Angiotensinogen promoter polymorphisms predict low diffusing capacity in U.S. and Spanish IPF cohorts.

BACKGROUND: Single nucleotide polymorphisms (SNPs) in angiotensinogen (AGT) at positions -20 and -6 are associated with increased severity and progression of various fibrotic diseases. Our earlier work demonstrated that the progression of idiopathic pulmonary fibrosis (IPF) was associated with the A-6 allele. This study examined the hypothesis that the homozygous CC genotype at -20 and the AA genotype at -6 would confer worse measures of pulmonary function (measured by pulmonary function tests) in IPF. METHODS: Multiple logistic regression analysis was applied to a NIH Lung Tissue Research Consortium cohort and a Spanish cohort, while also adjusting for covariates to determine the effects of these SNPs on measures of pulmonary function. RESULTS: Analysis demonstrated that the CC genotype at -20 was strongly associated with reduced diffusing capacity in males in both cohorts (p = 0.0028 for LTRC and p = 0.017 for the Spanish cohort). In females, the AA genotype was significantly associated with lower FVC (p = 0.0082) and V alv (p = 0.022). In males, the haplotype CA at -20 and -6 in AGT was also strongly associated with reduced diffusing capacity in both cohorts. CONCLUSIONS: This study is the first to demonstrate an association of AGT polymorphisms (-20A > C and -6G > A) with lower measures of pulmonary function in IPF. It is also the first to relate the effect of gender in lung fibrosis with polymorphisms in AGT.

Innate immune system gene polymorphisms in maternal and child genotype and risk of preterm delivery.

OBJECTIVE: There is little information about the combination of genetic variability in pregnant women and their children in relation to the risk of preterm delivery (PTD). In a sub-cohort of 487 non-Hispanic white and 288 African-American mother/child pairs, the Pregnancy Outcomes and Community Health Study assessed 10 functional polymorphisms in 9 genes involved in innate immune function. METHODS: Race-stratified weighted logistic regression models were used to calculate odds ratios for genotype and PTD/PTD subtypes. Polymorphisms significantly associated with PTD/PTD subtypes were tested for mother/child genotype interactions. RESULTS: Three maternal polymorphisms (IL-1 receptor antagonist intron two repeat (IL-1RN), matrix metalloproteinase- -C1562T, and TNF receptor two M196R (TNFR2)) and three child polymorphisms (IL1-RN, tumor necrosis factor-alpha -G308A, and TNFR2) were associated with PTD, but associations varied by PTD subtype and race. Two interactions were detected for maternal and child genotype. Among non-Hispanic white women, the odds of PTD was higher when both mother and child carried the IL-1RN allele two (additive interaction p < 0.05). Among African-American women, the odds of PTD were higher when both mother and child carried the TNFR2 R allele (multiplicative interaction p < 0.05). CONCLUSION: These results highlight the importance of assessing both maternal and child genotype in relation to PTD risk.

Life stressors and 5-HTTLPR interaction in relation to midpregnancy depressive symptoms among African-American women.

OBJECTIVE: In earlier analyses of nonHispanic White women we found a stronger relation between abuse history and midpregnancy elevated depressive symptoms in women with the serotonin transporter (5-HTTLPR) S/S genotype. Here, we focus on African-American women (N=698). Our inquiry is motivated by racial differences in depression diagnosis/treatment, stressors, and frequency of major 5-HTTLPR alleles (S, LA, LG). MATERIALS AND METHODS: Stressful life events (lifetime) and depressive symptoms (current) were ascertained at 15-27 weeks gestation. A Center for Epidemiological Studies Depression Score of more than or equal to 18 was considered 'elevated'. Life events were scored together and separated into six subconstructs. 5-HTTLPR genotypes were grouped as follows: (i) L and S alleles, (ii) S-LG equivalence ('triallelic to biallelic'), and (iii) LA/LA, all others, S/S ('high/intermediate/low'). Odds ratios (OR) for 'elevated' depressive symptoms-life events (total and subconstructs) relations were calculated for each genotype grouping. RESULTS: The prevalence of 'elevated' depressive symptoms did not vary by genotype. The relation between stressful life events and 'elevated' depressive symptoms was stronger in S/S compared with LA/LA genotype (interaction P=0.11). Of the six subconstructs, only abuse showed a statistically significant gene-environment interaction. The OR for the abuse-'elevated' depressive symptoms association was greater for S/S vs. LA/LA genotype (interaction P=0.03) and in the 'triallelic to biallelic' grouping (interaction P=0.04). In the 'high/intermediate/low' grouping, 'low' (S/S) had a higher OR (5.5) than both 'intermediate' and 'high' (ORs≤2.3) (interaction P=0.10). CONCLUSIONS: These results show the importance of examining racial groups, specific stressful events, and different 5-HTTLPR genotype groupings when exploring gene-environment interactions in depression.