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Background: Hypospadias risk-associated gene variants have been reported in populations of European descent using genome-wide association studies (GWASs). There is little known at present about any possible hypospadias risk associations in Han Chinese populations., Methods: To systematically investigate hypospadias risk-associated gene variants in Chinese patients, we performed the first GWAS in a Han Chinese cohort consisting of 197 moderate-severe hypospadias cases and 933 unaffected controls. Suggestive loci (p < 1 × 10 - 4 ) were replicated in 118 cases and 383 controls, as well as in a second independent validation population of 137 cases and 190 controls. Regulatory and protein-protein interactions (PPIs) were then conducted for the functional analyses of candidate variants., Results: We identified rs11170516 with the risk allele G within the SP1/SP7 region that was independently associated with moderate-severe hypospadias [SP1/SP7, rs11170516, P combine  = 3.5 × 10 - 9 , odds ratio (OR) = 1.96 (1.59-2.44)]. Results also suggested that rs11170516 is associated with the expression of SP1 as a cis-expression quantitative trait locus (cis-eQTL). Protein SP1 could affect the risk of hypospadias via PPIs., Conclusions: We performed the first GWAS of moderate-severe hypospadias in a Han Chinese cohort, and identified one novel susceptibility cis-acting regulatory locus at 12q13.13, which may regulate a variety of hypospadias-related pathways by affecting proximal SP1 gene expression and subsequent PPIs. This study complements known common hypospadias risk-associated variants and provides the possible role of cis-acting regulatory variant in causing hypospadias.

ATP-binding cassette A3 (ABCA3) is a phospholipid carrier that is mainly expressed in the alveolar epithelium. Biallelic mutations of ABCA3 has been associated with fatal respiratory distress syndrome and interstitial lung disease (ILD) in children. However, whether variations in ABCA3 have a role in the development of adult ILD, including idiopathic pulmonary fibrosis (IPF), remains to be addressed. In this study, we screened for germline variants of ABCA3 by exons-sequencing in 30 patients with sporadic IPF and in 30 matched healthy controls. Eleven missense variants, predominantly in heterozygous, were found in 13 of these patients, but only two missenses in 2 healthy controls. We then selected four of the detected missense variants (p.L39V, p.S828F, p.V968M and p.G1205R) to performed cohort analysis in 1,024 ILD patients, containing 250 IPF and 774 connective tissue disease-ILD (CTD-ILD) patients, and 1,054 healthy individuals. Our results showed that the allele frequency of p.G1205R, but not p.L39V, was significantly higher in ILD patients than in healthy controls. However, no additional subject carrying the variant p.S828F or p.V968M was detected in the cohort analysis. These results indicate that the heterozygous ABCA3 gene variants may contribute to susceptibility to diseases in the Chinese population.

Acute lymphoblastic leukemia (ALL) is a clonal hematologic disease, and is the most common cause of childhood malignancy. Recently, a new locus was identified at 10p12.31-12.2 through a genome-wide association study (GWAS) that included racially and ethnically diverse populations. We conducted a replication study with 570 cases of ALL and 673 cancer-free controls to validated the association of this locus with ALL susceptibility in a Chinese population. The results of our study confirmed that the 10p12.31-12.2 locus was linked to childhood ALL susceptibility in the Chinese population. Interestingly, we also found that the single nucleotide polymorphisms (SNPs) in this locus had a larger effect on susceptibility to high-risk ALL than on susceptibility to low-risk ALL.

The variation of G>T in the MUC5B promoter (rs35705950) has been associated with idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP) in Caucasians, but no information is available regarding this variant in the Chinese population. We recruited 405 patients with interstitial lung diseases (ILD), including 165 IPF patients and 2043 healthy controls, for genotyping the MUC5B gene in the Chinese population. One hundred three patients with pneumonia and 360 patients with autoimmune diseases (ADs) were recruited as disease controls. Our results indicated that the prevalence of the minor allele (T) of the polymorphism rs35705950 in healthy Chinese subjects was approximately 0.66%, which was lower than that described in the Caucasian population. The frequencies of the T allele were 3.33% and 2.22% in IPF and ILD patients, respectively, and these values were significantly higher than those of healthy controls (P = 0.001, OR = 4.332 for IPF, and P = 0.002, OR = 2.855 for ILD). A stratified analysis showed that this variant in MUC5B associated with the risk for ILD mainly in older male Chinese subjects. No difference was observed between patients with pneumonia, AD patients, and healthy controls.

CyclinD proteins, the ultimate recipients of mitogenic and oncogenic signals, play a crucial role in cell-cycle regulation. CyclinD2, one of the cyclinD family, is overexpressed in T-acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia and involved in the pathogenesis of leukemias. Recent reports indicated that CCND2 polymorphisms are associated with human cancer risk, thusly we hypothesized that CCND2 gene polymorphisms may contribute to childhood ALL susceptibility. We selected the polymorphism rs3217927 located in the 3'UTR region of CCND2 to assess its associations with childhood ALL risk in a case-control study. A significant difference was found in the genotype distributions of rs3217927 polymorphism between cases and controls (P = 0.019) and homozygous GG genotype may be an increased risk factor for childhood ALL (adjusted OR  =  1.84, 95% CI  =  1.14 -2.99). Furthermore, this increased risk was more pronounced with GG genotype among high-risk ALL (adjusted OR  = 1.95, 95% CI  =  1.04-3.67), low-risk ALL (adjusted OR  =  2.09, 95% CI  =  1.13-3.87), B-phenotype ALL patients (adjusted OR  =  1.78, 95% CI  =  1.08-2.95) and T-phenotype ALL patients (adjusted OR  =  2.87, 95% CI  =  1.16-7.13). Our results provide evidence that CCND2 polymorphism rs3217927 may be involved in the etiology of childhood ALL, and the GG genotype of rs3217927 may modulate the genetic susceptibility to childhood ALL in the Chinese population. Further functional studies and investigations in larger populations should be conducted to validate our findings.

Purpose: Germ line mutations in the DNA mismatch repair gene hMLH1 are a frequent cause of hereditary nonpolyposis colorectal cancer and about one-third of these are missense mutations. Several missense mutations in hMLH1 have frequently been detected in East Asian patients with suspected hereditary nonpolyposis colorectal cancer, but their pathogenic role has not been extensively assessed. The aim of this study was to perform functional analyses of these variants and their association with gastrointestinal cancer in East Asians., Experimental Design: Altogether, 10 hMLH1 variants were analyzed by yeast two-hybrid and coimmunoprecipitation assays., Results: The carboxyl-terminal replacements Q542L, L549P, L574P, and P581L in hMLH1 resulted in complete loss of activity in both yeast two-hybrid and coimmunoprecipitation tests and thus might be considered as pathogenic. The amino-terminal variants S46I, G65D, G67R, and R217C did not affect complex formation with hPMS2 in coimmunoprecipitation, but partly or fully lost their activity in yeast two-hybrid assay, and we suggested that these variants might reduce the efficiency of the heterodimer to go into the nucleus and thus the mismatch repair function might be blocked or reduced. The V384D and the Q701K variant resulted in the interaction of hMLH1 with hPMS2 at reduced efficiency and might raise the gastrointestinal cancer risk of the mutation carriers., Conclusions: This work availably evaluated the functional consequences of some missense mutations not previously determined in the hMLH1 gene and might be useful for the clinical diagnosis of hereditary gastrointestinal cancer, especially in East Asians.