Journal of Lipids / 2012 / Article / Tab 4

Review Article

A Pleiotropic Role for the Orphan Nuclear Receptor Small Heterodimer Partner in Lipid Homeostasis and Metabolic Pathways

Table 4

Studies on the association between SHP (NR0B2) genetic variation and birth weight, high BMI obesity, and fasting insulin diabetes.

AuthorCountryStudy populations/mutationSubjects numberMutation(s)Association with birth weight increaseAssociation with BMI/ obesityAssociation with increased insulin levelsAssociation with diabetesConclusions

Nishigori et al. [111]JapanYoung-onset type 2 diabetes274In 7 subjects, 5 different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, R213C) and 1 apparent polymorphism (R216H) (all in a heterozygous state)YesYesNoShp genetic variation: most common monogenic determinant of obesity and increased birth weight in Japanese

Hung et al. [110] UKGOOS (severe early-onset obesity) 329R34G and R36C Missense mutationsYesNo (selection of extreme obesity: stronger effect from other major gene?)YesGenetic variation in the SHP locus may influence birth weight and have effects on BMI, possibly through effects on insulin secretion
G171A (12%)Yes
-195CTGAdel (16%) common polymorphismsNo (lower birth weight)No (lower fasting levels)
UKALSPAC (cohort of children) 1,079G171ANoYes (higher BMI and waist circumference at 7 yrs)Yes (higher fasting levels and 30-min response)Subtle effects in heterozygosity, stronger effects in homozygosity
-195CTGAdelNo (lower BMI)
UKEly Study (Caucasian adults) 600G171AData not availableYes (BMI increased)No
-195CTGAdelYes (female: higher BMI),
No (male: lower BMI)

Mitchell et al. [113] UKYoung-onset type 2 diabetes, obesity, birth weight 1,927Birth weight: the only child homozygous for the A allele had a birth weight ≥4 kgNoNoNoMutations in SHP < UK than in Japanese obese type 2 subjects
G171A coding polymorphism in 14.1% of UK subjects
The A allele (G/A genotype) not associated with obesity or increased birth weight
Obesity: no association if G/A genotype; yes (?) (if A/A homozygotes)Yes (?)Homozygous for the rare A allele: predisposed to moderate obesity and possibly increased birth weight

Echwald et al. [114] DenmarkEarly-onset obesity (men) 7502 silent variants c.65C4T [p. Y22Y], c.339G4A [p. P113P]Very low prevalence of functional SHP variants associated with obesity among Danes
3 missense variants c.100C4G [p. R34G], c.278G4A [p. G93D], c.415C4A [p. P139H]Yes (only among obese)A role for G171A polymorphism low penetrance SHP variants) for obesity risk in Europe?
G171A polymorphism (8.9%)No ( versus obese)Major differences in prevalence and impact of SHP variants between Danish and Japanese obese
Nonobese controls 795No variants G171A polymorphism (7.1)
Functional analyses in MIN6-m9 and HepG2 cell lines93D mutant protein: reduced in vitro inhibition of the HNF4α transactivation of the HNF-1α promoter expression

Note: SHP is expressed in the liver, pancreas, spleen, small intestine, and adrenal gland in humans [18] and inhibits the transcriptional activity of hepatocyte nuclear factor-4 α (HNF4α). ALSPAC: Avon Longitudinal Study of Parents and Children; GOOS: Genetics of Obesity Study; HNF4α: hepatocyte nuclear factor-4α.

Article of the Year Award: Outstanding research contributions of 2020, as selected by our Chief Editors. Read the winning articles.