Genetics of Fetal Growth Regulation

Significance

Being Small for Gestational Age Seriously Affects Health: Reduced birth weight is a major risk factor for illness in the neonatal period and throughout life, with the smallest 7.5 percent of infants accounting for two-thirds of infant deaths. Term, low birth weight infants are at least five times more likely to die in the first year and are second only to premature infants in their rates of morbidity and mortality. Small newborns have an increased risk of several adverse outcomes, especially cerebral palsy. As adults, individuals born small for gestational age (SGA) are at elevated risk of pregnancy-induced hypertension, gestational diabetes, hypertension, non-insulin dependent diabetes, and cardiovascular disease. The ability to both predict and prevent fetal growth restriction early in gestation has enormous potential to reduce illness and death in children and adults.

Birth Weight has a Major Genetic Component: Clausson et al.’s study of the offspring of 2,009 female dizygotic and monozygotic twin pairs estimated a birth weight heritability of 42%. In a study of 3,562 captive macaques that minimized environmental heterogeneity, Ha et al. estimated a total heritability for birth weight of 51%, with an additive genetic component of 23%. These findings demonstrate that comparatively simple and readily identifiable genetic factors influence birth weight. Consistent with this recent research, SGA births tend both to cluster in families and to recur in successive generations.

Importance of Replication in Genetic Association Studies: Historically, most findings of genetic association with complex phenotypes either have not been examined in additional studies or have failed to replicate. The poor replicability of genetic associations has been attributed to undetected population stratification (i.e., ethnic, environmental, socioeconomic), lack of power in some studies, and heterogeneity in underlying disease mechanisms. For these reasons, it is vital to conduct genetic association studies in more than one ethnicity and more than one population and to explicitly measure possible confounders of association (i.e., population stratification, income level, smoking) and to analyze their potential interaction with genetic effects, as is done in our proposed study.

Some of Our Published Results

Suggestive Association of SNPs at -1 and +3 of pituitary Growth Hormone (GH-N) with Low Birth Weight: Through sequencing of GH-N in normal birth weight and small for gestational age newborns, we identified 25 SNPs spanning the regulatory and coding portions of GH-N. For statistical analyses we considered only sites with a minor allele frquency >5% and initially included only one member of a set of sites in complete linkage disequilibrium. Combined logistic regression suggested association of a C allele at site -1 with SGA status (p=0.03). We chose to examine this site more closely for three reasons. First, the C allele at this site is in complete linkage disequilibrium with C at site +3. Second, these two sites are very closely spaced and located at the transcription start site, suggesting a possible influence on the level of transcription of pituitary GH. Third, the C allele has higher frequency among low birth weight subjects (6%) relative to normal birth weight subjects (0.4%).

We performed separate ANOVA for normal and low birth weight subjects with gestational age and AA vs. AC genotype at site –1 as factors (CC was not observed). Within both groups individuals AC at site –1 have lower mean birth weights, and genotype at site –1 barely misses significance at a=0.05. These results are highly suggestive of an effect on term birth weight of sites –1 and +3 of GH-N, or sites in linkage disequilibrium with them. This contradicts the common wisdom that pituitary growth hormone plays no role in regulating fetal growth. We restricted our study to full term deliveries. It is possible that late in gestation, when fetal GH-N is expressed and GHR receptors are present in a wide variety of fetal tissues, pituitary growth hormone begins to have a growth stimulatory role.

High Accuracy of Haplotype Inference: Using a set of 308 empirically-determined haplotypes in the promoter of the pituitary growth hormone gene, we compared the accuracy of computational inference of haplotypes by the expectation-maximization (EM) algorithm (programs PL-EM and SNPHAP) and by Bayesian analysis (programs Phase and Haplotyper). Each method correctly assigned haplotypes to about 90% of the subjects, and virtually no difference in accuracy was observed among the methods by several measures, including comparisons of inferred and empirical frequencies and assignment of haplotypes to subjects. The mean squared error between true and inferred haplotype frequencies was very small (2.0-4.8x10-5). Importantly, all haplotype with true frequencies >1% were identified, and no incorrect haplotype was assigned a frequency greater than 1%. Therefore, with computational approaches to inferring haplotypes it is unlikely we will fail to identify a haplotype with a significant effect on birth weight or will implicate a false haplotype as important in birth weight variation.

Role of Polymorphisms in Other Genes in Fetal Growth Regulation: We have results in review from other candidate genes that indicate a major role of SNPs in their regulatory and coding regions in control of fetal growth, so I invite you to check back periodically to share some of the progress we are making in understanding the etiology of fetal growth restriction.

A considerable proportion of this research has been supported by funds from the Children's Foundation Research Center.

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