A Potential Novel Spontaneous Preterm Birth Gene, AR, Identified by Linkage and Association Analysis of X Chromosomal Markers

Abstract

Preterm birth is the major cause of neonatal mortality and morbidity. In many cases, it has severe life-long consequences for the health and neurological development of the newborn child. More than 50% of all preterm births are spontaneous, and currently there is no effective prevention. Several studies suggest that genetic factors play a role in spontaneous preterm birth (SPTB). However, its genetic background is insufficiently characterized. The aim of the present study was to perform a linkage analysis of X chromosomal markers in SPTB in large northern Finnish families with recurrent SPTBs. We found a significant linkage signal (HLOD = 3.72) on chromosome locus Xq13.1 when the studied phenotype was being born preterm. There were no significant linkage signals when the studied phenotype was giving preterm deliveries. Two functional candidate genes, those encoding the androgen receptor (AR) and the interleukin-2 receptor gamma subunit (IL2RG), located near this locus were analyzed as candidates for SPTB in subsequent case-control association analyses. Nine single-nucleotide polymorphisms (SNPs) within these genes and an AR exon-1 CAG repeat, which was previously demonstrated to be functionally significant, were analyzed in mothers with preterm delivery (n = 272) and their offspring (n = 269), and in mothers with exclusively term deliveries (n = 201) and their offspring (n = 199), all originating from northern Finland. A replication study population consisting of individuals born preterm (n = 111) and term (n = 197) from southern Finland was also analyzed. Long AR CAG repeats (≥26) were overrepresented and short repeats (≤19) underrepresented in individuals born preterm compared to those born at term. Thus, our linkage and association results emphasize the role of the fetal genome in genetic predisposition to SPTB and implicate AR as a potential novel fetal susceptibility gene for SPTB.

Prevention of preterm birth: Harnessing science to address the global epidemic

“…These loci were further evaluated in nuclear families from Finland, where similar associations with common variants were found (17,18). More recently, families with highly penetrant spontaneous PTB phenotypes from Finland were subjected to whole-exome sequencing analysis and found to have an overrepresentation of rare variants in genes in the complement and coagulation cascade pathways (19).…”

Genomics of Preterm Birth

“…The same group performed a specific analysis on these same families for possible X chromosome loci contribution to preterm birth risk. This approach resulted in identification of a linkage peak near the androgen receptor (AR) locus (Karjalainen et al 2012). Families highly enriched for pregnancies ending in spontaneous preterm birth have also begun to be analyzed using whole exome sequencing to identify more highly penetrant rare variants contributing to preterm birth risk.…”

Androgen Receptor Gene Tagging Single Nucleotide Polymorphisms are not Associated with Polycystic Ovary Syndrome in South Indian Women

“…However, SNP rs5919393 is found to be monomorphic in Chinese population [27] and in the present study (Table 2). SNP rs5919411 (A/G) reported in prostate cancer [28], and rs12014709 (G/T) in spontaneous preterm birth [29] and Hypospadias [30], but failed to found any significant association.…”