Recent evidence indicates that
IkappaB kinase beta (Ikkbeta) may be a mediator of acquired forms of
insulin-resistance. In this study, we examined whether genetic variability at the Ikkbeta locus (
IKBKB) contributes to the development of genetic forms of early-onset
type 2 diabetes transmitted with an autosomal dominant mode of inheritance. Linkage with four markers flanking the
IKBKB gene was evaluated in 32 multigenerational families. Included in the study were 233 diabetic (mean age at Dx = 37 +/- 18) and 152 nondiabetic subjects. The overall LOD scores were negative (-54.9 and -46.2 on the centromeric and telomeric sides, respectively) indicating that variability in
IKBKB was not a major determinant of diabetes in these families. Positive values, however, were observed for selected pedigrees. All 17 families for which linkage with the
IKBKB locus could not be excluded were screened for sequence differences in the 22 exons and 1.6 kb of the 5' flanking region by dideoxyfingerprinting or direct sequencing. Polymorphisms were identified in the 5' flanking region (-1775del/insC and -1547T > A), exon 11 (c.1083A > G, L361L) and in intron 12 (IVS12+14t > a). However, no mutations segregating with diabetes could be found in these families. Furthermore, all four polymorphisms had similar allele frequencies in the 32 family probands, 171 individuals with common, later-onset
type 2 diabetes, and 182 nondiabetic controls. We conclude that sequence differences in the
IKBKB gene do not play a major role in either early-onset, autosomal dominant
type 2 diabetes, or common forms with a later-onset.