and eight microsatellite markers spanning t
he OB gene region (7q31.3) were genotyped in 101 obese French families
. Affected-sib-pair analyses for extreme obesity, defined by BMI >35 k
g/m(2), revealed suggestive evidence for linkage to three markers loca
ted within 2 cM of the OB gene (D7S514, D7S680, and D7S530). The OB ge
ne is therefore a candidate for genetic predisposition to extreme obes
ity in a subset of these families.