Table 4.
Studies on the association between SHP (NR0B2) genetic variation and birth weight, high BMI obesity, and fasting insulin diabetes.
| Author | Country | Study populations/mutation | Subjects number | Mutation(s) | Association with birth weight increase | Association with BMI/ obesity | Association with increased insulin levels | Association with diabetes | Conclusions |
|---|---|---|---|---|---|---|---|---|---|
| Nishigori et al. [111] | Japan | Young-onset type 2 diabetes | 274 | In 7 subjects, 5 different mutations (H53fsdel10, L98fsdel9insAC, R34X, A195S, R213C) and 1 apparent polymorphism (R216H) (all in a heterozygous state) | Yes | Yes | — | No | Shp genetic variation: most common monogenic determinant of obesity and increased birth weight in Japanese |
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| Hung et al. [110] | UK | GOOS (severe early-onset obesity) | 329 | R34G and R36C Missense mutations | Yes | No (selection of extreme obesity: stronger effect from other major gene?) | Yes | — | Genetic 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 polymorphisms | No (lower birth weight) | No (lower fasting levels) | |||||||
| UK | ALSPAC (cohort of children) | 1,079 | G171A | No | Yes (higher BMI and waist circumference at 7 yrs) | Yes (higher fasting levels and 30-min response) | — | Subtle effects in heterozygosity, stronger effects in homozygosity | |
| -195CTGAdel | No (lower BMI) | ||||||||
| UK | Ely Study (Caucasian adults) | 600 | G171A | Data not available | Yes (BMI increased) | No | — | ||
| -195CTGAdel | Yes (female: higher BMI), No (male: lower BMI) |
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| Mitchell et al. [113] | UK | Young-onset type 2 diabetes, obesity, birth weight | 1,927 | Birth weight: the only child homozygous for the A allele had a birth weight ≥4 kg | No | No | — | No | Mutations 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 | |||||||
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| Echwald et al. [114] | Denmark | Early-onset obesity (men) | 750 | 2 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 (P = 0.07 versus obese) | Major differences in prevalence and impact of SHP variants between Danish and Japanese obese | |||||||
| Nonobese controls | 795 | No variants G171A polymorphism (7.1) | |||||||
| Functional analyses in MIN6-m9 and HepG2 cell lines | 93D 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.