Differential Association of Niemann-Pick C1 Gene Polymorphisms with Maternal Prepregnancy Overweight and Gestational Diabetes

Abstract

A genome-wide association study (GWAS) and subsequent replication studies in diverse ethnic groups indicate that common Niemann-Pick C1 gene (NPC1) polymorphisms are associated with morbid-adult obesity or diabetes independent of body weight. The objectives for this prospective cross-sectional study were to determine allele frequencies for NPC1 polymorphisms (644A>G, 1926C>G, 2572A>G, and 3797G>A) and association with metabolic disease phenotypes in an ethnically diverse New Mexican obstetric population. Allele frequencies for 1926C>G, 2572A>G, and 3797G>A were significantly different between race/ethnic groups (non-Hispanic white, Hispanic, and Native American). The results also indicated a significant pairwise linkagedisequilibrium between each of the four NPC1 polymorphisms in race/ethnic groups. Moreover, the derived and major allele for 1926C>G was associated (OR 2.11, 95% CI 1.10-3.96, P = 0.022) with increased risk for maternal prepregnancy overweight (BMI 25.0-29.9kg/m 2 ) while the ancestral and major allele for 2572A>G was associated (OR 4.68, 95% CI 1.23-17.8, P = 0.024) with increased risk for gestational diabetes in non-Hispanic whites, but not Hispanics or Native Americans. In summary, this is the first transferability study to investigate common NPC1 polymorphisms in a multiethnic population and demonstrate a differential association with increased risk for maternal prepregnancy overweight and gestational diabetes. This is an Open access article distributed under the terms of Creative Commons Attribution 4.0 International License.

The C57BL/6J Niemann-Pick C1 mouse model with decreased gene dosage is susceptible to increased weight gain when fed a high-fat diet: Confirmation of a gene-diet interaction

“…These findings were subsequently replicated in other populations and extended to include an additional NPC1 gene risk variant (1926C> G encoding Ile642 Met ) associated with type 2 diabetes independent of body weight (Al-Daghri et al, 2012; Robiou-du-Pont et al, 2013; Sandholt et al, 2011). Consistent with these results, we have recently reported that the human NPC1 gene risk variants reside in complete linkage-disequilibrium (D′ > 0.99) among certain ethnic groups (non-Hispanic white, Hispanic, and Native American) and associated with maternal overweight or gestational diabetes independent of body weight in our local obstetric population (Garver et al, 2015). …”

Modeling Niemann-Pick disease type C1 in zebrafish: a robust platform for in vivo screening of candidate therapeutic compounds

“…The etiology of the growth retardation and apparent infertility are not known, and these phenotypes along with a more detailed neuropathological characterization will require further investigation. Although polymorphisms in the NPC1 gene have been associated with obesity ( Garver et al, 2015 ), impaired growth is not typically observed in NPC1 patients. The growth defect in the npc1 mutant zebrafish may be due to impaired feeding, a common neurological problem found in NPC1 patients.…”