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Variants of folate metabolism genes and risk of left-sided cardiac defects.

ABSTRACT: Congenital heart defects (CHDs) are the most common, serious group of birth defects. Although relatively little is known about the causes of these conditions and there are no established prevention strategies, evidence suggests that the risk of CHDs may be related to maternal folate status as well as genetic variants in folate-related genes. Efforts to establish the relationships between these factors and CHD risk have, however, been hampered by a number of factors, including small study sample sizes and phenotypic heterogeneity.The present study examined the relationship between nine genetic variants in eight folate-related genes and a relatively homogeneous group of left-sided cardiac defects in a cohort of 386 case-parent triads. Log-linear analyses were used to assess both maternal and inherited genetic effects.Analyses of the study data provided marginal evidence that the maternal MTR A2756G (unadjusted p = 0.01) and the inherited BHMT G742A (unadjusted p = 0.06) genotypes influence the risk of this subset of CHDs. However, neither association achieved significance when the false-discovery rate was controlled at 0.05.These results, which are based on the largest study sample and most comprehensive assessment of the relationship between left-sided cardiac defects and folate-related genes reported to date, provide little evidence that this subset of CHDs is folate related. However, even larger studies and more comprehensive evaluations of the folate pathway genes are required to fully explore the relationship between folate and left-sided cardiac defects.

SUBMITTER: Mitchell LE

PROVIDER: S-EPMC2860744 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Variants of folate metabolism genes and risk of left-sided cardiac defects.

Mitchell Laura E LE Long Jin J Garbarini Jennifer J Paluru Prasuna P Goldmuntz Elizabeth E

Birth defects research. Part A, Clinical and molecular teratology 20100101 1

<h4>Background</h4>Congenital heart defects (CHDs) are the most common, serious group of birth defects. Although relatively little is known about the causes of these conditions and there are no established prevention strategies, evidence suggests that the risk of CHDs may be related to maternal folate status as well as genetic variants in folate-related genes. Efforts to establish the relationships between these factors and CHD risk have, however, been hampered by a number of factors, including ...[more]

PMID: 19777601

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Project description:BackgroundCongenital heart defects (CHD) are structural defects of the heart affecting approximately 1% of newborns. They exhibit low penetrance and non-Mendelian patterns of inheritance as varied and complex traits. While genetic factors are known to play an important role in the development of CHD, the specific genetics remain unknown for the majority of patients. To elucidate the underlying genetic risk, we performed a genome wide association study (GWAS) of CHDs in general and specific CHD subgroups using the FinnGen Release 10 (R10) (N > 393,000), followed by functional fine-mapping through eQTL and co-localization analyses using the GTEx database.ResultsWe discovered three genome-wide significant loci associated with general CHD. Two of them were located in chromosome 17: 17q21.32 (rs2316327, intronic: LRRC37A2, Odds ratio (OR) [95% Confidence Interval (CI)] = 1.17[1.12-1.23], p = 1.5 × 10-9) and 17q25.3 (rs1293973611, nearest: BAHCC1, OR[95%CI] = 4.48[2.80-7.17], p = 7.0 × 10-10), respectively, and in addition to general CHD, the rs1293973611 locus was associated with the septal defect subtype. The third locus was in band 1p21.2 (rs35046143, nearest: PALMD, OR[95%CI] = 1.15[1.09-1.21], p = 7.1 × 10-9), and it was associated with general CHD and left-sided lesions. In the subgroup analysis, two additional loci were associated with septal defects (rs75230966 and rs6824295), and one with left-sided lesions (rs1305393195). In the eQTL analysis the variants rs2316327 (general CHD), and rs75230966 (septal defects) both located in 17q21.32 (with a LD r2 of 0.41) were both predicted to significantly associate with the expression of WNT9B in the atrial appendage tissue category. This effect was further confirmed by co-localization analysis, which also implicated WNT3 expression in the atrial appendage. A meta-analysis of general CHD together with the UK Biobank (combined N = 881,678) provided a different genome-wide significant locus in LRRC37A2; rs16941382 (OR[95%CI] = 1.15[1.11-1.20], p = 1.5 × 10-9) which is in significant LD with rs2316327.ConclusionsOur results of general CHD and different CHD subcategories identified a complex risk locus on chromosome 17 near BAHCC1 and LRRC37A2, interacting with the genes WNT9B, WNT3 and MYL4, may constitute potential novel CHD risk associated loci, warranting future experimental tests to determine their role.

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Variants of folate metabolism genes and risk of left-sided cardiac defects.

Publications

Variants of folate metabolism genes and risk of left-sided cardiac defects.

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