Genome-wide linkage analysis to urinary microalbuminuria in a community-based sample: The Framingham Heart Study

Introduction. Microalbuminuria is a powerful risk factor for cardiovascular disease. It is not known whether genetic factors play a role in the expression of microalbuminuria in population-based samples. Methods. Genome-wide variance components linkage-analysis using 401 markers spaced at similar to10 cM was performed on subjects from 330 extended families of the Framingham Heart Study; a subanalysis was performed on families enriched for hypertension. Urinary microalbumin was indexed to urinary creatinine [urine albumin/creatinine ratio (UACR)] and was log-transformed for analysis. Residuals of log-transformed UACR adjusted for age, gender, body mass index, diabetes, systolic blood pressure, hypertension treatment, smoking, and serum creatinine were used in the linkage analysis. Results. Among 1055 subjects (52% women), mean age 56 years, median UACR was 5.8 mg/g (11%>30 mg/g). The unadjusted heritability for UACR was 0.20; after multivariable adjustment, heritability was 0.16. The peak multivariable-adjusted multipoint logarithm of odds (LOD) score was 2.22 on chromosome 8 at 135 cM (marker D8S1179); one LOD support interval=129-145 cM. In the subanalysis in families enriched for hypertension (N=676), the peak multivariable-adjusted LOD score of 2.11 was observed at the same location. Conclusion. We found suggestive linkage to urinary microalbumin on chromosome 8. At least one potential candidate gene implicated in the pathogenesis of nephropathy (HAS2) lies in this region. Further research is warranted to understand the genetic basis of microalbuminuria.